Vascular News 83 – September 2019 (OUS new)

September 2019 | Issue 83

Global vascular guidelines on chronic limb-threatening ischaemia: Redefining a critical disease The publication of the Global Vascular Guidelines on the Management of Chronic LimbThreatening Ischaemia this year sees the product of four years of collaborative work by vascular experts and societies around the world. The goal of having surgeons and providers to agree on the optimal treatment pathways for patients with chronic limbthreatening ischaemia was described in an announcement from the Society for Vascular Surgery as a “quixotic quest”, which has come to fruition in the guidelines’ publication. The document was published in two of the societies’ journals: the European Journal of Vascular and Endovascular Surgery (EJVES) and the Journal of Vascular Surgery (JVS).

T

he document focuses on the definition, evaluation and management of a large global patient population and a disease associated with mortality, amputation, and impaired quality of life. With particular emphasis on guiding evidence-based practice, creating standardised frameworks for treatment as well as research, providing insight into areas of low-level evidence or unmet needs, and changing the overall perception of the disease to include a wider spectrum and stages of severity.

Co-editors were Michael Conte from the Society for Vascular Surgery, Philippe Kohl from the European Society for Vascular Surgery and Andrew Bradbury from the World Federation of Vascular Societies. Nearly 60 additional authors worked on the project. Participants spanned six continents and represented all specialties that treat chronic limb-threatening ischaemia.

Speaking to Vascular News prior to the publication of the guidelines, Conte said “the Global Vascular Guidelines are a combined effort from the Society for Vascular Surgery, the European Society for Vascular Surgery and the World Federation of Vascular Societies, who have all produced independent guidelines in the past.” In the effort to create a set of collaborative joint guidelines, Conte said, “the very first and most important project that we undertook was advanced limb ischaemia—which we are now calling chronic limb-threatening ischaemia.”

From CLI to CLTI: What is in a name?

The shift in terminology from the widely used definition of critical limb ischaemia (CLI) to chronic limbthreatening ischaemia (CLTI) is indication of a key shift in conceptualising, identifying and treating this patient population. “We have changed the terminology around

Michael Conte

this problem,” Conte said, “to recognise the fact that in current practice, what constitutes limb-threatening ischaemia may be different in different scenarios. The previous concept of critical limb ischaemia suggests that there is some threshold value of perfusion below which everyone is critical, and above which everyone is okay.

What we realised is that with diabetes and the expanding Continued on page 4

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“Unprecedented” development of NICE aortic aneurysm guideline THE DRAFT VERSION of the National Institute for Health and Care Excellence (NICE) guideline created a furore, when released for consultation in 2018, with its recommendation that patients with an unruptured aneurysm should only be offered open surgery, if they were fit and able to undergo the procedure. Many surgeons, service providers and stakeholders have called the draft guideline “unimplementable” and its publication has been repeatedly deferred since then.

“The guideline now sits with the NICE Board,” says Ian Loftus (London, UK), president of the Vascular Society for Great Britain and Ireland (VSGBI), who calls this step unprecedented. “There must be compromise on both sides and re-wording to make this guidance workable,” he tells Vascular News, noting that NICE is working closely with the stakeholders to progress the guideline.

VSGBI and the British Society of Interventional Radiology (BSIR) have together been in discussion with NICE and communicated the concerns of the vascular community. In a letter to members of VSGBI, Loftus writes: “It has been challenging for all concerned and at present there is no date set for publication. We remain in touch with NICE, [...] and have reiterated our desire to help to find a workable solution that is in the best interests of our patients.” He adds: “We did raise our concerns about the wording of the guidelines, with both NICE and BSIR, but were unable to change it.”

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September 2019 | Issue 83

Chronic limb-threatening ischaemia

Global vascular guidelines on chronic limbthreatening ischaemia: Redefining a critical disease Continued from page 1

range of neuroischaemia that we see in patients, more moderate ischaemia may still be limb-threatening in certain situations when there are large wounds and bad infections. In current vascular practice, we are treating more of those patients, so I think in current times to pretend that there is a critical measurement that we can say defines ‘critical’, is really not reality. Instead, we prefer the name ‘chronic’, to denote something that is present for at least two weeks. ‘Chronic limb-threatening ischaemia’ describes the whole spectrum of wounds, ischaemia and foot infection.”

Optimising decision-making with a PLAN

Patient risk estimation, limb staging and anatomic pattern of disease is the focus of a decision-making process with the acronym PLAN, set out by the authors of the guidelines and described by Conte as “a new framework of decision-making that starts with the patient, then looks at staging the limb—and only then looks at staging the vascular anatomy”. This method emphasises a structured approach in decision-making, which, according to Conte, “is very important because over the last number of years with the evolution of technology, there has been an over-emphasis on vascular lesions, to the detriment of not thinking about the patient and the limb first.”

Instead, the first stage of the PLAN approach is to assess the risk of the patient, both the perioperative risk and the long-term survival, as well as ambulatory function and goals for treatment. The second step is limb staging, determining whether the limb is salvageable and defining the severity of the disease. The presumed benefit of revascularisation in CLTI is linked to both the severity of ischaemia and the degree of limb threat, the authors state.

The guidelines further highlight that CLTI is associated with advanced age, multiple comorbidities, and frailty. Therefore, while goals of treatment include relief of pain, healing of wounds, and preservation of a functional limb, the authors note that revascularisation “may incur significant morbidity and mortality, requiring multiple hospitalisations, prolonged outpatient care, and thus considerable health and social care costs. Whereas the majority of patients with CLTI should be considered candidates for limb salvage, some may be appropriately

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treated with primary amputation or palliation after shared decision-making.”

“Once you know how severely threatened the limb is,” Conte explained to Vascular News, “the next stage in whether the patient is a candidate for revascularisation is to assess their vascular anatomy.” The extent of benefit of revascularisation, the guidelines state, is also linked to anatomic durability of the selected intervention, adding: “these concepts are central to PLAN and to the development of evidence-based revascularisation strategies in CLTI.” Although the anatomic pattern of arterial occlusive disease is described as a “dominant consideration” in evidence-based revascularisation, it is importantly set out in PLAN as clearly secondary to “the broader context” of patient risk and limb threat. Using the classification and staging systems proposed in the guidelines to define the pattern and severity of limb disease, specialists can better identify the optimal strategy for intervention with the knowledge that the intervention is also the right step for the patient at this stage.

We are proposing a new way to stage the vascular anatomy that really is more in line with the way we think in CLTI.” The endorsed system for accurately staging the severity of limb threat is the SVS’ threatened limb classification based on grading of wounds, ischaemia and foot infection (WIfI). The WIfI system is widely used already, but is complemented in the PLAN strategy by a new system created for these guidelines: the Global Anatomic Staging System (GLASS).

“In the new guideline,” Conte explained to Vascular News, “we are proposing a new way to stage the vascular anatomy that really is more in line with the way we think in CLTI, which is ‘how do we restore inline flow from the groin all the way to the foot?’—not one lesion at a time, but to get it all the way there. Often in these patients, that means crossing more than one lesion, because most of them have multi-segment disease. The outcomes are a multiplier of each other; they are not one at a time.”

GLASS introduces two novel concepts: firstly, the so-called target arterial path and secondly, an estimated limb-based patency.

Limb-based patency, the guidelines clarify, is defined as maintenance of in-line flow throughout the target arterial path, from groin to ankle. This allows for a

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“more direct comparison of anatomic outcomes across revascularisation strategies in CLTI”, the authors state, as the “complexity of disease traversed by the target arterial path is integrated in the GLASS”.

“When you have an angiogram, the surgeon or interventionalist decides which is the below-the-knee target that they are trying to get open all the way to the foot,” Conte expanded. “Then, you take a line and draw from the groin, through the target artery to the foot so that you can define a complexity of that pathway based on the location, length and severity of stenoses or occlusions which, by consensus, we then grouped into three categories.”

The GLASS stages I to III correlate with low-, intermediate-, or high-complexity infrainguinal disease patterns, the authors state in the guidelines document.

There is also an expected correlation to immediate technical success and one-year limb-based patency for endovascular intervention. However, as a novel system created for this purpose, there is not yet any prospective data to validate the tool. On the potential limitations of the guidelines, Conte commented that he expects some criticism levelled against the introduction of the endorsed staging systems, due to the lack of prospective validation. However, he points out, “Neither was TASC when it first came out; neither were many cancer systems when they first came out. People sit down and think about the problem, and they think about what makes sense in terms of how to group it, and then when we get more data, the staging system should be modified to reflect prospective data.”

Another potential limitation identified by Conte is in the strength of recommendations in areas where evidence is lacking. “There was always disagreement about the strength of evidence that might support some of the previous guidelines,” he told Vascular News.

“Should the guidelines follow practice, or should the guidelines follow evidence—and should evidence guide practice? Those are two very different things, because marketing drives practice sometimes.”

The field around CLTI treatment includes a lot of areas where further Level I evidence is needed, or evidence is altogether lacking. Conte describes only a “small fraction” of recommendations in the guidelines as “high-level grading in terms of strength and evidence”, while “many others” are weaker, and some are simply “just good practice statements”.

“Finally,” Conte added, “there are a couple of areas that the guidelines will show where we literally have just said it is indeterminate for this type of patient which approach might be best, and frankly there is no consensus in some of these cases.”

By highlighting such areas, the authors hope that funding agencies and industry will be able to better help fill in those gaps in knowledge in the future.

Please contact the Vascular News team with news or advertising queries Tel: +44 (0) 20 7736 8788 Published by: BIBA Medical, 526 Fulham Road London, UK SW6 5NR Tel: +44 (0) 20 7736 8788 Printed by: Buxton Press

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September 2019 | Issue 83

Chronic limb-threatening ischaemia

Cell therapy may provide benefit for “no-option” critical limb ischaemia patients at two years Two-year results from the MOBILE (Marrowstim treatment of limb ischaemia in patients with severe peripheral arterial disease) trial indicate that injecting concentrated bone marrow aspirate (cBMA, Zimmer Biomet), versus placebo, into patients with critical limb ischaemia is associated with a significant increase in amputation-free survival at two years.

However, the results also suggest that diabetic/Rutherford 5 patients do not benefit from the therapy.

K

atherin E Leckie (Division of Vascular Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, USA) presented the results of the MOBILE trial at the 2019 Society for Vascular Surgery (SVS) Vascular Annual Meeting (VAM; 12–15 June, National Harbor, USA).

She reported that the trial focused on the 30% of patients with critical limb ischaemia who have “no options for revascularisation”. She added the lack of revascularisation treatment options for these patients leads to 53,000 major amputations being performed in the USA each year, noting that—when all costs were considered—amputation was the “sixth most expensive operation” in the country and cost US$6 billion dollars per year.

In MOBILE, 152 patients (155 limbs) with Rutherford 4 or Rutherford 5 critical limb ischaemia were randomised to receive an injection of cBMA (119) or placebo (36). The cells used were mesenchymal stem cells, which Leckie explained can be taken from “bone marrow, the umbilical cord, adipose tissue, teeth, and the placenta” but were taken from bone marrow for this study. She said that a benefit of MOBILE, compared with previous stem cell trials, was that the extraction of cells from the bone marrow and subsequent injection back into the patient only involved one procedure for the patient.

US research study confirms need to address management of claudication More than half of physicians in the USA have an early peripheral vascular intervention (PVI) rate of 0% for patients with newly diagnosed claudication, according to the results of a study conducted by investigators at Johns Hopkins University, Baltimore, USA. However, 5.6% of physicians have an outlier early PVI rate of 14% or more, emphasising the need for data sharing programmes that address lowvalue care in the management of claudication.

COURTENAY HOLSCHER (Baltimore, USA) presented the results at the Society for Vascular Surgery’s (SVS) Vascular Annual Meeting (VAM; June 12–15, Washington, DC, USA),

The primary endpoint of the study was the rate of amputation-free survival (a combined endpoint of no amputation and no all-cause mortality) at 52 weeks, with a secondary endpoint being the rate of major amputation of the index limb. At one year, there was no significant difference in the rate of amputation-free Katherin E Leckie survival between groups: 79.8% for cBMA vs. 69.5% for placebo (p=0.224).

However, Leckie and colleagues performed a post-hoc analysis to review the results at two years. This showed that there was a significant difference—76.5% for cBMA vs. 55.9% for placebo (p=0.028)—with a hazard ratio of 0.49 in favour of cBMA. Leckie reported that the separation between cBMA and placebo occurred at 56 weeks (i.e. after the primary endpoint).

Furthermore, with the post-hoc analysis, Leckie et al also looked at the effect of cBMA in certain subgroups—those with and without diabetes and those with Rutherford stage 4 versus those with Rutherford stage 5. This part of the post-hoc analysis found that

underlining the importance of initiatives led by SVS and the Choosing Wisely campaign to “identify practices that should be questioned by physicians and patients”.

With the performance of unnecessary medical procedures adding to the growing crisis of healthcare costs in the USA, physicians have been advised not to use interventions such as surgical bypass, angiogram, angioplasty or stenting as a first-line treatment for the majority of patients with intermittent claudication.

This recommendation correlates with guidelines published by SVS and the American Heart Association (AHA), which state that interventions should only be performed on patients with “lifestylelimiting claudication” following a trial of medical management and exercise therapy. Holscher added: “It is important to remember these guidelines reflect consideration of intervention risks, including the risk of limb loss associated with endovascular interventions.”

In order to evaluate adherence to these guidelines amidst a steady rise in the number of PVI procedures performed, the study examined physician practice patterns of early PVIs carried out within six months of new claudication diagnoses. “We hypothesised that practice patterns would allow identification of outlier physicians with high early PVI rates, and that physician characteristics would be associated with

while cBMA did provide a significant benefit for patients without diabetes and Rutherford stage 4, it did not provide a benefit for diabetic patients and/or those with Rutherford stage 5.

According to Leckie, she and colleagues also found that the quantity of CD105±CD34dim was relevant to the effect of cell therapy. The mean cell count in non-diabetic patients who did not have an amputation was significantly higher than non-diabetic patients who did have an amputation: 134.1 vs. 34.3 (p=0.0452).

However, there was no significant difference in mean cell count between diabetic patients who underwent amputation and those who did not.

“Cell therapy becomes significantly effective at two years with a 50% reduction in death/major amputation.

The quantity of CD105±CD34dim is associated with freedom from amputation in non-diabetics, but the Rutherford 5 diabetic is unresponsive to autologous cell therapy,” Leckie concluded. She added that the MOBILE trial provides important information to inform future trials but it also raised questions such as is there a “more potent cell population” and whether such a population would benefit patients with diabetes.

Leckie told Vascular News: “The results of the twoyear analysis indicate that the positive effect of cell therapy is later than we anticipated. In fact, it was at 56 weeks that the divergence between the cell treated and placebo groups in amputation-free survival became significant. This delay in therapeutic effect suggests that cell therapy may slow or halt the progression of disease from rest pain to tissue loss.” She adds that, with a National Institute of Health grant, she and her colleagues are now investigating the mechanisms “by which cell therapy, both autologous bone marrow derived cells and allogeneic mesenchymal stem cells, may prevent amputations”. “These studies are focusing on what the cells secrete after injection into ischaemic human skeletal muscle, how these secreted factors promote angiogenesis and muscle fibre regeneration, and ways to potentiate these effects using hydrogels and genetic modification of the cells,” Leckie notes.

early PVI,” Holscher said.

As part of Holscher and colleagues’ research, Medicare fee-for-service claims were used to identify patients diagnosed with claudication for the first time between 1 January 2015 and 31 December 2017. The study included physicians who had diagnosed more than 10 patients with claudication and performed at least one PVI during the same period, while excluding patients who had previously undergone a PVI or been diagnosed with chronic limbthreatening ischaemia—either just before or after the initial claudication diagnosis. Patients with less than one year of Medicare coverage before the claudication diagnosis were also excluded.

Statistical analysis of the available data showed that nearly 195,000 patients were newly diagnosed with claudication during the three-year period, and 3.2% of these

Unnecessary medical procedures [are] adding to the growing crisis of healthcare costs in the USA.”

patients underwent an early PVI within six months of their diagnosis. In addition to this, patients counted in the study were mostly male, white and living in an urban residence, as well as having an average age of approximately 71 years.

As many as 5,664 physicians were included in the study, 54.5% of which had an early PVI rate of 0%. Those with an early PVI rate of 14% or more (5.6%) were almost exclusively male (98.4%) and had been practising for an average of 21 years since graduation from medical school, compared to 23 years for physicians with an early PVI rate below 14%.

Regarding the limitations of the study, Holscher stated: “Our findings are limited by our use of Medicare data, and that includes the potential for miscoding as well as a lack of clinically relevant information regarding the activity level and severity of symptoms presenting with claudication.”

Nevertheless, she concluded that physicians with fewer years in practice, a smaller volume of claudication practice and a higher percentage of services delivered in an outpatient surgery centre (ASC) or office-based lab (OBL) setting were “associated with higher early PVI utilisation”. “We feel this may represent an opportunity for peer-benchmarked performance reports using SVS’ Vascular Quality Initiative (VQI) or another quality mechanism,” added Holscher.

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September 2019 | Issue 83

Paclitaxel

FDA: Paclitaxel device clinical trials “may continue”; Agency is working to change informed consent documents and product labelling

Clinical studies of paclitaxel-coated balloons and paclitaxel-eluting stents “may continue and should collect long-term safety (including mortality) and effectiveness data”, says the US Food and Drug Administration (FDA) in a letter to healthcare providers on 7 August.

This is due to “the demonstrated short-term benefits of the devices, the limitations of the available data, and uncertainty regarding the long-term benefit-risk profile of paclitaxel-coated devices”.

T

he letter provides an update on the agency’s stance on the use of paclitaxel devices to treat peripheral arterial disease (PAD) in the femoropopliteal arteries. The FDA says clinical studies investigating these devices in the lower leg “require appropriate informed consent and close safety monitoring to protect enrolled patients”, and confirms they are working with study investigators to modify informed consent documents to include information about the late mortality signal.

The FDA states: “Based on the conclusions of our analysis and recommendations of the advisory panel, the FDA is taking additional steps to address this signal, including working with manufacturers on updates to device labelling and clinical trial-informed consent documents to incorporate information about the late mortality signal. The FDA is also continuing to actively work with the manufacturers and investigators on additional clinical evidence development for assessment of the long-term safety of paclitaxel-coated devices.”

physicians should explore their patients’ expectations, concerns and treatment preferences.

Ensure patients receive optimal medical therapy for PAD and other cardiovascular risk factors as well as guidance on healthy lifestyles including weight control, smoking cessation, and exercise.

Report any adverse events or suspected adverse events experienced with the use of paclitaxel-coated balloons and paclitaxel-eluting stents. Voluntary reports can be submitted through MedWatch, the FDA Safety Information

safety of paclitaxel-coated devices.

Analyses of additional randomised trials and registry datasets are being planned to provide further insights into the magnitude and potential causes of the late mortality risk.

The FDA is working with manufacturers on labelling updates for paclitaxelcoated devices to include information about the late mortality signal.

For ongoing trials of paclitaxel-coated devices, the FDA is working with study investigators to modify informed consent documents to include information about the late mortality signal.

Meta-analysis finds a higher risk of death in the long term when paclitaxel-coated devices are used in the leg

The publication of a meta-analysis in the Journal of the American Heart Association (JAHA) on 6 December 2018 sparked an international controversy over the use of paclitaxel devices, after Konstantinos Katsanos (Patras, Greece) and colleagues concluded that there was an increased association of mortality at five years when these products were used to treat PAD in the femoropopliteal arteries (see page 30).

Writing at the time, Katsanos et al said that the meta-analysis provided good statistical evidence to back its findings,

which included the presentation of the agency’s own analysis of long-term follow-up data from pivotal premarket randomised trials, an FDA Circulatory System Devices Panel Advisory Committee concluded that there is a “late mortality signal”, as first described in the JAHA paper authored by Katsanos et al in December 2018.

However, they also concluded that better data collection was necessary going forward, as some data were missing, a small sample size meant there were wide confidence intervals, and there was pooling of studies of different paclitaxel devices that were not intended to be combined. The panel determined that there were not enough data to confirm a class effect, and no consensus was reached on the cause(s) of death.

“One of the take-aways from this has been that in the field of lower extremity revascularisation, the quality of these data and the rigour of these clinical trials has been somewhat amiss, that even with the adjustments in follow-up, anywhere from 6% to 26% of the patients’ data are missing at one- and five-year follow-up,” surmised Todd Rasmussen, a vascular surgeon in Kansas, USA. On the second day, themes of the meeting included the risk-benefit consideration for patients, and how best to convey the choice of paclitaxel

The FDA’s recent recommendations

In full, the recommendations from the FDA on 7 August are: Continue diligent monitoring of patients who have been treated with paclitaxelcoated balloons and paclitaxel-eluting stents.

When making treatment recommendations, and as part of the informed consent process, consider that there may be an increased rate of long-term mortality in patients treated with paclitaxel-coated balloons and paclitaxel-eluting stents.

Discuss the risks and benefits of all available PAD treatment options with your patients. For many patients, alternative treatment options to paclitaxel-coated balloons and paclitaxel-eluting stents provide a more favourable benefit-risk profile based on currently available information.

For individual patients judged to be at a particularly high risk of restenosis and repeat femoropopliteal interventions, clinicians may determine that the benefits of using a paclitaxel-coated device outweigh the risk of late mortality.

In discussing treatment options,

Misti Malone at the CX Symposium 2019

and Adverse Event Reporting programme. Device manufacturers and user facilities must comply with the applicable Medical Device Reporting (MDR) regulations. Health care personnel employed by facilities that are subject to the FDA’s user facility reporting requirements should follow the reporting procedures established by their facilities. Prompt reporting of adverse events can help the FDA identify and better understand the risks associated with medical devices.

FDA actions

In full, the FDA actions are: The FDA continues to work with the manufacturers and investigators on additional clinical evidence development to assess the long-term

but some leading physicians stated that it lacked individual patient-level data from the randomised controlled trials.

The quest for individual patient-level data is ongoing, though earlier this year several manufacturers released their own patient-level analyses, which reported no increased mortality with these devices.

Summary of earlier FDA statements

In June this year, the agency convened a Circulatory Systems Devices Panel meeting (19–20 June, Washington, DC, USA) on the late mortality safety signal associated with paclitaxel-coated balloons and paclitaxel-eluting stents used to treat PAD in the femoropopliteal arteries.

Following the two-day discussion,

treatment in the context of short-term benefit and improved quality of life weighed against a signal of late mortality risk. The panel largely agreed that patient choice is central, as clinical benefits are clearly demonstrated and increased quality of life may be an acceptable trade-off for long-term risks for many patients.

Furthermore, consistently noted throughout panel discussion was the importance of collaboration between industry, regulatory bodies and other stakeholders to ensure data gaps are filled and strategically tackled.

Recommendations regarding future study designs as well as optimisation of ongoing trials were discussed, with no consensus on the value of registry data as opposed to more time-consuming and

Issue 83 | September 2019 expensive randomised controlled trials.

However, FDA representative Bram Zuckerman stated in the last hour of the meeting, “Unfortunately, we have a signal here that remains undetermined.

One of the reasons why is that the death adjudication uniformly in these FDA trials was poor.” He summarised, “Going forward, mortality will be given a higher priority, and we will need to think about how it can be best assessed and adjudicated.”

The panel agreed that in terms of determining efficacy, studies can follow up to one year for these endpoints, while safety should be assessed over a longer-term follow-up of three to five years.

Concluding the panel , Bram Zuckerberg states that the two-day meeting and presentation has been “extremely helpful” for the FDA, who will now consider the analysis of the panel, and “look forward to continued collaboration in this field.”

In its most recent letter to healthcare providers, dated 7 August 2019, the FDA summarises the deductions of the advisory committee in June: “In the three randomised trials which enrolled a total of 1,090 patients, the crude mortality rate at five years was 19.8% (range 15.9–23.4%) in patients treated with paclitaxel-coated devices compared to 12.7% (range 11.2–14%) in subjects treated with uncoated devices.

The relative risk for increased mortality at five years was 1.57 (95% confidence interval 1.16–2.13), which corresponds to a 57% relative increase in mortality in patients treated with paclitaxel-coated devices. A meta-analysis performed

by VIVA (Vascular InterVentional Advances) physicians of patientlevel data provided by manufacturers reported similar findings with a hazard ratio of 1.38 (95% confidence interval 1.06–1.80). […] The Panel determined, and the FDA concurs, that additional clinical study data are needed to fully evaluate the late mortality signal.”

MHRA response: Do not use paclitaxel devices in the routine treatment of patients with intermittent claudication

Prior to the Circulatory Systems Devices Panel meeting convened by the FDA in late June, the UK Medicines and Healthcare products Regulatory Agency (MHRA) acted to limit the future use of paclitaxel-eluting stents and paclitaxelcoated balloons in routine clinical care following recommendations from the independent Expert Advisory Group (EAG) on the use of these devices.

The independent EAG was formed following the publication of the Katsanos et al JAHA meta-analysis, and consists of leading UK clinicians from multiple specialties, including interventional radiology, vascular surgery, toxicology and statistics. The group reviewed the findings of the Katsanos et al paper, and concluded that the statistical analysis used by the investigators was robust.

Do not use paclitaxel devices in the routine treatment of patients with

Paclitaxel-eluting devices intermittent claudication until further notice, the Medical device alert issued by the MHRA announced, “as the potential mortality risk generally outweighs the benefits”. However, the use of drug-coated balloons and drug-eluting stents may still be considered in patients with critical limb ischaemia, taking National Institute of Care Excellence (NICE) guidance into consideration, in view of their increased risk of restenosis and reduced life expectancy, the MDA acceded.

The EAG also considered that “there is a possible dose-dependent effect of the use of paclitaxel-coated/eluting devices on mortality although no scientific or clinical explanation is

9

Based on the conclusions of our analysis and recommendations of the advisory panel, the FDA is taking additional steps to address this signal.” currently available.

“There are some established causal links between multiple factors and mortality, but the association of increased mortality and the use of paclitaxel-coated/-eluting devices is established by randomised controlled trials which control for confounding in known factors. There is no evidence to suggest that confounding persisted

within these studies. Current knowledge gaps include dose-time relationship, outcomes of paclitaxel-coated balloons versus paclitaxel-eluting stents, patient factors, effect on patients with claudication compared with those with critical limb ischaemia, peer-reviewed publication of commercial evidence, mechanistic explanation, and biological evidence.”

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September 2019 | Issue 83

Carotid interventions

Rate of stroke in medically managed patients with severe asymptomatic carotid stenosis similar to surgical patients Data from a large, community-based cohort of patients with severe (≥70–99%) carotid stenosis indicate that the rate of stroke among medically managed patients was lower than that seen in previous studies. Additionally, the rate was similar to the rate of stroke seen in surgically managed asymptomatic patients.

P

resenting the data at the 2019 Society for Vascular Surgery (SVS) Vascular Annual Meeting (VAM; 12–15 June, National Harbor, USA), Robert Chang, (The Permanente Medical Group, Kaiser Permanente South San Francisco Medical Center, USA) reported that a lack of contemporary natural-history outcomes in patients with asymptomatic carotid stenosis “has led to equipoise about the role of procedural intervention in this population.” Therefore, Chang and colleagues reviewed the incidence of stroke in patients with asymptomatic carotid stenosis who did not undergo carotid endarterectomy or carotid stenting.

Of 94,822 patients from an integrated healthcare system who had undergone carotid artery imaging between 2008 and 2012, 4,663 had evidence of severe (≥70–99%) carotid stenosis. Of these, 3,855 were asymptomatic (no stroke or transient ischaemic attack within six months of the index imaging study) and had not undergone ipsilateral carotid endarterectomy or stenting. This final cohort of 4,355 arteries in 3,855 patients had a mean age of 73.7±9.6 years, 57% were male, and 73% were Caucasian. Patients were followed through 2017 for the primary outcome, which was ipsilateral carotid-related ischaemic stroke.

Secondary outcomes included all-cause mortality and the link between risk factors (such as progression of disease) and stroke.

During the follow-up period, 1,553 patients underwent 1,658 carotid interventions and were censored at the time of intervention. Chang noted that patients who did not undergo an intervention were

Contemporary stroke risk is lower than previously thought in this selected patient population.” older, had more diabetes, and a higher comorbidity burden than those who did undergo intervention.

However, more patients in the intervention group had high-grade carotid stenosis.

In the overall cohort (4,355 arteries), prior to any intervention being performed, 135 ipsilateral strokes related to carotid stenosis occurred. Of the stroke

Ultrasound surveillance following carotid endarterectomy “costly and unlikely to improve outcomes” According to a recent study, ultrasound surveillance following carotid endarterectomy is “costly and unlikely to improve outcomes or affect management”, even if over 80% ipsilateral restenosis is detected. The investigators suggest that “further research should determine the utility of routine contralateral carotid duplex ultrasound surveillance in this population, who may be at higher risk for progression to severe contralateral carotid disease”.

SHIRA STRAUSS and colleagues at The Ottawa Hospital (Ottawa, Canada) base this conclusion on the finding that severe carotid restenosis following carotid endarterectomy is “rare and not associated with worse outcomes”, and note that, despite historical recommendation, The Ottawa Hospital’s management of severe restenosis has been conservative based on its “benign natural history.”

Strauss recently presented these results at the Society for Vascular Surgery 2019 Vascular Annual Meeting in National Harbor, Maryland (SVS VAM; 12–15 June).

The investigators collected data from

the period 2003–2018, during which 1,190 carotid endarterectomies were performed in 1,129 patients at The Ottawa Hospital. The majority of these cases (78%) were for symptomatic carotids ranging from 70–99% stenosis.

A total of 769 surgeries in 729 patients had duplex ultrasound surveillance data available for a mean of 3.52 years, which detected over 80% ipsilateral restenosis in 31 patients (4.03%).

There were 32 postoperative strokes, report Strauss and colleagues, of which 25 (73.5%) occurred within 30 days of surgery—prior to the initial surveillance duplex ultrasound—and 16 occurred within the first 24 hours. They note that

Robert Chang

patients, 93 died overall with 15 dying within 30 days of the stroke and another 21 dying within the year. The median survival time after a stroke was 16.5 months. During the follow-up period, there were 114 strokes—before any intervention—not related to the carotid stenosis. The rate of allcause mortality at five

years was 54%.

Chang stated that, using Kaplan-Meier analysis, the five-year rate of freedom from ipsilateral carotid stroke was 95.2%. He added that this rate was lower than the rate seen in previous studies of the natural history of asymptomatic carotid stenosis. Also, according to Chang, the rate of stroke was comparable with the rate of stroke seen with surgery. “Previous trial data show an absolute stroke risk reduction over five years from 15% to 12% with medical therapy to 5% to 6% with surgery,” he commented.

Using a Forest Plot Cox model, the investigators assessed the potential predictors of ipsilateral stroke in this asymptomatic cohort. They found that baseline high-grade stenosis, progression to highgrade stenosis, and progression to occlusion were all predictors of stroke whereas statin therapy during follow-up was significantly protective of stroke.

“This study adds to the growing evidence that contemporary stroke risk is lower than previously thought in this selected patient population. In addition, evidence that progression of disease or high-grade disease may be predictive of stroke should spur more investigation into this area. Further research is clearly warranted to identify those at risk and those who might benefit from intervention,” Chang concluded.

no stroke beyond 30 days was attributed to ipsilateral carotid restenosis.

As per The Ottawa Hospital postcarotid endarterectomy protocol, the estimated cost of duplex ultrasound surveillance in this cohort was US$359,925 in total, or US$11,610 per restenosis. Duplex ultrasound surveillance did not lead to a single ipsilateral redo surgery during this period.

Duplex ultrasound was completed at The Ottawa Hospital’s accredited Vascular Diagnostic Center as per protocol, which currently involves performing surveillance at three and 12 months postoperatively, and yearly thereafter.

Strauss elaborated on follow-up protocol at The Ottawa Hospital: “In the earlier years of the study period the protocol was a lot more extensive—at three months, six months, nine months, 12 months and then yearly thereafter, which eventually decreased to ultrasound at three months and yearly thereafter postCEA. We are now in a transition period where some of the staff are starting to slow that down even further.”

Follow-up duplex ultrasound and clinical data were obtained from Vascubase and electronic medical records (vOacis). Primary outcomes included time to over 80% restenosis, post-carotid endarterectomy stroke rate, and number of surgical reinterventions. Statistical analyses involved survival analysis, χ2 and Fisher’s exact tests, and cost effectiveness analysis.

Moderator Brajesh Lal (University of Maryland School of Medicine, Baltimore, USA) applauded the amount of “due diligence” carried out in collecting follow-up data in this “very well done study”, however also noted that about a third of the study population were lost, asking why these people did not return. In response, Strauss remarked: “It is a flaw within any retrospective study that we cannot account for those who are lost to followup. One of the drawbacks of the study is we would not know if a patient presented to one of the peripheral hospitals for a stroke or a TIA, so certainly those would be lost to follow-up”.

In addition, Lal mentioned a paper which reports results contrary to the conclusions of the present study. “In the meta-analysis of the ICSS data and the CREST data with four years of followup there is actually a strong relationship between restenosis after carotid endarterectomies but no relationship to stroke after post-stenting restenosis,” he said, going on to ask how Strauss would respond to this data.

“From what I found in my literature review, even when most patients do develop greater than 80% restenosis, most of them do not actually develop ischaemic events and therefore there is not really much reason to intervene,” replied Strauss, adding that “once again, with a retrospective study it is hard to assess whether or not most patients go on to develop ischaemic attacks.”

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September 2019 | Issue 83

Endovascular aneurysm repair

EVAR versus open repair: Not bowled OVER by the latest trial results Janet Powell Comment & Analysis The OVER trial investigators, led by the late Frank Lederle, recently released the long-term results of endovascular aneurysm repair (EVAR) versus open repair. Janet Powell writes for Vascular News about the 14-year outcomes— recently published in the New England Journal of Medicine— how they compare to other similar randomised controlled trials’ results, and what the data contribute to the ongoing conversation about the durability of EVAR.

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he publication of the very longterm results of the OVER trial realises the last main research aim of Frank Lederle: he was still working on this a couple of months before his untimely death from pancreatic cancer.

So, congratulations to Frank and the team that persisted in seeing this through to publication. When Frank presented the preliminary findings at the European Society for Vascular Surgery (ESVS) in Lyon, France September 2017, there was a possibility that the late survival would be better in the EVAR group, but the data were not yet complete.

Now, like the EVAR-1 and DREAM trials, the OVER trial has shown that over the 14 years of follow-up, there was no difference in survival—the

main outcome—between the open repair and endovascular groups. These three trials also agree that the burden of reinterventions over 14 years is much higher in the EVAR group, and this remains a worry in cost-conscious health economies. The fourth trial, the ACE trial from France, has no long-term patient follow-up.

Although concordant in their principal findings, there are some differences in the secondary outcomes reported from the OVER trial—particularly cause of death. The explanation for this likely emanates from differences in patient selection and the methodology used for late follow-up. It is not correct to suggest that the OVER trial used more technologically advanced endografts

than the other trials; it was the only trial to use a significant number of AneuRx (Medtronic) endografts. Equally, the OVER triallists’ suggestion, that the US surgeons perhaps were more highly skilled than their European counterparts, is not evidence-based.

Though no trial recruited more than 10% women, the OVER trial recruited almost none. Their patients were much younger, had significantly smaller aneurysms and a much lower burden of coronary artery disease, but double the proportion of patients with diabetes or current smoking compared with the EVAR-1 trial. These differences are likely to impact upon secondary outcomes. For instance, the high prevalence of diabetes (which is associated with slower aneurysm progression) in the OVER trial patients might have contributed to the lower reported rate of secondary rupture after EVAR compared to the EVAR-1 trial.

The low rate of secondary rupture and late aneurysm-related death reported in the OVER trial also might have resulted from methodological differences between the late follow-up in the OVER and EVAR-1 trials. In the EVAR-1 trial, all deaths and clinical events were adjudicated by an independent endpoints committee and clinical events from routine data validated by hospital records. In the OVER trial, all deaths and clinical events since 2011 (more than half the deaths) were obtained from routine administrative data only, and not adjudicated by an independent committee. Instead, the authors of the OVER trial paper attributed the cause to late deaths. Moreover, in 93 (≈25%) of the late deaths, there were insufficient data for the authors to assign a cause of death. Under such circumstances, together with important differences in

Five-year results from the INCRAFT INSPIRATION regulatory study Five-year data from the INSPIRATION US investigational device exception (IDE) pivotal trial confirms favourable safety and effectiveness of the INCRAFT device. Presenting the trial at the Society of Vascular Surgery (SVS) Vascular Annual Meeting (VAM; 12–15 June, National Harbor, USA), Michel Makaroun, University of Pittsburgh (Pennsylvania, USA) surmised that the INCRAFT device “offers unique benefits in patients with challenging access anatomy”, while it “may provide a useful option for patients with infrarenal abdominal aortic aneurysms”.

“THE ONE-YEAR results were presented here at SVS four years ago,” announced Makaroun. “Now, all the five-year visits have been completed, with the follow-up visit compliance at 93%, and the follow-up imaging at 84% compliance.”

The safety and efficacy endpoints were both met.

Specifically, Makaroun acknowledged that major adverse events through 30 days were noted in six patients (3.2%; 95% CI, 0–6.1%) and successful aneurysm treatment at one year was achieved in 87.9% (95% CI, 83–100%). Pointing to the Kaplan-Meier plot depicting aneurysm-related and all-cause mortality, Makaroun said, “Freedom from mortality at five years is around 73%, [while] aneurysm-related mortality is extremely low [one patient; 0.5%].”

In terms of the abdominal aortic aneurysm sacs, he added, “The diameter changes are somewhat standard, except for the slightly higher rate of enlarged aneurysms at five years [23.4%]. Forty-two per cent had a shrinkage

of more than 5mm and 35% were stable over the period of observation.”

“The main reason that the device was delayed,” acknowledged Makaroun, “was that some early stent fractures were observed in the suprarenal stent. Overtime, the core laboratory identified stent fractures mostly in the suprarenal stent in 20 patients (18.9%) through five years with only one identified by the site.”

Of note, he added, “You have probably heard that the core lab was switched after a year; all of the fractures were actually discovered by the second core lab. The first one had not identified the same fractures that the second core lab identified.”

Further, he confirmed that the Kaplan-Meier estimate of the number of fractures overtime was around 15% at five years. According to Makaroun, no migrations at the proximal neck occurred in any patient. Limb occlusions were reported in 11 patients (5.8%) through five-year follow-up, with seven occurring in the first year (3.7% of

baseline characteristics, it is probably unwise to compare the secondary outcomes of aneurysm-related mortality or other causes of late death between the OVER and EVAR-1 or DREAM trials.

Interestingly, the OVER trial reported that in patients aged 70 years and older, the long-term overall survival was lower in the EVAR group than in the open repair group (and the converse for those <70 years). Similar observations have been made from Medicare data.

This raises an important question about endograft fixation in the aging aorta: “Does fixation become more tenuous with age, due to ongoing degenerative aortic disease?”.

In summary, three randomised trials have shown that the early survival advantage of EVAR versus open repair is not maintained and that after 14–15 years, there is no difference in overall survival between the two treatment groups despite the increased number of reinterventions in the endovascular groups. Since the inclusion/eligibility criteria for all three trials specified that the morphology of the aneurysm should be within instruction for use (IFU) of the proposed device, these results may not apply to the increasing number of patients who have had endografts outside IFUs, with or without adjunct procedures; their reintervention and mortality rates might be much higher than those in the randomised trials. The quest now is how to ensure the durability of the new generation of endografts and provide judicious surveillance to ensure that endovascular treatment is costeffective, with ever-improving outcomes for future patients.

Janet Powell is a visiting professor of Vascular Biology and Medicine at Imperial College, London, UK.

190 implanted). The only two open surgical conversions were related to occlusions, both of which also occurred in the first year, due to mural thrombus deposition with embolisation and main body occlusion.

The INCRAFT INSPIRATION regulatory trial enrolled 190 (mean age: 74; 90% male) patients in total: 134 at 27 sites in the USA and a further 56 patients at five sites in Japan. After the enrolment period (July 2012–August 2013), patients were followed with contrast enhanced CT scans and X-ray’s at one, six and 12 months, and annually through five years. Regarding the patient population, Makaroun remarked, “the only unusual thing was that nearly half the patients had an iliac artery diameter of <7mm bilaterally [83/187 patients]”.

Updating the SVS audience on the INCRAFT stent graft system, Makaroun explained the design of the modular tri-fab system. Encased within a polyester graft fabric, the system is comprised of electro-polished nitinol stents and active suprarenal fixation barbs. He added that the limbs are flexible, with 2–3cm in situ length adjustment options that will allow you to provide accurate distal landing.

“They have a limited number of parts, only 23, with four main body diameters and five iliac limb diameters.

The profile is a very low profile, at 14F, except for the 34 main body that is a 16F device.” Pointing to an array of photographs of the graft within the anatomy, Makaroun highlighted, “The system is very flexible […], it can navigate some very tortuous anatomy without getting into trouble […] without necessarily straightening up the anatomy too much. The system is very accurate and allows for a slow, deliberate and accurate deployment in a proximal site.”

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September 2019 | Issue 83

Physician wellbeing

The public health crisis of physician burnout persists, as new evidence points to advancing age, physical pain, and work-life conflict as its predictors New research finds that a third of practicing vascular surgeons meet criteria for burnout, subsequently increasing the incidence of depression and suicide ideation within this cohort of physicians. Presenting these data at the Society of Vascular Surgery (SVS) Vascular Annual Meeting (VAM; 12–15 June, National Harbor, USA), Dawn Coleman (University of Michigan, Ann Arbor, USA) listed: advancing age, physical pain and work-life conflict as independent predictors for burnout.

ACCORDING TO COLEMAN, physician burnout— currently defined as a “mental state characterised by emotional exhaustion, depersonalisation, and a diminished sense of personal accomplishment”—has become a public health crisis.

Addressing the SVS delegates, she put forward: “Presently, more than 50% of US physicians selfreport burnout. This has a variety of both personal and professional repercussions.” In terms of the latter, Coleman said burn-out has been linked to a decrease in quality of care, patient satisfaction, productivity, medical effort, an increase in medical errors and an enhanced rate of physician turnover. She acknowledged that in relation to personal consequences, burn-out can result in broken relationships, alcohol and substance abuse, as well as depression and suicide.

Coleman also emphasised that, “In light of the increasing prevalence of cardiovascular disease, vascular surgeon burnout presents a legitimate public health concern due to the impact on the adequacy of the vascular surgery workforce, which is projected to be a rising issue in the future.”

Thus, in 2018, Coleman and colleagues set out to explicitly define the prevalence of burnout amongst practicing vascular surgeons in addition to identifying risk factors for burnout in order to facilitate future SVS initiatives to avert this crisis.

The study investigators anonymously surveyed active SVS members using a validated burnout assessment, the Maslach Burnout Index (MBI). Embedded within a questionnaire that also captured relevant demographic and practice-related characteristics, the MBI measured levels of emotional exhaustion and depersonalisation. Coleman said that the accepted threshold of a score of 27 or greater on the MBI Emotional

Exhaustion module was used to identify surgeons suffering from burnout. Specifically, risk factors were identified using bivariate analyses, while multivariate logistic regression models were developed to identify independent risk factors for burnout.

Of the 2,905 active SVS members, 960 (33%) responded to the survey. According to Coleman, after excluding retired surgeons and incomplete submissions, responses from 872 practicing vascular surgeons were analysed. In terms of responder demographics, the mean age was 49.7 (±11.0), the majority of respondents (81%) were male, and the mean number of years in practice was 15.7 (±11.7). Primary practice settings were academic (40%), community practice (41%), Veteran’s hospital (3.3%), active military practice (1.5%) or listed as “other”.

“In total, 41% of our respondents met criteria for burnout, 36% endorsed screened positive for symptoms of depression in the past month and 8% supported thoughts of taking their own life during the last 12 months, with the percentage increasing to 15% in SVS members with burnout,” Coleman stated.

Furthermore, through the unadjusted analysis, Coleman and colleagues found that the factors significantly associated with burnout (p<0.05) included clinical work hours, on-call frequency, electronic medical record (EMR) documentation requirements, perceived conflict between work and personal responsibilities, as well as physical pain.

Moreover, Coleman acknowledged that the multivariate analysis revealed that age, work-related physical pain, and conflict between work and personal responsibilities were expressed as independent risk factors for burnout.

Specifically, when SVS members were questioned on whether they agree with the statement: “My work schedule leaves me enough time for my personal/family life,”

Capping medical residency hours does not hamper new doctors’ quality of training When new rules capped training hours for medical residents at 80 hours per week in 2003, critics worried that the change would leave physicians-in-training unprepared for the challenges of independent practice. New research published in the British Medical Journal (BMJ) and led by scientists at Harvard Medical School, Boston, USA, shows that these warnings were largely unjustified.

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he analysis—believed to be the first national study examining the impact of reduced hours on physician performance—found no evidence that reduced training hours had any impact on the quality of care delivered by new physicians.

This is notable given that recent

polling from a survey sent out by the Society of Interventional Radiology (SIR) found that there was a significantly increased risk of experiencing burnout, characterised by depersonalisation and emotional exhaustion, for those physicians who work more than 80 hours per week.

Dawn Coleman

50% of responders disagreed or significantly disagreed.

Commenting on this finding, Coleman said, “Importantly, there was a significant disparity when you consider those with high emotional exhaustion or depersonalisation scores, suggesting that in responders meeting criteria for burnout, they had more or a disparity in this regard.”

She ultimately concluded that to mitigate the aforementioned personal, economic, and social impact of vascular surgeon burnout, findings such as these will facilitate SVS efforts to improve vascular surgeon wellbeing.

During a final word to the SVS delegates, Coleman affirmed, “There is no question that a lot of what we feel as vascular surgeons is system level. I think that we are all naturally quite resilient. We all really like to operate, we like to work and we like to care for patients. We like responding to crises. [Yet] a lot of what we hear is the fact that we go back to our hospitals and we do not have a tremendous amount of support, or we do not feel valued or have control over our day-to-day lives.

“There are also people, who are not surrounded by healthy [work] cultures, and I would charge every member of the audience to be accountable for each other, because none of us are alone. What we are excited to consider moving forward as a taskforce, is a member programme that will allow an opportunity for community in a more standardised fashion. Essentially, peer support and even perhaps individual and group opportunities for coaching and culture change.

“Be kind and take care of each other, because we have bigger battles than microaggression, and a lot of patients to take care of.”

Following a series of high-profile patient injuries and deaths believed to stem from clinical errors caused by fatigue, medical accreditation agencies initiated a series of sweeping changes to the regulations governing resident hours and other aspects of training. These efforts culminated in 2003 with the US Accreditation Council for Graduate Medical Education capping the training of medical residents at 80 hours per week.

“This is probably the most hotly debated topic in medical education among physicians,” says Anupam Jena, the HMS Ruth L Newhouse associate professor of Health Care Policy in the Blavatnik Institute, a physician in the department of medicine at Massachusetts General Hospital (Boston, USA), and lead author of the study. “Many doctors trained under the old system think that today’s residents do not get enough training under the new system. You hear a lot of senior physicians looking at younger doctors coming out of training and saying, ‘They are not as prepared as we were.’”

The researchers found no significant differences in 30-day mortality, 30-day readmissions, or inpatient spending between physicians who completed their residency before and after the residency hour reforms.

Given the changes in hospital care over the past decade, the researchers knew that they could not just compare the difference between outcomes of recently trained doctors before and after the cap, since overall outcomes have improved thanks to better diagnoses and treatments, as well as better coordination of care and new digital tools that are designed to prevent harmful drug interactions and other human errors.

The study analysed 485,685 hospitalisations of Medicare patients before and after the reform. The training hour reforms were not associated with statistically significant differences in patient outcomes after the physicians left training. The findings suggest that US residency work hour reforms have not made a difference in the quality of physician training, Jena concludes.

Issue 83 | September 2019

“Surgery is a contact sport” “Being a vascular surgeon is an incredible privilege. The ability to perform life-saving operations and improve quality of life is unparalleled. Vascular surgeons, like professional athletes, spend thousands of hours of training, performing physically demanding work, and it takes a toll.” A new survey suggests that most vascular surgeons have chronic pain as a result of their work. In particular, it indicates that 75% of surgeons have (at least) moderate pain after a day of performing open surgery. Furthermore, pain causes sleep problems and reduces surgical stamina.

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ax Wohlauer (Department of Surgery, University of Colorado, Aurora, USA), who presented the results of the survey at the 2019 Society for Vascular Surgery (SVS) Vascular Annual Meeting (VAM; 12–15 June, National Harbor, USA), said that a previous study on workrelated pain found that: “Surgeons and construction workers have comparable rates of chronic neck, shoulder, and back pain.” He added “performing surgery is a contact sport” because it involves repetitive movements and the exertion of force to manipulate tissue. Wohlauer explained that surgeons stand for prolonged periods and maintain fixed, sometimes awkward body postures. The aim of the survey was to provide further information on work-related pain among vascular surgeons.

Wohlauer et al sent a questionnaire to 2,910 SVS members about the amount of work-related pain that they experienced on a daily basis. Pain was reported using the 0–10 Borg CR scale in which zero represents no pain and 10 signifies maximum pain.

Physician wellbeing a day performing open surgery was 4.4±2.3, which indicates being in “somewhat strong” pain according to the Borg CR scale. For endovascular and endovenous procedures, the mean pain scores were 3.9±2.4 (moderate) and 2.0±2.0 (mild), respectively.

Additionally, after a day performing open surgery, about 75% of surgeons had an average pain score of three or above— i.e. at least moderate. Similarly, 70% of operators had an average pain score of three or above after a day performing endovascular procedures. However, only about a third of surgeons reported an average pain score of three or above after performing endovenous procedures.

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respondents had problems sleeping, 12% felt that the pain interfered with their relationships, and 33% said that it affected their posture. In terms of work life, 20% said that they had “reduced stamina”, 13% felt that their pain slowed down operations, and 15% “taught less” because of being in pain.

Given the effects of work-related pain indicated by the survey, Wohlauer commented, “addressing work-related pain serves to improve the lives and careers of vascular surgeons”. He added that work-related pain may lead to early retirement in some operators and, therefore, “enhancing surgical longevity would help to address the current

After a day performing open surgery, about 75% of surgeons had an average pain score of three or above.”

Max Wohlauer

Of the 771 (26.5% of those surveyed) respondents, the mean age was 51.4±10.9 years, the average time spent in practice was 17.2±11.6 years, and 83.6% were male (retirees were excluded from the results).

The average pain scores differed depending on the type of surgery performed. The mean pain score after

Nearly half of vascular surgery trainees may have experienced sexual harassment A new survey suggests 47% of vascular surgery trainees have experienced sexual harassment and a further 14% have witnessed it. The most common type of sexual harassment reported was a sexist slur or intimate nickname or being told unwanted sexually explicit comments, questions, or jokes. However, 44% of respondents felt reporting sexual harassment would be a “waste of time” as “nothing would come of their complaints”.

WRITING IN CLINICAL RESEARCH, Melanie Nukala (Division of Vascular and Endovascular Surgery, SSM Health St Louis Hospital, St Louis University of Medicine, St Louis, USA) and others state

Regardless of the type of procedure they were performing, operators said that pain tended to be highest in the neck, lower back, and upper back (versus upper and lower extremities).

Despite the majority of vascular surgeons saying that they were in pain after a working day, according to Wohlauer, only 23% had sought medical care about the issue, only 6% had missed work because of work-related pain, and only 10% had undergone an ergonomic evaluation. Furthermore, 2% said that they were leaving surgery because of work-related pain.

Wohlauer noted that work-related pain affected both the operator’s personal life and their work life. He explained that the survey found that 26% of

that a previous study found that up to 36% of surgical trainees who report being harassed in any way, say that they have experienced specifically sexual harassment.

The authors add: “Given the high incidence of sexual harassment in medical training on the whole and the increase in women in vascular surgery, we sought to understand contemporary views of sexual harassment by vascular surgery trainees.”

Of 133 survey respondents (of 498 vascular surgery trainees sent the questionnaire), 61% were men, 37% were women, and 2% did not specify their gender.

Overall, 47% reported being sexually harassed and 14% reported witnessing it. The most common type of harassment was a sexist slur or an intimate nickname or being told unwanted sexually explicit comments, questions, or jokes. The survey found that those

38% of respondents felt that sexual harassment was more common in surgical fields.” reporting sexual harassment were more frequently women, and the perpetrators were more commonly men.

While 65% of respondents knew of the available mechanisms for reporting sexual harassment, less than 50% felt comfortable reporting sexual harassment to the department leadership. Additionally, Nukala et al comment, 44% thought reporting it “would be

national workforce shortages in vascular surgery”.

“Strategies to reduce the risk of developing work-related pain include: exercise, posture awareness, yoga, regular stretching, taking ‘microbreaks’ while operating.” Moreover, Wohlauer told Vascular News: “Steps that vascular surgeons can do to minimise existing work-related pain include adjusting the height of the table and monitor, using padded floor mats, footwear and support stockings, wearing custom fit lead correctly. Wearing wraparound two-piece lead that fits properly and using a lumbar support belt can reduce lumbar back strain. Positioning monitors straight ahead and 15 degrees below eye level can reduce neck strain.”

a waste of time to report as nothing would come of their complaints”, nearly 25% were concerned about the potential repercussions of reporting it, and another 25% “did not want to identify as targets of sexual harassment”. However, 52% of those who reported being sexual harassed felt that the behaviour was “harmless in intent or nature”.

Thirty-eight per cent of respondents felt that sexual harassment was more common in surgical fields than in other fields. According to Nukala, reasons for this include being more in common in surgical fields included “historical male dominance of surgical fields, the present of hierarchy, and power dynamics in the operating room, and the tolerance/ignoring of these behaviours by institutions of those in leadership positions”.

The authors conclude: “Increasing education on harassment and reporting mechanisms may be necessary in vascular surgery training programmes.”

Study author Matthew R Smeds (Division of Vascular and Endovascular Surgery, SSM Health St Louis Hospital, St Louis University of Medicine, St Louis, USA) told Vascular News: “Sexual harassment can have negative consequences on academic productivity, adjustment of work habits, and bad work relationships and ultimately may affect job satisfaction, wellbeing, and patient care. With the increasing number of women entering vascular surgery, and recent difficulties in healthcare systems in recruiting and keeping qualified vascular surgeons, now is the time to look into solutions to rectify these issues in order to continue to be able to attract women to our field.”

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September 2019 | Issue 83

Conference coverage

Counselling patients with dementia achieves better outcomes after vascular surgery Speaking at the 2019 Society for Vascular Surgery (SVS) Vascular Annual Meeting (VAM; 12–15 June, National Harbor, USA), Samir Shah (Division of Vascular Surgery, Brigham and Women’s Hospital, Boston, USA) reported that patients with dementia have worse outcomes after vascular surgery than those without dementia. He added these findings should be used to counsel dementia patients and their carers “to achieve goal-concordant” care.

“OUR INVESTIGATION SHOWED that dementia is an independent risk factor for poorer traditional and patientcentred outcomes,” Shah told Vascular News. “Specifically, our analyses included multivariable analyses that adjusted for demographic factors (e.g. age) as well as comorbidities.”

Shah stated at VAM that while dementia is associated with poorer outcomes, such as increased mortality, after other types of surgery, the effect of dementia on postvascular surgery outcomes was unknown.

This lack of data was in spite of a high prevalence of dementia among patients undergoing vascular surgery.

To explore the link between dementia

and post-vascular surgery outcomes, Shah and colleagues reviewed Medicare free-for-service claims data between January 2011 and December 2011. Of 210,918 patients undergoing vascular surgery (first admission only), 27,920 had dementia. Dementia patients were older, more likely to be female, and more frequently had comorbidities (e.g. diabetes). Overall, the majority of patients lived in the community.

In terms of vascular procedure, dementia patients underwent significantly more emergent/urgent procedures than those without dementia (61% vs. 38%, respectively; p<0.001) but underwent significantly fewer high-risk procedures

(18% vs. 27%, respectively; p<0.001).

Shah commented that although he and his co-investigators did not have any information on decisions taken prior to surgery, they speculated that there was a “general reluctance” among dementia patients, their carers, and their physicians for the patients to undergo elective procedures. He added that this policy, therefore, may have led to more emergent/ urgent procedures. “Similarly, there may be a desire to avoid high-risk procedures in this group of patients,” Shah observed.

Following surgery, according to Shah, “traditional outcomes” were worse with dementia patients. Both 30-day and 90-day mortality were increased in dementia patients compared with patients without dementia: 10% vs. 6% (p<0.001), respectively, and 21% vs. 9%, respectively (<0.001). Hospital length of stay was also significantly longer in dementia patients—8.92 days vs. 5.41 days for patients without dementia (p<0.001).

Other differences between dementia and non-dementia patients included dementia patients being less likely to be discharged home, more likely to be discharged to a higher level of care, and having an extended stay in a skilled nursing facility.

Concluding, Shah commented: “Freefor-service Medicare patients with dementia undergoing vascular surgery are older and have more comorbidities, more likely to

Standard supervised exercise treadmill training associated with “severe calf muscle damage” in significant portion of PAD patients A study of 42 claudicant patients has documented “pathological changes in calf muscle” in 17 patients, following standard supervised exercise treadmill training. Shuai Li (University of Nebraska Medical Center, Omaha, USA), who presented the outcomes in a late-breaking trial session at the Society for Vascular Surgery (SVS) Vascular Annual Meeting (VAM; 12–15 June, National Harbor, USA), spoke to Vascular News about the study.

Prior to your study, what data were available for the effect of supervised exercise training on calf muscles?

Exercise therapy for claudicating patients with peripheral arterial disease (PAD) has been the object of numerous studies for more than 50 years. Most studies, by far, have been concerned with efficacy to improve walking function and quality of life. A relatively small number of studies have been concerned with exercise Shuai Li adaptations in lower extremity muscles of these patients and most have evaluated changes in capillary abundance and mitochondrial function.

Surprisingly, our laboratory has been the first to evaluate myofibre pathology, oxidative damage and fibrosis in lower extremity muscle, before and after standard treadmill exercise therapy for these patients.

What were the key aims of your study?

The aim of our study of treadmill exercise therapy was to test the concept that improved calf muscle pathology is the basis for improved treadmill walking performance and quality of life of claudicating PAD patients treated with standard treadmill exercise therapy. Instead, we

found that for a large proportion of patients, calf muscle pathology worsened although treadmill walking performance improved. We think that this walking improvement represents a training effect and will be lost over time, after therapy.

In your study, you reviewed myofibre size/shape, oxidative damage, and fibrosis. How do these factors correlate with calf muscle damage?

We have discovered that myofibre size/ shape and oxidative damage and fibrosis in the calf muscle of patients with PAD worsen with more advanced disease. We consider hypoxia-induced oxidative damage a key contributor to the pathology of lower extremity muscle and the walking dysfunction of PAD.

What were the key findings of your study?

Our study documented moderate-to-severe progression of calf muscle damage in 40% of PAD patients who completed six months of standard treadmill therapy, even though treadmill walking performance improved to the same extent as those patients who experienced no progression of calf muscle damage. Disease progression

undergo emergent/urgent procedures, and poorer traditional outcomes.” He added that these results should be used to “help counsel patients/surrogates to achieve goalconcordant care”.

Regarding the ethics of performing vascular surgery in patients who, because of the dementia, may not be able to consent to a procedure and/or who have a poor quality of life, Shah commented that dementia patients were not a “homogenous group” and have varying levels of dementia. Therefore, knowing their goals (e.g. a preference to avoid invasive procedures with prolonged hospital lengths of stay) is “so important before discussing procedures”. “Research is ongoing to see how procedure decisions are made. So, we can avoid certain procedures or do certain procedures that may be less durable but are less physiologically demanding,” he stated.

Speaking to Vascular News, Shah elaborated: “With regard to discussing procedures with persons with dementia, it is essential to first assess whether patients have capacity to make decisions, which often are complex and nuanced in vascular disease. It is often helpful to involve family members or other surrogates even in cases where patient retain capacity. Early involvement of primary care physicians, geriatricians, and palliative care as appropriate is also helpful when appropriate.”

was associated with no improvement of quality of life and with a trend for reduced six-minute walking distance.

According to your study, 40% of patients had signs of severe damage to their calf muscle. Did these patients exhibit any symptoms such as pain?

Patients who experienced moderate-to-severe progression of calf muscle damage had improved treadmill walking performance but felt that their walking pain had not improved after therapy. This contrasts with patients who did not experience progression of calf muscle pathology.

These patients had improved treadmill performance and felt that their walking pain had improved significantly.

Why do you think supervised exercise training was associated with muscle damage in these patients?

It has been noted in the literature that the ischaemia associated with standard treadmill exercise therapy, requiring walking to moderate-to-severe pain, multiple times per therapy session, three times per week for six months, has the potential of producing muscle damage. We agree and think that repeated bouts of ischaemic hypoxia produced by treadmill exercise therapy drives progression of muscle damage, likely by induction of oxidative damage to myofibres, blood vessels and nerves.

What are the implications of your study for supervised exercise therapy?

We believe that our data best support the need for alternative exercise strategies.

What further research is needed?

There is evidence that alternative exercise therapy produces improved walking performance and quality of life. Perhaps, the most immediate research need is to evaluate, in the same studies, walking performance, quality of life and lower extremity muscle pathology among patients treated with different regimens of exercise therapy. Moreover, it will be necessary to complete follow-up studies to determine the durability of any beneficial changes.

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Training for rupture EVAR response: Formula 1 style Colin Bicknell Comment & Analysis What do Formula 1 cars, space shuttles and airplanes have in common with a ruptured aneurysm? In this article, Colin Bicknell writes about the importance of a well-oiled response strategy for endovascular aneurysm repair (EVAR) of a ruptured aortic aneurysm.

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September 2019 | Issue 83

Endovascular aneurysm repair

n 31 July 1994, during the German Grand Prix, Jos Verstappen’s pit stop refuelling resulted in the spontaneous ignition of litres of fuel, after the high-pressure hose failed to engage with his Benetton F1 racing car. The pit stop team and driver were ablaze. The fire was extinguished four seconds later. The driver at the centre of the furnace suffered minor burns to the face only.

Four seconds only to extinguish the fire. It is clear that this was a professional, well-rehearsed team, where the end results of meticulous, planned training are evident in this crisis scenario.

The question is, can we get to be as good as this in vascular and endovascular teams dealing with ruptured aneurysms?

If we are to, then there are certain principles that we need to pay attention to in training and rehearsal.

Vitally important is a need to pay attention to the whole pathway and every aspect of that pathway. Many years ago, after the Challenger space shuttle crash, Diane Vaughan examined the reasons the disaster occurred in her popularised book. The book explores far beyond the technical failure of the O-ring. Her in-depth analysis moved beyond the technical failure and beyond individual

actors to explore the organisational and environmental context in which the launch decision was made. She concluded that there were aspects of the working patterns of NASA that led to a “normalisation of deviance” and a belief that the risk of failure of the O-ring was acceptable. This environment, with many teams working together to achieve something highly complex and technical, has some real parallels with EVAR for ruptured aneurysms, and we can learn from this examination of the system.

The culture and the way we work in the NHS and elsewhere in international healthcare is very variable, depending on many factors. As part of a large multicentre study, researchers at Imperial examined the culture at 10 different vascular units with 275 multidisciplinary theatre team members in each. The scores for team work overall were on the borderline of acceptability, but proportion of respondents with positive perceptions is very low in some units and there is significant variation. As a vascular community, we have not matched our desire to centralise vascular units with our desire to pay attention to training the whole team.

It is intuitive that there is a need to focus on reducing error, but the focus

needs to be well directed. The LEAP study1 was a National multi-centre study of 185 cases of aortic surgery that examined the landscape of error modes in the vascular theatre. In total, 856 errors were recorded, a median of 4 errors per procedure (1.2 errors per hour). There was a wide spread of errors in different categories, but errors around equipment used, errors independent of the procedure and communication and team-working errors featured strongly compared to technical errors, where we traditionally place most emphasis on training. Fourteen errors directly contributed to patient harm, half of these occurred because of team related failures.

In addition, patients with an increased number of major errors were more likely to need reoperation, postoperative complications and death This study demonstrated patterns of error that informed us that we need to pay attention to the equipment, communication and system the procedure takes place in, equally as much as the technical aspects of EVAR. If we are to improve, we do have to question where we start. Again, we can turn to sport and training for some guidance. The British cycling team is world beating. Much of their success is attributed to a focus on detail—which one would also expect in the operating theatre. The principles of marginal gains has been popularised by Dave Brailsford, UK cycling performance director. He has said, “The principle comes from the idea that if you break down everything you can think of that goes into riding a bike, and then improve it by 1%, you will get a significant increase when you put them all together.” This principle should be used in training teams.

If the above solves what we rehearse then the next question is how we rehearse.

It was described over 100 years ago by Robert Yerkes and John Dodson that performance increases with physiological or mental arousal or stress, but only up to an inflexion point, after which, when the stress is too high, performance decreases. This should mean that it is commonplace for teams to train together in a stressful environment, both to enhance their performance in training to see what can be achieved and to rehearse effectively to reduce the time where there is an overload of stress in the when dealing with the rupture and maintain an optimum level of performance. Of course, this is not commonplace. It is, however, possible to train in using immersive simulation either in purpose built simulated angiography suites or using simulator integrated into the hybrid lab.

Lastly, we need to move further than just relying on safety checks that have the potential to cause a degree of misplaced trust in team preparedness. Checklists have their place but are not infallible. On 25 March 2019, the newspapers reported that a British Airways plane bound for Germany landed in Scotland, despite all checks being made without question. We all see the same in the vascular theatre.

To summarise, If we are to get ruptured EVAR to the next level we need to train to include the entire pathway of care

and every aspect, work on our culture of team-working, focus on error reduction in the right way and train as teams in highpressure environment.

At Imperial, we propose given this evidence that proactive team training should be a mandatory part of training, and of effective institutional governance.

Training should be as a team utilising an immersive simulated angiography suite or in situ in an empty theatre (perhaps every time a case is cancelled) where we can monitor, feedback and rehearse situations and now, even patient specific cases.

For rupture situations the simulated immersive environment appears valid according to studies examining fully simulated cases. Experts complete each step of the procedure faster and with greater proficiency and the subjective views of experts demonstrate the realistic nature of the simulator. In this highly controlled environment, a definite advantage of training can be seen if a structured debriefing focusing on technical and non-technical skills is integrated into a training programme.

Retesting after this shows significant improvements in communication, coordination, co-operation, leadership and team monitoring.

The programme should include, but not be limited to, a weekly multidisciplinary team training schedule that involves all team members from the ward and theatres, involving surgeons, anaesthetists, radiologists, radiographers and nursing staff. The programme should be structured, tackling routine and emergency scenarios and should be able to react to serious incidents that occur in real cases. Teams should be able to safely, practice and introduce new pathways of care using this model. At Imperial, this is what we aspire to.

Can the rupture situation be as smooth and as prepared as the F1 pit stop? The experience of the major teams in F1 is that getting the pit stop crew to be the best in world is highly complex. It involves interviewing and selecting crew to be a tyre changer, and for each and every role, training them all like athletes, studying their gaze patterns to ensure lightening fast reactions and getting the cars to stop within millimetre accuracy.

Think of the ruptured aneurysm patient coming in, always to the same bed in the same position, treated by the specialist phlebotomist that takes the cross match selected for this role after a series of interviews, before the trained athlete runs the blood to the lab, alongside the other twenty members all selected to do their specific jobs and trained 365 days a year. Of course this is impractical, but there is much we can achieve if we focus on teams, their culture and the whole pathway, and train for crisis in an immersive real-life environment, focusing on reducing error.

Colin Bicknell is a senior lecturer and consultant vascular surgeon at Imperial College London, UK. References 1. Lear R, Riga C, Godfrey AD, et al. Multicentre observational study of surgical system failures in aortic procedures and their effect on patient outcomes. Br J Surg. 2016 Oct;103(11):1467–75.

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September 2019 | Issue 83

Aortic aneurysm

Simulation training decreases mortality from ruptured aortic aneurysm New research from Finland found dramatic decreases in mortality from ruptured abdominal aortic aneurysms following a series of simulated staff training sessions on how to handle those lifethreatening emergencies with endovascular aneurysm repair (EVAR).

W

hen haemodynamic compromise exists in this situation, a multitude of events from patient transport through to surgical repair must coordinate properly if the patient is to have any chance of survival.

“An increasing number of experts acknowledge the benefits of endovascular repair in ruptured aortic aneurysm,” says first author Pekka Aho (University of Helsinki, Finland). “While smaller, dedicated teams for elective endovascular repairs are common, the same may not be in emergencies, particularly those that occur during off hours.

“Our great challenge in treating aortic emergencies using modern, endovascular techniques was to train 120 scrub nurses, 100 anesthesia nurses, 23 vascular surgeons, 40 anaesthesiologists, and 40

radiographers,” Aho says.

In the paper published in the Journal of Vascular Surgery (JVS), the authors write: “To streamline the procedure of EVAR for ruptured aneurysm and to provide this method even to unstable patients, we initiated regular simulation training sessions.”

Aho and his colleagues, led

by Maarit Venermo, led 29 simulations of ruptured aneurysm emergencies between 2015 and 2017, according to their report in the June 2019 edition of the Journal of Vascular Surgery (JVS).

Each simulation session started with a phone call to the vascular surgeon announcing a rupture in the radiology suite. The simulations ended when the aortic occlusion balloon was in place (endoclamping).

The immediate results of their efforts included:

Analysis of complex endovascular repair at single centre finds worse outcomes for women

A single-centre study of standard, fenestrated and branched endovascular aneurysm repair patients in Nürnberg, Germany, has found that outcomes for women are worse but the reasons are not yet clear, as literature on the topic is lacking. The results and literature review of gender differences in treating abdominal aortic aneurysm were presented by Athanasios Katsargyris (Klinikum Nürnberg, Germany) at the 23rd annual Critical Issues symposium (23–24 May, Liverpool, UK).

KATSARGYRIS BEGAN WITH an overview of previous studies that have examined the difference in outcomes for female aneurysm patients receiving endovascular aneurysm repair (EVAR). In a UKbased study by D Lowry and colleagues, published in the European Journal of Vascular and Endovascular Surgery in 2016, data from a large cohort showed some “clear differences” in comparing the approximately 11% of patients who were women to the rest of the cohort. “Women were older at presentation of aneurysm, compared to male patients,” Kastargyris said. “They had a longer hospital stay, 30-day mortality and 30-day readmission rates were higher, and finally, survival through to one year was also better for men compared to women.” A second study from Sarah

Maarit Venermo

An increasing number of experts acknowledge the benefits of endovascular repair in ruptured aortic aneurysm.” ● Decreased time to endoclamping from 20–35 minutes to 10–13 minutes ● Significant improvement in the confidence and knowledge of the staff.

Deery et al, published in 2017 in the Journal of Vascular Surgery, similarly examined a large cohort of EVAR patients to identify differences in outcome for men versus women, finding that women were “at higher risk for 30-day death and major complications after intact abdominal aortic aneurysm repair”. Again, Katsargyris drew attention to the older age of female EVAR patients in this cohort. Another finding identified in current literature, Katsargyris noted, is that “women more often have a hostile anatomy, and will more often receive EVAR outside of instructions for use”. Lastly, Katsargyris pointed to the notable SWAN study by Janet Powell et al, which examined approximately 52,000 men and 11,000 women, “we saw again here that women present with higher 30-day mortality—but what was also reported here was that women were less often eligible for EVAR, and for this reason the authors concluded that management of abdominal aortic

It seems indeed as though women present with inferior outcomes compared to men.” aneurysm for women needs improvement urgently.”

As for complex EVAR of fenestrated EVAR (FEVAR), Katsargyris explained he had not found many publications yet available on this topic. Only one paper known to him, authored in 2016 by David Timaran et al in the Journal of Vascular Surgery, had examined gender-related outcomes for a group of 79 thoracoabdominal endovascular aortic repairs (TEVARs), which again found worse outcomes for female patients.

“While we objectively documented improvements within the simulation itself, our next step was to see if these translated to the real-life performance in endovascular repair,” says Venermo.

The paper includes the results of 185 ruptures treated from 2013 through 2017, spanning the institution of simulation training. The before and after results include: ● An increase in endovascular repair for ruptures from 23% to 62%, ● A decrease in time from arrival to operating room start from 65 minutes to 16 minutes, and ● A decrease in 30-day operative mortality from 39% to 25%.

The JVS paper concludes that simulation training for ruptured aneurysm EVAR significantly improves the treatment process in real-life patients and may enhance the outcome of ruptured abdominal aortic aneurysm patients.

“This is one of the first papers to show that simulation may have immediate positive consequences and an impact on real patient care,” notes Venermo.

“Simulation training has led not only to improvements in the simulation sessions, like faster aortic occlusion, but also to a significantly improved self-confidence of the operating room personnel. We believe this has translated into improved outcomes for our treatment of ruptured aortic aneurysm.”

Importantly, the manuscript provides significant detail as to how to institute such an important programme.

“If we put all this together,” said Katsargyris, “it seems indeed as though women present with inferior outcomes compared to men, and there are some potential reasons observable in the literature here.”

However, he maintained that despite the indication that women are older compared to men, presenting more often with hostile anatomy and therefore treated more often outside instructions for use, and also need more procedures, “it seems there are other factors here that need to be investigated and clarified.”

“After all,” he explained, “even if we try to take out and control for all potential confounding factors, we see that still, female gender appears to remain an independent negative prognostic factor for outcomes.”

At Klinikum Nürnberg, Katsargyris and colleagues collected data for three different patient types of procedures performed between 2010 and 2018: standard EVAR (442 elective patients with 399 men [90.3%] and 43 women [9.7%]), FEVAR ( 454 patients, 412 men [90.7%] vs. 42 women [9.3%]), and branched EVAR (BEVAR; 377 patients, 295 men [78.2%] vs. 82 women [21.8%]). Although no significant differences could be found between male and female outcomes in the EVAR and FEVAR groups, Katsargyris drew attention to the BEVAR cohort, which also had a higher percentage of women: “In this group, we could not find any difference with regards to anatomical risk factors, however, looking at the early outcomes we could see that 30-day mortality was higher for women at 12% versus 5.8% for men.”

This was found despite the fact that both groups had equal technical success rate out of the overall 95% success rate. Moreover, Katsargyris reported that no significant difference was found in 30-day major complications that could offer an explanation for this mortality discrepancy. Overall, Katsargyris noted that more investigation is needed, as literature on the topic is “scarce” for FEVAR, and “non-existent” for BEVAR.

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September 2019 | Issue 83

Diabetic foot

IWGDF unveils new infection and PAD guidelines for diabetic foot patients Members of the International Working Group on the Diabetic Foot (IWGDF) presented up-to-date guidelines for the diagnosis, prognosis and treatment of diabetic foot ulcers at the 29th conference of the European Wound Management Association (EWMA; 5–7 June, Gothenburg, Sweden), highlighting development in the areas of infection and peripheral arterial disease (PAD).

F

irst revealed at the 8th International Symposium on the Diabetic Foot (22–25 June 2019, The Hague, The Netherlands), the eight new documents also include recommendations for offloading, the prevention of wounds, wound classification and wound healing.

The process of making the guidelines, according to Benjamin A Lipsky (University of Washington, Seattle, USA), involved the formulation of clinical questions and key outcome measures “that clinicians would care about” when treating patients with diabetic foot problems. Once this had been achieved, recommendations were graded to establish how useful they might be.

Diagnosis and treatment of foot infections

It is estimated that 25% of all persons with diabetes will eventually develop a foot infection, and this problem remains the most common cause of both diabetes-related hospitalisations and lower extremity amputations. As non-specialists are usually responsible for treating these infections, a new guideline was considered necessary by the IWGDF, expanding what was published in 2016 on the diagnosis and management of foot infections in persons with diabetes.

In addition to this, the updated recommendations aim to combat a “global antimicrobial crisis”. Lipsky said: “We are not producing new antibiotics and the ones we have are not as useful because of the developing resistance of microorganisms, so we have to use the antibiotics we have available in the wisest possible way.”

In support of the guideline, the infection committee of the IWGDF produced an update of a 2015 systematic review of interventions for treating infection, and a first time systematic review on the diagnosis of infection. The guideline updates the severity of infection

Nicolaas Schaper

suitable for most moderate and mild cases.

The performance characteristics of a number of diagnostic tests are also detailed in the guidelines, such as a probe-to-bone test, various serum inflammatory markers and imaging techniques. Lipsky added that if there is an infected wound, “you should culture tissue, not send swab specimens”, and process them using standard methods as opposed to newer molecular techniques. In selected cases, potentially infected bone should be sampled for a definitive diagnosis of osteomyelitis or to establish the causative pathogen(s) and antibiotic susceptibility results.

Turning his focus to guidelines for treating infection, Lipsky emphasised that antibiotics shown to be effective in clinical trials should be selected based on the likely pathogen(s), severity of infection and risk of adverse events, and be administered orally in

If a patient has PAD and does not heal within 4–6 weeks, then go to imaging and revascularise.” classification scheme developed by the committee in 2004, attributing osteomyelitis—an infection of the bone—the separate designation of “O”.

Key recommendations on diagnosis, as explained

by Lipsky, encourage physicians to assess all diabetic foot ulcers according to the IWGDF classification system, which grades diabetic foot patients from 1–4 depending on whether they have no infection, a mild infection, a moderate infection or a severe infection.

In cases of serious infection, a patient should be hospitalised, while outpatient treatment would be

Benjamin A Lipsky

mild and most moderate cases. Regarding the duration of therapy, he stated: “Most of us treat for much too long. There is good evidence based on randomised controlled trials that no more than one to two weeks of treatment is necessary for the vast majority of soft tissue infections, and no more than six weeks for bone infections.”

Treating patients with PAD

Presented by Nicolaas Schaper (Maastricht, The Netherlands), the new guideline on the management of PAD in patients with a foot ulcer and diabetes aims to tackle its association with a poor prognosis and support non-vascular specialists with diagnosis and treatment, especially as there is currently “weak evidence” to underpin clinical practice.

Looking at those affected by PAD, Schaper underlined that 50% of foot ulcer patients suffer from this disease, including younger people. These patients also face a much higher risk of amputation as a result of diabetes, which causes the disease to progress faster. Schaper explained this situation using the results of a recent study: “If a patient has claudication, one in 20 of those with diabetes underwent amputation. If a patient does not have diabetes, the amputation rate is one in a 100, so it is a huge increased risk.”

The first part of the guideline centres around the diagnosis of PAD, asserting that the disease should be excluded in diabetic foot patients as soon as possible.

This cannot be achieved with a clinical examination alone, as even those with severe PAD can demonstrate a good pulse; instead, more advanced examinations to test ankle and toe pressure are required. While there is no single modality in place, PAD is considered unlikely if triphasic pedal Doppler waveforms are measured, the ankle-brachial index is between 0.9 and 1.3, and the toe-brachial index is 0.75 or higher.

Once PAD has been diagnosed, a physician must assess the probability of healing when estimating the need for revascularisation. Using the WIfI classification system, which considers other key aspects such as the wound, ischaemia and foot infection, it is possible to deduce the amputation risk and determine whether revascularisation would be beneficial.

Although this system is a useful guide, there is still a great amount of uncertainty and physicians must be prepared to change strategy. Schaper said: “We advise that if a patient has PAD and does not heal within 4–6 weeks, then go to imaging and revascularise. If all your initial tests are normal and you treat the patient optimally, there is still a chance that the patient has PAD, because all the tests are unreliable.” For diabetic foot patients with both PAD and infection, Schaper further emphasised the need to treat immediately, as once there is an infection as well as diabetes, the amputation rate rises to as high as one in two.

Following the completion of these two stages, any approach to treatment should involve a multidisciplinary team of vascular specialists and aim to direct blood flow to one or more arteries, preferably in the anatomical region of the ulcer. The revascularisation technique should also be selected based on the individual factors of each patient.

In their closing remarks, both speakers considered the key controversies and conclusions raised by their respective guidelines. For patients with PAD, Schaper affirmed that revascularisation decisions are complex due to the potential for spontaneous healing, and called upon physicians to optimise other aspects of care.

Lipsky also raised a number of important questions about what the best approach to imaging bone and soft tissue infections might be, as well as the potential viability and usefulness of topical or local antimicrobial therapies, which are among the topics that will be explored further with the foundation of a new guideline established.

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September 2019 | Issue 83

Advertorial

SPONSORED ADVERTORIAL

Application of Heli-FX EndoAnchor implants to improve complex TEVAR outcomes: A consensus document

By Vincent Riambau, Robin Heijmen, Hervé Rousseau, Theodoros Kratimenos, Andreas Reyes

Introduction

T

horacic endovascular aortic repair (TEVAR) is currently accepted as the standard of care for the treatment of descending thoracic aortic aneurysms.1 Nevertheless, there are certain anatomical scenarios that can put standard TEVAR at risk for early failure and in other conditions where TEVAR is contraindicated, more complex repairs with proximal extension in the aortic arch may be required. Several authors reported an overall endoleak rate of 7.3%–38%2 after standard TEVAR, the vast majority being type I and III, half of which required reinterventions.

Several studies have examined haemodynamics in the thoracic aorta and related morphological changes from physiological to pathological conditions such as aneurysms.3,4 An evaluation of aortic stiffness changes after TEVAR has highlighted the need of more compliant endografts to reduce left ventricle stroke work and consequent adverse left ventricle remodeling.4 A new generation endograft (Valiant NavionTM, Medtronic) has improved conformability, significant profile reduction, and encouraging shortterm outcomes. Moreover, in the past several months, a new software has been developed and validated in order to better visualise apposition and position in the descending thoracic aorta after TEVAR.22 Additional evaluations on larger patient populations will further assess this software’s best use and application in the decision-making process of reinterventions to prevent complications before they occur.

Although new generation devices have been successful, achieving good proximal and distal sealing and fixation can still be challenging in certain scenarios such as tortuous descending thoracic aortas (DTA), large aneurysms, and short and/or wide sealing zones.

Recent evidence have shown a non-negligible rate of type I endoleaks, especially distal type Ib, which were responsible for reinterventions and ruptures over time.5 These kinds of complications may be underestimated and underreported in current literature, indicating a potential need for additional tools to reduce reinterventions and ruptures after TEVAR.

Heli-FX technology

The Heli-FXTM EndoAnchor system (Medtronic) has been extensively described with endovascular aneurysm repair (EVAR) and is used to strengthen sealing and fixation, especially in cases of hostile proximal necks (short, wide, angulated, conical).

The Heli-FXTM system replicates a vascular surgery anastomosis to reduce any potential leakage from the

proximal sealing zone, even minimal and undetected at CT scan or MRI. Both multicentre studies and registries7–18 have reported promising results with EndoAnchor implants, especially in patients treated prophylactically. Heli-FX EndoAnchor implants are also approved to be used in combination with TEVAR, both proximally and distally, but very few publications describe this application.19,20 The goal of our board was to achieve an initial consensus on Heli-FX EndoAnchor use in TEVAR including identifying indications and contraindications as well as validating preoperative planning.

Board consensus for prophylactic thoracic endovascular suture aortic repair (TESAR) Indications

Standard TEVAR is at higher risk of complications when anatomical challenges threaten proximal and distal sealing. The acronym SWACY (short, wide, angulated, conical, young patient) has been used for indications of endovascular suture aneurysm repair (ESAR) in the abdominal aorta.14 We examined the same anatomical and patient characteristics and the additional risk that they pose for TEVAR. Notably, this consensus is primarily directed towards the treatment of thoracic aortic aneurysms and blunt thoracic aortic injuries, and not for more fragile aortas like type B aortic dissections and intra-mural haematoma.

Neck length

Proximal neck length should be ≥2cm for a successful thoracic endovascular suture aortic repair (TESAR).

Although anecdotal experiences from single centres have shown positive results in necks shorter than 2cm,19 there is insufficient evidence to recommend TESAR in necks shorter than 2cm. Some authors even report an ideal proximal sealing zone of at least 3cm for a safe seal, so we suggest the use of Heli-FX EndoAnchor for necks shorter than 3cm without pushing the boundaries of instructions for use of the chosen stent graft.

The same concepts apply for distal sealing length.

When a long distal thoracic aorta coverage is required, a very precise distal deployment resulting in necks ranging between 2cm and 3cm is paramount in order to avoid type Ib endoleak and/or celiac trunk coverage. Distal thoracic aorta tortuosity increases the risk of upward migration by up to 60% at five years for necks ranging 1.5–3cm in length, as recently presented at the VEITH

Proximal prophylactic use of Heli-FX EndoAnchor implants (Courtesy of Hervé Rousseau)

Distal prophylactic use of Heli-FX EndoAnchor implants in tortuous DTA (Courtesy of Andres Reyes)

Symposium by Vincent Riambau, and the use of HeliFX EndoAnchor has the potential to prevent upward migration and type Ib endoleak in such challenging scenarios.

Neck diameter

Neck diameter accurate measurement is extremely important during TEVAR pre-operative sizing. All companies provide a defined range of aortic neck diameters and appropriate oversizing recommendations for a safe sealing and/or fixation. However, some of the larger diameter aortas that are possible to be treated within the instructions for use could be considered aneurysmal when using the definition of a diameter ≥35mm and thus would be prone to enlargement over time. For distal applications, an appropriate cut-off may be 32mm. The potential benefit of Heli-FX EndoAnchor technology in preventing neck dilatation has been published for infrarenal necks in abdominal aortic aneurysm repair and we believe that same concept could be applied in both proximal and distal thoracic scenarios.18

Neck angulation

Heli-Fx EndoAnchor implants for thoracic application do not have specific indications that go beyond stent graft IFUs, so prophylactic treatment does not allow for off-label TEVAR in zone 0 and 1. For highly angulated landing zone 2 and 3 when risk of “bird beak” effect can compromise proximal sealing, we agreed that the use Heli-FX EndoAnchor technology could improve graft sealing on the inner curve of the aortic arch.

Conicity

While the definition of neck conicity has changed over time,9,11,12 we agreed to apply the one most frequently used by core labs, with an additional modification requiring the thoracic minimum landing zone to be >2cm. We then defined the neck to be conical if there was an increase in diameter of up to 10% between the diameter at the most proximal edge of the sealing zone and the diameter at the most distal edge of the sealing zone. If the increase in diameter was greater than 10%, it was agreed that it is no longer considered a neck and instead is the beginning of the aneurysm.

The panel agrees to Heli-FX EndoAnchor use in conical necks where the neck length is ≥2cm but acknowledges most neck lengths in these cases will be shorter than 2cm.

Issue 83 | September 2019

Advertorial 2011

2013

2018

Three cm upward distal migration, treated and fixed by Heli-Fx EndoAnchor implants (Yellow circle; image courtesy of Vincent Riambau)

lower. In contrast, Heli-FX application as a bail-out can be considered no matter which landing zone the graft was originally implanted in, including cases where the previous TEVAR was off label (zone 0-1 landing).

However, due to the complexity of manipulating on proximal-mid arch, this should be reserved to experienced users and should not encourage off label usage of the primary graft.

Technical considerations

Proximal revision case to treat type Ia endoleaks (lack of proximal wall apposition) with zipper technique (progressive implants from distal to proximal; courtesy of Hervé Rousseau)

Life expectancy

The panel believes that the generic definition of young patient that is currently applied in the abdominal use of Heli-FX EndoAnchor needs to be rephrased as life expectancy longer than 10 years. The panel also agrees on the use of Heli-FX EndoAnchor for patients that have a life expectancy ≥ than 10 years.

TESAR revision

The main indications for revision cases are Type Ia and Ib correction, migration, bird beak effects, and neck dilatation.19,20 Prophylactic Heli-FX EndoAnchor use is limited to grafts that are implanted in zones 2 or

Use of Heli-FX EndoAnchor in TEVAR follows the same deployment steps of the abdominal application since the system is the same other than the French size, devices length and steerable distal portion of the guiding sheath length. The same two-step deployment allows for partial deployment of the Heli-FX EndoAnchor, checking for the appropriate position, and retrieving/adjustment before the second and final deployment. A minimum of six Heli-FX EndoAnchor implants are recommended by IFUs and we suggest splitting into two rows to distribute fixation at different levels which may strengthen it even further.

Contraindications

There are anatomical scenarios where the use of HeliFX EndoAnchor technology is contraindicated or the panel does not recommend their use. These include: ● Presence of calcium at the intended deployment location thicker than 2mm which may prevent from adequate penetration of the Heli-FX EndoAnchor implants through the aortic wall or even create a fracture of the anchor itself. When

Panel tips for better placement and deployment of Heli-FX EndoAnchor implants MANUAL

VISUAL

Feeling adequate tactile feedback indicating you are pushing the applier properly on the endograft-aortic wall.

The guiding sheath and the applier should be perpendicular to the aortic wall. Always use the steerable sheath to adjust orientation before the second step of deployment.

Selection of guiding sheath size may differ for the Always verify that proximal markers of the inner and outer arch curves. In particular for the endograft are aligned. outer curve, the smallest 22mm may be easier to rotate even in large diameter endografts.

Use of a large sheath (20F), if possible, may facilitate guiding sheath rotation/manipulation.

A better visualisation is achieved with a 14–7x zoom.

Femoral artery access is most commonly used.

In some cases both femoral arteries need to be accessed to be able to easily deploy the desired number of Heli-FX EndoAnchor implants in the selected location. If one femoral is highly diseased, a right axillary/subclavian access has also been described.

No movements of the guiding sheath, applier, and Heli-FX EndoAnchor system should be seen during deployment.

Use of excessive force to rotate the guiding sheath is contraindicated and may lead to guiding sheath abrasion.

Heli-FX EndoAnchor implants should penetrate the aortic wall through adventitia.

25

50% or more of the aortic wall at the intended deployment level is calcified use of the system is contraindicated. ● If a 2mm gap between endograft and aortic wall exists due to progressive enlargement or presence of thrombus. ● As of this time, the use of Heli-FX EndoAnchor in fragile aortas like dissections, IMHs and connective tissue diseases has not been studied nor documented. We agreed to include these pathologies under contraindications with the goal of avoiding further damage to an already diseased aortic wall. ● It has been reported that deployment of Heli-FX EndoAnchor implants as reinforcement in the mid-thoracic aorta and in the middle of the stent graft can be procedurally safe and effective.

However, it can also lead to type IIIb endoleaks if upward migration occurs and therefore, we suggest avoiding Heli-FX EndoAnchor use in this application.21 ● The panel recommends following the manufacturer IFUs for their respective stent graft without pushing boundaries towards more challenging anatomies, for example landing zones shorter than 2cm, until new evidence will show safety and effectiveness in such complex cases.

Panel conclusions

The entire panel is confident that TEVAR outcomes can be significantly improved by appropriate use of Heli-FX EndoAnchor technology especially in the above-mentioned challenging scenarios. As the use of Heli-FX EndoAnchor implants with TEVAR is still relatively new, the panel believes much can be learned from current experiences and there is a need for longer follow-up. Nevertheless, the current evidence and feedback we have collected in the short term have been promising.

References 1. Riambau V et al. Editor’s Choice: Management of Descending Thoracic Aorta Diseases Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS). Eur J Vasc Endovasc Surg (2017) 53, 4e52 2. Ricotta JJ et al. Endoleak management and postoperative surveillance following endovascular repair of thoracic aortic aneurysms. J Vasc Surg 2010;52:91S-99S. 3. van Bakel T et al. Blood Flow after Endovascular Repair in the Aortic Arch: A Computational Analysis. AORTA 2018;6:81–87.

4. Van Bakel TMJ et al. Cardiac remodelling following thoracic endovascular aortic repair for descending aortic aneurysms. Eur J Cardiothorac Surg. 2019 Jun 1;55(6):1061-1070.

5. Azizzadeh A et al. Pivotal results for the Valiant Navion stent graft system in the Valiant EVO global clinical trial. J Vasc Surg 2019;1-10 6. Conrad MF, et al. Results of the VALOR II trial of the Medtronic ValiantThoracic Stent Graft. J Vasc Surg 2017;66:335-42 7. Melas N et al.Helical EndoStaples enhance endograft fixation in an experimental model using human cadaveric aortas. J Vasc Surg 2012;55:1726-33 8. Jordan WD et al. One-year results of the ANCHOR trial of EndoAnchors for the prevention and treatment of aortic neck complications after endovascular aneurysm repair. Vascular 2015 0(0) 1–10 9. de Vries JPPM et al. Analysis of EndoAnchors for endovascular aneurysm repair by indications for use. J Vasc Surg 2014;60:1460-7 10. de Vries JPPM et al. Rationale of EndoAnchors in abdominal aortic aneurysms with short and angulated necks. J Cardiovasc Surg 2014; 55: 103-7 11. Jordan WD et al. Results of the ANCHOR prospective, multicenter registry of EndoAnchors for type Ia endoleaks and endograft migration in patients with challenging anatomy. J Vasc Surg 2014;60:885-92 12. Kopp R et al. Are EndoAnchors up to the Challenge of a Hostile Proximal Neck? Journal of Endovascular Therapy 2015, Vol. 22(2) 171–173 13. de Vries JPPM. Is it Time to Insert EndoAnchors into Routine EVAR? Eur J Vasc Endovasc Surg (2017) 53, 458e459 14. Jordan WD et al. Outcome-based anatomic criteria for defining the hostile aortic neck. J Vasc Surg 2015;61:1383-90 15. Goudeketting SR et al. Midterm Single-Center Results of Endovascular Aneurysm Repair With Additional EndoAnchors. Journal of Endovascular Therapy 2018, 1–11 16. Jordan WD et al. Midterm Outcome of EndoAnchors for the Prevention of Endoleak and Stent-Graft Migration in Patients With Challenging Proximal Aortic Neck Anatomy. Journal of Endovascular Therapy 2015, Vol. 22(2) 163–170 17. Arko FRIII et al. Endosuture aneurysm repair in patients treated with Endurant II/IIs in conjunction with Heli-FX EndoAnchor implants for short-neck abdominal aortic aneurysm. J Vasc Surg 2019;1-9 18. Tassiopoulos AK et al. Predictors of early aortic neck dilatation after endovascular aneurysm repair with EndoAnchors. J Vasc Surg 2017; 1-8 19. Kasprzak P et al. EndoAnchor Placement in Thoracic and Thoracoabdominal Stent-Grafts to Repair Complications of Nonalignment. Journal of Endovascular Therapy 2013;20:471-480 20. Ongstad SB et al. The use of EndoAnchors to rescue complicated TEVAR procedures. The Journal of Cardiovascular Surgery 2016 October;57(5):716-29 21. Müller-Eschner M et al. Type IIIB Endoleak after Thoracic Endovascular Aortic Repair Caused by Endoanchor Dislocation. Ann Vasc Surg 2015;29:1019 22. van Noort K et al. A New Methodology to Determine Apposition, Dilatation, and Position of Endografts in the Descending Thoracic Aorta After Thoracic Endovascular Aortic Repair. Journal of Endovascular Therapy 2019; 1–9

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September 2019 | Issue 83

Interview

Profile

Alan Lumsden

Alan Lumsden is chair of the Department of Cardiovascular Surgery and Medical Director at the Houston Methodist DeBakey Heart and Vascular Center in Houston, USA. He spoke to Vascular News about his current research interests and the three rules of endovascular surgery: imaging, imaging, and more imaging.

What led you to become a vascular surgeon?

When I immigrated to the USA from the UK and worked in Grady Memorial Hospital in Atlanta, I was fascinated with trauma—I had never seen a gunshot wound during my training in Edinburgh. First night on call in Grady, two people came in shot. I was thinking, “Oh my goodness have I made a big mistake!” But you get used to it, and it is the best of training for a young surgeon.

The greatest challenges were the major vascular injuries.

At that time, I wanted to be a trauma surgeon and that was the reason I did a vascular fellowship. But after you have been doing trauma for five years in residency, you realise that is going to be a tough lifestyle, and I became fascinated by the vascular surgery.

Who have been your professional mentors, and what lessons did you learn from them?

I have been very fortunate to have great people at different stages of my career. As house officer in Sir Patrick Forrest unit in Royal Infirmary of Edinburgh, UK, I worked with a registrar called Mike Dixon. He really started me on the academic route with his passion and drive for research.

I would not be in the USA were it not for Dr Mike Henderson, now at CCF. Mike gave me the break I needed to move to Emory University and work in his lab on portal hypertension. The chairman there was Dr Dean Warren of Warren Shunt fame. Emory was the epicentre of all portal hypertension research. That also got me exposed to the vascular surgery group: Garland Perdue, Bob Smith and Atef Salam. They were all involved in portal hypertension shunt surgery; now that is real surgery! Later, I would join Bob and Atef and subsequently became their chief—now that is a little weird. I never thought I would leave Emory—it is an awesome institution. Then, however, came an invitation to go to Houston: DeBakey, Cooley, Crawford and the biggest vascular surgery training programme in the USA—and guess what? Not one vascular surgeon! No endografts being placed, all big open aortic surgery.

That was the opportunity—so I went.

What are the most significant ways you have seen the vascular field develop over the course of your career?

My training included zero endovascular cases. Dr Lou Martin, Emory chief of Interventional Radiology and a great guy, kept saying “Alan, you have to learn how to do this”..But we did not learn, until Dr Steve Oweida, my senior fellow, went to the Arizona Heart Institute and watched what Ted Diethrich was doing. It was absolutely transformational. Ted went to Arizona Heart from Houston Methodist with DeBakey— from the big open surgery centre to developing the endovascular world. Frankly, an unbelievable transition. So how did he do it? Well, they were doing all their own translumbar angiograms between open thoracoabdominal cases.

In other words, sticking a needle through the back, injecting dye and pulling a bunch of flat plates behind the patient, hoping you caught something.

So, the main change is in introducing imaging into our operating environment and bringing in the devices.

From my perspective, the first, second and third rules of endovascular surgery are: imaging, imaging and more imaging.

How do you anticipate the field might change in the next decade, and what developments—technological or otherwise—would you most like to see realised?

Integrating even more imaging—we are building a system with an MRI and a real CT scan in our operating room. Also, catheter robots are transforming the thoracic interventional world—this will come back to us. We created the Methodist Institute for Robotics Imaging and Navigation. It is the interplay of imaging and robotics, which is potentially transformational.

In the last year, which new paper or presentation has caught your attention?

Because of my interest in cerebral embolisation during arch procedures, the paper by Lansky et al published in the Journal of the American College of Cardiology, is a pivotal moment. It defines diffusion-weighted MRI positive lesions as a type 2 stroke. That means 70% of TAVR patients have strokes—ie., areas of dead brain.

But it is not just TAVRs; they just happen to be on the front end of this. I think cerebral embolisation is ubiquitous during procedures in left heart, aortic valve and arch. Now we have to reduce this. There are NO good cerebral emboli.

What has been the proudest moment of your career to date?

Being appointed as chairman of the Department of Cardiovascular Surgery, then Medical Director at Houston Methodist DeBakey Heart and Vascular Center. I love working with our heart surgeons and cardiologists. This is not always a popular sentiment in vascular surgery circles. However, our folks are spectacular clinicians and technicians. When a cardiovascular enterprise presents a united front in an institution, that is when you get the kind of resources we have.

What are your current areas of research and work?

All about integrating imaging into our operative environment. I am also focusing on transcranial Doppler—this is the only tool which allows us to real time see what is happening in the head as we work downstream.

What advice would you give someone starting their career in vascular surgery?

Take advice but be confident in your ideas. I wasted a lot of time listening to naysayers, about almost everything. I guess it is just part of our DNA. However, remember what John Bergen said about stent grafts: “Never been an advance that has not been opposed by wise and good men”.

In your opinion, what are the biggest challenges currently facing vascular surgeons and specialists?

Easy: preventing loss of open surgical skills. I ran one of

the first endografting courses in Atlanta, USA, and now I am running an open aortic training course in Houston.

This is going to be a problem.

Could you tell us about one of your most memorable cases?

The ones I remember most are the ones with bad outcomes. As a fellow at Eagleston Children’s Hospital in Atlanta, we operated on an eight-year-old child who had a four wheeler turn over on him, and had a contained rupture at diaphragm, but the child did not look normal. Believe it or not, there was a geneticist available who we asked to consult, almost on way to the operating room. He said this child may have Ehlers Danlos, and advised us to caution the family that

Issue 83 | September 2019

Interview

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Fact File

Current appointments (selected)

2019: President International Society of Endovascular Specialists 2010–Present: Chair Walter W. Fondren III Distinguised Endowed Chair 2009–Present: Medical Director Methodist DeBakey Heart & Vascular Center, Houston, USA 2006–Present: Board of Directors Member Michael E. DeBakey International Surgical Society 2002–Present: Active staff The Methodist Hospital, Houston, USA

Previous appointments (selected)

2017: Educational Director and Medical Director International Society of Endovascular Specialists 2008: President Society for Vascular Surgery 2002–2007: Professor and Chief Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, USA 1995–2002: Chief Division of Vascular Surgery, Emory University School of Medicine, Atlanta, USA 1991–2001: Director Emory Venous Clinic and Emory Endovascular Training Center, Atlanta, USA 1982–1984: Lecturer Royal Infermary of Edinburgh, Edinburgh, UK

Education

1978–1981: Bachelor of Medicine and Surgery University of Edinburgh, Edinburgh, UK 1974–1978: Bachelor of Medical Sciences University of Edinburgh, Edinburgh, UK he may not survive. We fixed the aorta, took off the shodded clamp, which had almost transected the aorta, and the child died. It was devastating for all, especially the family. I call it the “longest walk”, going from the operating room to a waiting room to deliver news that a family member has died. I never get used to that, and I always say that the day that part of my work no longer bothers me, is the day I retire.

How do you like to spend your time outside of work?

Kayak fishing and cycling with my partner Merrilee— we both love the outdoors and have a house down on Galveston Bay. Other than the occasional hurricane, it is a great place.

I think cerebral embolisation is ubiquitous during procedures in left heart, aortic valve and arch.

Now we have to reduce this. There are NO good cerebral emboli.”

Awards (selected)

2013: Honorary Fellowship of the Royal College of Surgeons of Edinburgh 1999: Teaching Award Vascular Surgery, Baylor College of Medicine 1998: Medical Design Excellence Award, Ethicon EndoSurgery 1997: Liebig-Peripheral Vascular Surgery Society Presidential Award

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No significant differences between hybrid and open approaches for managing thrombosed AV grafts Data from the University of Pittsburgh Medical Center (Pittsburgh, USA) indicate that the open approach to managing thrombosed haemodialysis grafts with venous anastomotic lesions is not associated with superior primary patency when compared to the hybrid approach. These findings also show that an existing stent in an arteriovenous graft is a strong predictor of loss of patency and graft abandonment.

C

atherine Go (Division of Vascular Surgery, University of Pittsburgh Medical Center, Pittsburgh, USA) presented the data at the 2019 Society for Vascular Surgery (SVS) Vascular Annual Meeting (VAM; 12–15 June, National Harbor, USA).

She told delegates that AVGs were “plagued by poor patency”, and that failure of an AVG leads to “increased cost and morbidity”, adding that thrombosis in an AVG most commonly occurred because of a venous anastomosis stenosis.

However, according to Go, the “jury is still out” about how to manage such thromboses. Two metaanalyses—published in 2002 and 2019, respectively— have reported the superiority of the open treatment over purely endovascular methods, but few studies have investigated the hybrid technique, which Go reported is commonly used at her centre (University of Pittsburgh Medical Center). She explained that this involves “open thrombectomy followed by endoluminal treatment (balloon angioplasty, cutting balloons, or stents/stent grafts)”.

“Based on historical data, we hypothesised that open revision for AVG venous anastomosis is associated with better patency when compared to hybrid therapies”, Go stated. Therefore, in the retrospective study, Go and colleagues compared patency outcomes for patients who underwent open repair for a first-time AVG thrombosis with those for patients who underwent the hybrid approach. The primary endpoints were primary patency (time from index thrombectomy to first reintervention or thrombosis) and secondary patency (time from index thrombectomy to graft abandonment).

The investigators also reviewed technical success and primary-assisted patency (time from index thrombectomy to first re-thrombosis).

Overall, 97 patients underwent intervention for occluded AVGs at the University of Pittsburgh Medical Center between 2014 and 2018. Of these, 34 underwent the open approach (73.5% patch angioplasty and 26.5% jump bypass) and 63 (22.2% stent graft, 7.9% cutting balloon, and 1.6% bare metal stent) underwent the hybrid approach.

At 30 days, there were no significant differences in rate of the failure of the approach: 29.4% for open versus 27% for hybrid (p=0.799). Multivariate analysis showed that a higher number of prior fistulograms and African-American race were both predictive of protection against failure. There were also no significant differences between groups in primary patency, primary-assisted patency, or secondary patency at either six months or 12 months.

Go reported that the number of prior fistulograms was again predictive of protection against primary

Catherine Go

An existing stent at the venous anastomosis is a strong predictor of loss of patency and abandonment.” patency failure (at six/12 months). Central occlusion and a hypercoagulable state were predictive of loss of primary-assisted patency. An existing venous anastomosis stent predicted both loss of primary patency and loss of secondary patency.

“AVG patency after thrombectomy is poor. Open versus hybrid treatment of AVG venous anastomosis stenosis is not associated with differences in patency.

An existing stent at the venous anastomosis is a strong predictor of loss of patency and abandonment,” Go reported. She added that, given the association between an existing stent and graft abandonment, an operator should “start planning future access options” when using a stent to salvage a thrombosed AVG.

First human results of biotube vascular graft reported with three-year results The first human study using in-body tissue-engineered autologous vascular graft has published three-year results for two cases in the Journal of Vascular Access. With one successful case and one less successful in the long term, the investigators state “this is the first inhuman study that successfully supports the concept of internal shunt restoration for haemodialysis using [a] biotube.”

THE INTERNAL SHUNT restoration technique uses completely autologous vascular grafts— so-called biotubes—based on in-body tissue architecture, writes authors Yasuhide Nakayama et al. “Biotubes (diameter, 6mm; length, 7cm) were prepared as autologous collagenous tubular tissues with approximately 0.5mm wall thickness by embedding moulds (two per patient), assembled with a silicone rod and a stainless steel pipe with many slits, into the patients’ abdominal subcutaneous tissue for two months”, the investigators explain.

The procedure was performed in two female patients with end-stage renal disease, who were undergoing haemodialysis at the time of enrolment.

Both were high risk for failure, the authors describe, due to repeated stenosis “every few months” for the previous 1.5 years, occurring at the venous outflow regions.

The investigators successfully formed biotubes in the bodies of both patients, subsequently implanting them to form a bypass over the venous stenosis region in the arteriovenous fistula. No haemostatic drugs were needed intraoperatively to control bleeding at the suture line, they report, and patients were treated with oral anticoagulants for one month post-procedure. Follow-up included angiography, and the biotubes were punctured at three months following implantation.

At one week, blood flow in the originally stenosed veins reportedly “almost disappeared”, with “no sign of dilatation or stenosis” in the biotubes. Circumferential narrowing of the biotube was observed in one case at four months, but blood flow remained sufficient, and no reintervention with angioplasty was required over three years. The second patient, however, saw prominent stenosis at the proximal anastomotic site. Angioplasty was performed in the biotube at seven months after implantation, with repeated reinterventions required over the following two years until the biotube was replaced at 30 months with an ePTFE graft. Two months later, the graft was occluded.

The authors conclude that while “the initial outlook of this technology was not promising”, their investigation demonstrates the high burst strength of the “more robust” biotubes, which had previously not been possible.

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Interim safety analysis of PAVE trial data identifies “no concerns” regarding mortality and paclitaxel devices in AV access Providing an update on the UK-run PAVE trial (paclitaxel assisted balloon angioplasty venous stenosis in haemodialysis access) at the 2019 EndoVascular Access Meeting (EVA; 21–22 June, Patras, Greece), Narayan Karunanithy (Guy’s and St Thomas’ Hospital and King’s College London, London, UK) explained that although recruitment had slowed to six months behind schedule, the one-year results will be released in autumn this year. that we have identified no concerns with THE PAVE TRIAL was established in regards to morbidity or mortality [when 2016 to assess the efficacy of paclitaxelusing paclitaxel-coated balloons], but more coated balloon angioplasty in addition to detailed information about this will come high-pressure balloon angioplasty to treat out following our baseline data lock”. dysfunctional native haemodialysis access.

The investigators are currently The double-blind, multicentre randomised performing this baseline data lock, which controlled trial is funded by the National Karunanithy describes as “quite a rigorous Institute for Health Research (NIHR). process […] looking at data management Karunanithy explained at EVA that, “given and data verification of a huge number recent developments”, the triallists hope to of case report forms”. He explained: extend follow-up to five years.

“We have got a very rigorous continuous This comment is in response to the Narayan Karunanithy programme of in house endpoint checking publication of a meta-analysis in December for fistulograms done at the time of intervention or follow 2018 by Konstantinos Katsanos (Patras, Greece) et up. In addition, we have a robust independent core lab al, who, writing in the Journal of the American Heart analysis programme that is ongoing for patients treated in Association (JAHA), reported an increased risk of death at this trial.” two and five years following the use of paclitaxel-coated The PAVE trial completed its enrolment of 212 patients balloons and stents in the femoropopliteal artery. on 4 October 2018, following an extension to the study In the last three months, Karunanithy and colleagues timeline approved in July that year. The patients are have conducted an interim safety analysis with the randomised 1:1, to either the treatment arm (angioplasty patients enrolled in the trial so far. “The statement we with a paclitaxel-coated balloon) or to the control arm. would like to say,” Karunanithy declared at EVA, “is

Interim results of a multicentre analysis support paclitaxelcoated balloon use in CVS The interim results of a multicentre, European retrospective analysis investigating the use of drug-coated balloons (DCBs) in symptomatic central venous stenosis (CVS) suggest that these devices could be a valid option for treatment, slowing down the effect of neo-intimal hyperplasia (NIH) leading to restenosis. Though with data mining still underway, the investigators warn against drawing any premature conclusions. Panagiotis Kitrou (Patras University Hospital, Patras, Greece) presented these preliminary results at the annual EndoVascular Access Meeting (EVA; 21–22 June, Patras, Greece) earlier this year.

A

gainst the backdrop of the current paclitaxel controversy (where Konstantinos Katsanos, along with Kitrou and other colleagues, reported in the Journal of the American Heart Association (JAHA) an increased risk of death at two and five years following the use of paclitaxel devices in the leg), Kitrou first provided insight into how the publication has affected his own clinical practice. He told delegates: “We [at Patras University Hospital] have not changed our practice with regard to DCB use in dialysis access management. We believe that paclitaxel is an independent predictor of death, but its effect is different in different populations. Thus, a claudicant suffering more comorbidities compared to a claudicant with fewer comorbidities

will have a greater number of factors antagonistic for the same event, which is death. Hence the signal and the effect of paclitaxel becomes faint and diluted while the actual benefit from NIH inhibition becomes more apparent.”

For patients with CVS, the gold standard treatment is percutaneous transluminal angioplasty (PTA).

“However,” Kitrou explained, “the patency rates may be as low as 28.9% at six months. This rate doubles to 60% when you use a high pressure balloon. The main problem [when using balloons] remains elastic recoil.

You may also use a stent or a covered stent, with the latter being a much more aggressive treatment.”

Going through today’s evidence on CVS treatment, Kitrou showed EVA

The primary endpoint is time to end of clinically-driven target lesion primary patency. The investigators have a number of secondary endpoints, looking at radiological, clinical and nephrological outcomes, such as target lesion late lumen loss, procedural success, and the number of thrombotic events, as well as the number and severity of adverse events and patient quality of life assessment.

When listing the inclusion and exclusion criteria for the study, Karunanithy drew the EVA audience’s attention to the fact that only patients with a single lesion were investigated. He said the rationale for this was “to keep the data as clean as possible”, though later admitted that this was the primary reason why consented patients were later rejected from inclusion in the trial analysis. Of 482 consented patients, only 212 were randomised to one of the study arms, giving an eligibility rating of 44%.

However, regarding patient follow-up, Karunanithy is content: “We have got a very tight follow-up, so we are very happy with our follow-up regime for these patients— out to 24 months for some of the earlier recruited patients”. The triallists have also been monitoring, in a blinded fashion, the event rate for their patient cohort.

Without knowing which side of the study the patients are on—the treatment arm or the placebo arm—the investigators report that the event rate appears to be on target to meet their primary and secondary endpoints. To date, 45 of 211 patients (21.3%) have lost target lesion primary patency, and 46 of 211 patients (21.8%) have lost access circuit primary patency.

More detailed information about [the PAVE trial] will come out following our baseline data lock.”

attendees the results from a 2015 retrospective analysis by Alexander Massmann et al that compared standard balloon angioplasty with paclitaxel-coated balloon angioplasty for symptomatic central vein restenosis in patients with impaired native haemodialysis fistulas. The study investigators concluded that paclitaxelcoated balloon angioplasty yielded a statistically significant longer freedom from target lesion revascularisation compared to standard balloon angioplasty. Although, Kitrou noted, Massmann and colleagues did include axillary veins, so he thinks these results “are not strictly for central veins”.

He next talked the audience through his own randomised controlled trial from 2017, which included 40 patients with de novo, restenotic and occluded lesions. Twenty patients were treated with the Lutonix DCB (BD), and twenty were treated with a non-coated balloon. In this study, the primary end-point was a clinically-assessed intervention-free period. In this, Kitrou et al found a significant difference in favour of DCBs. Additionally, DCB angioplasty was numerically better in the longitudinal analysis compared to plain balloon angioplasty.

Despite the fact that these studies found a significant difference between treatment arms consistently in favour of paclitaxel-coated balloons, Kitrou highlighted that these results have been observed in fewer than 30 patients.

The present, multicentre, European, retrospective analysis therefore will provide data detailing DCB use in a greater number of patients. The primary outcome measures are a clinicallyassessed intervention-free period of the treated segment at six months, a dialysis access circuit with no need for clinicallydriven target lesion repeat intervention for symptom recurrence (verified angiographically), and no procedurerelated minor and major complications.

The study included 87 patients from 11 centres across Greece, Germany, France, Italy, Portugal, and the UK. Though still only early data, the interim analysis reveals that at six months, the target lesion primary patency was 52%, and the median target lesion primary patency was 280 days, meaning lesions remained open following intervention for an average of nine months. “The results are already much better compared with our randomised controlled trial”, Kitrou said, referring to his 2017 study.

The investigators also measured primary patency of the access circuit.

This was 48% at six months, and the median time to reintervention was 257 days. The access circuit survival was approximately 70% at six months, Kitrou shared.

“There is a lot of work in progress, we are still mining data—we are looking at this huge Excel [document] with a lot of data in there, and we will soon have more to share with you,” Kitrou concluded.

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“More creative solutions” needed for end-stage vascular access patients Nick Inston Comment & Analysis Nick Inston calls for “more creative solutions” to vascular access challenges, commending interventional radiologists’ innovative reputation as instrumental to increasing the number of treatment approaches available to physicians. Outlining the complexities of end-stage vascular access in an ever-increasing patient population, Inston expresses the need for a multidisciplinary team approach, claiming that the “outlook is improving” due to the fruitful crosspollination of ideas and skills.

T

he age of the dialysis population continues to increase, and whilst some of this may be attributed to older patients initiating dialysis, the main component is improved survival in prevalent dialysis patients.

As a consequence, the vascular access needs of this population become more challenging. As primary access sites become depleted, more creative solutions must be employed.

In a small but increasing group of patients, standard, multiple, autologous, and synthetic options may have all failed, and these patients may be deemed to have exhausted all vascular access options except for the use of a central venous catheter (CVC). This situation may be termed end-stage vascular access (ESVA).

If a patient with a limited lifespan expresses a wish to remain on a CVC, this may be a suitable option.

However, this group of patients are likely to require multiple interventions to maintain their CVC patency and may require kinase infusions and even emergency CVC exchange to maintain an ability to dialyse.

In those patients keen to pursue definitive access options, classifying the underlying issues is helpful. This can be done on an anatomical basis, such as the radiological classification outlined by the Society of Interventional Radiology (SIR), or by using a simplified, more basic classification, such as that described by Julien Al-Shakarchi (University Hospital Birmingham, Birmingham, UK).

A simple classification for endstage vascular access failure is proposed based on a sequential broad categorisation of: stage 1) no upper limb vascular access option; stage 2) no lower limb vascular access options; stage 3) no vascular access options at any site.

These can have the underlying anatomical problem added to allow more detailed definition (see Table 1).

An illustrative example may be a patient with tight superior vena cava (SVC) and brachiocephalic stenosis who has a right iliac vein occlusion and a left groin line. This would be classed as ESVA 2a, and possible solutions that could be considered are a left femoral vein transposition or loop thigh arteriovenous (AV) graft, attempts at recanalising the upper body central veins with recanalisation and stenting, or use of a Surfacer device (Bluegrass Vascular) and insertion of a HeRO (Merit Medical).Other options may be a non-standard graft configuration—here a right axillo-femoral graft may be possible. Peritoneal dialysis should not be forgotten.

When balancing each of these, the

risks and benefits should be carefully considered.

Lower leg access is not without complications. Femoral vein transposition, whilst having the advantage of use of the autologous vein and of reducing infection, is associated with lower limb congestion and venous insufficiency. Additionally, amputation has been reported with this method.

Lower limb prosthetic grafts are associated with high rates of infection and low patency.

Recanalisation of upper body central vessels may require expert interventional radiology skills and devices. The Surfacer device has potential, but robust data are not yet available to allow evaluation. Even with recanalised vessels, the next step towards definitive access requires either extensive stenting or the use of a HeRO device. In patients with CVC infections (common in groin access), this is contraindicated. In such patients, a staged approach to recanalisation with initial upper body CVC, eradication of infection, and subsequent conversion to a HeRO graft may be a better approach.

Patients with arterial insufficiency can pose a problem, and inadequate inflow may not only threaten the access, but also the limb. The resistance within longer grafts and HeRO grafts requires a suitable inflow, including a reasonable blood pressure. Hypotension should be carefully evaluated when these options are being considered.

A further consideration is that of transplantation. Younger patients with ESVA may have had a long history of renal replacement and multiple CVCs. In the example above, a groin line in the only patent iliac vein poses a great threat to future kidney transplantation.

It may be proposed that such patients are considered higher priority in organ

Stage ESVA

Potential options for definitive vascular access

1. No upper limb VA option a. A xillary vein stenosis a. S ubclavian vein stenosis b. B rachiocephalic/ innominate vein stenosis c. SVC stenosis

- Non-standard graft configurations (e.g. necklace) - Sharp recanalisation and HeRO - Surfacer + HeRO - Lower limb options

2. No upper limb VA option a . Iliac stenosis b. I VC stenosis

- Contralateral femoral vein transposition of AVG - Non-standard graft configurations - Sharp recanalisation and HeRO

3. No options at any site c .C VC via a non-standard site (e.g. translumbar, transhepatic, other) d. N o access options and treatment withdrawal

- Arterial arterial prosthetic loop - Axillary right atrial graft

Table 1. Stages of ESVA from Al-Shakarchi et al. The classification has arterial insufficiency (including hypotension) which has been removed from this table as different approaches are required.

allocation schemes, as a working transplant is their optimal option. When considering such patients for lower limb access, there is little to support avoidance of lower limb options, and many transplants have been performed successfully above patent ipsilateral loop thigh grafts.

For patients where attempts to gain access are unsuccessful—stage 3 ESVA—there are still solutions that can be found.

This group traditionally was treated with a translumbar or transhepatic CVC. For many, this was seen as a preterminal option, although data support reasonable short and mid-term survival.

A relatively simple definitive option in these patients is the arterial arterial prosthetic loop (AAPL), which is an interposition graft in the subclavian/ axillary artery.

This unique configuration requires special consideration when cannulated and cannot be used for drug delivery, but has been shown to have good patency with low complications.

Smaller series of axillary atrial grafts are published and advocated by some authors, however complications are greater and more significant.

In deciding treatment options, an access life plan should be defined, as highlighted in the recent Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines from the National Kidney Foundation. Where multiple options exist, these should be considered and staged with the simplest and safest option first, whilst retaining the possibility of further interventions later down the line.

The best approach to managing these difficult cases is with a multidisciplinary team, using a treatment utilising their experience and expertise, and chosen based on its applicability to the patient. The availability of surgical and radiological expertise is required not only for the index procedure, but also for many of these patients’ subsequent interventions and salvage procedures, conducted to maintain patency. An identified pathway should be defined with access to suitable facilities to allow this.

ESVA provides a very challenging problem for the vascular access surgeon, and the bad news is the incidence is likely to increase.

Fortunately, there are an increasing number of possibilities for treatment with innovative devices and techniques.

Historically, the prognosis was bleak for patients with ESVA, but by combining surgery and interventional radiology skills, the outlook is improving. As always in access, the approach used should be the right access, for the right patient, at the right time. This applies especially to ESVA, where the whole team’s input and detailed discussion with the patient are essential.

Nick Inston is a consultant transplant and vascular access surgeon at the University Hospital Birmingham NHS Trust, Birmingham, UK.

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September 2019 | Issue 83

Peripheral arterial disease

Statin medications associated with significantly lower amputation risk Patients with peripheral arterial disease (PAD) were significantly less likely to face amputation after surgical intervention if they were on statin medications, according to a newly released report in the Journal for Vascular Surgery (JVS). Those patients also had fewer deaths over the 88-month review period.

“STATIN USE INDEPENDENTLY and significantly improved overall survival and limb salvage in patients with PAD after intervention,” says lead author Gaurav Parmar. The retrospective analysis reviewed 488 patients undergoing either endovascular or open revascularisation for PAD at the University of Alabama in 2009–2010. The authors report that 41% of patients were taking a statin and 56% were taking antiplatelet medications.

Of the total patients, 191 were treated endovascularly, and 297 surgically. In this study, the use of statins was associated with improved survival at five years (89% vs.

78%, p<.001). Further, statin use at time of intervention was found to be significantly protective against amputation, with a hazard ratio of 0.31. Antiplatelet therapy was associated with improved survival, but not limb salvage.

“An important finding from this study is that the prevalence of both statin and antiplatelet therapy was low in our patient population, despite the known cardiovascular benefits,” Parmar comments. “This may be due to lack of physician awareness or a major focus on limb-related rather than cardiovascular outcomes.”

Several years ago, the Society for Vascular Surgery’s Vascular Quality Initiative (VQI) established the prescribing of antiplatelets and statins for vascular

An important finding from this study is that the prevalence of both statin and antiplatelet therapy was low in our patient population, despite the known cardiovascular benefits.”

Holden et al find no causal link between paclitaxel dose and all-cause mortality

The methodology underpinning the conclusion by Konstantinos Katsanos (Patras, Greece) et al that there is a positive dose-response relationship between paclitaxel and mortality is flawed, argues Andrew Holden (Auckland, New Zealand) and colleagues in a paper published in the Journal of Endovascular Therapy (JEVT). Holden and co-authors list the limitations they see in the summary level metaanalysis published in December 2018 in the Journal of the American Heart Association (JAHA), and call for physicians to “significantly modify the way vascular device trials are performed in the future”.

I

n the JAHA meta-analysis, Katsanos et al linked paclitaxel-coated balloons and paclitaxel-eluting stents to allcause mortality, reporting a significant increase in deaths at two and five years in the cohort of femoropopliteal disease patients exposed to the drug compared to those treated who were not. Holden et al write: “Although no plausible mechanism of action was identified, the authors postulated that the excess mortality was caused by paclitaxel”.

However, Holden and colleagues do not find this correlation with paclitaxel levels and mortality, and thus claim there is no causative link between dose and death.

On 15 March 2019, the US Food and Drug Administration (FDA) released an updated letter to healthcare providers detailing that while the results of their preliminary review of the JAHA metaanalysis data was ongoing, they had “identified a potentially concerning signal of increased long-term mortality in study

patients at discharge as its first national quality initiative.

The JVS article authors also recommend that statins be prescribed to PAD patients who have had a vascular intervention.

“We feel like the benefits of statin therapy are so critical to outcomes in the treatment of vascular disease,” notes Benjamin J Pearce, one of the authors, “that we have begun taking the responsibility of prescribing within our practice.”

The 2016 American Heart Association PAD guidelines recommend statin therapy for all patients with PAD on the basis of reduced cardiovascular morbidity and mortality (Class 1 recommendation). Statin therapy both lowers cholesterol levels and stabilises atherosclerotic plaque formation due to its anti-inflammatory properties.

For patients with PAD naïve to statins, the authors’ protocol involved starting 20mg simvastatin at the time of intervention, increasing this to 40mg in clinic at followup, and to 80mg if an indication for high-dose exists.

“Patients with PAD continue to receive suboptimal medical therapy compared with patients with coronary artery disease owing to a lack of physician awareness, presence of atypical symptoms, or a major focus on limb-related rather than cardiovascular outcomes,” Parmar said. “Efforts are ongoing within our vascular division to improve use of these medications across our institution.”

subjects treated with paclitaxel-coated products compared to patients treated with uncoated devices”. The statement also noted that each of the trials used “all-cause” mortality calculation methods that differed significantly and had the potential to influence the way those results were interpreted.

The three pivotal premarket trials evaluating paclitaxel-coated products for the treatment of peripheral artery occlusive disease that informed this statement—Medtronic IN.PACT SFA I and II; Cook Zilver PTX; and BD LEVANT 2 randomised controlled trials—each used a different methodology to calculate mortality. “To facilitate a direct mortality comparison between the three trials”, Holden and colleagues write that they “asked each of the companies to provide five-year mortality using the same proportional methods as used by Medtronic [calculated as the number of patients who died, divided by the number of

patients followed up to five years]”.

Explaining the rationale behind this strategy, Holden et al say: “This consistent methodology allowed for a direct comparison of product dose to test the dose-response theory proposed by the meta-analysis. The highest five-year mortality was found to be associated with the lowest paclitaxel dose device (Zilver PTX), while the lowest mortality was associated with the highest dose device (IN.PACT). It is our view that this directly refutes the causal relationship theory between paclitaxel dose and all-cause mortality.”

Using this proportional method, the investigators report no significant difference in the five-year mortality between paclitaxel-coated balloons compared to controls in the Medtronic IN.PACT and BD LEVANT 2 trials. The Zilver PTX drug-eluting stenr displayed a significant difference (p=0.008) between the arms. When the Zilver PTX randomised controlled trial five-year data are reanalysed by an intentionto-treat analysis, the mortality of the paclitaxel-eluting stent remains the highest (22.7%) of the three paclitaxel devices, but the mortality difference compared to the control arm (18.5%) loses its significance (p=0.45).

As patients previously lost to follow-up are contacted and potentially added into the analysis, the proportional calculation may differ (as the denominator, number of patients followed up to five years, will increase), though the study authors do not think this will change the outcome.

Commenting on these findings, Holden and colleagues say: “We believe it is likely, even with more complete patient

follow-up, that the lack of correlation between paclitaxel dose and mortality will persist”. They suggest Kaplan-Meier survival plots could be calculated in the future, if more data were collated.

As Holden et al believe the causation theory behind paclitaxel and mortality “now appears unlikely”, they suggest several alternative hypotheses to explain the original JAHA meta-analysis results, including performance and detection bias, trials being inadequately powered for mortality, significant target lesion crossover from the control to treatment arms, and patients lost to follow-up.

They conclude: “Perhaps the most important lesson from this paclitaxel debate may be the need to reconsider and significantly modify the way vascular device trials are performed in the future. We believe there should be an additional emphasis placed on adherence to guidelines-based medical therapy of all enrolled patients, as well as safety endpoints such as mortality. Greater effort must be made to reduce subjects lost to follow-up and properly classify the mortality status of those subjects who withdraw.

“It is only with well-conducted safety evaluations that we will completely clarify this issue regarding paclitaxel.

Given the known and undisputed benefits of paclitaxel coating on stents and angioplasty balloons, we owe it to our patients to pursue that truth before we restrict these devices from use.”

The medical community awaits an individual patient data meta-analysis to provide greater clarity regarding the alleged link between paclitaxel and mortality.

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September 2019 | Issue 83

MedTech Insights

Source: BIBA MedTech Aortic Segmentation Monitor

CE mark reinstated for Nellix endovascular aneurysm sealing system Endologix has announced that the CE mark for the Nellix endovascular aneurysm sealing (EVAS) system has been reinstated. The CE mark for the system was suspended on 22 January; now that it has been reinstated, Nellix will be made available for use at approved centres in a post-market clinical investigational setting outside the USA. Within the USA, Nellix continues to be an investigational device as part of the EVAS2 study.

A FEW WEEKS prior to the suspension of the CE mark, on 4 January, Endologix released a statement that it was taking “decisive action to optimise patient outcomes” with the Nellix system. In the statement, the company reported that unrestricted sales and use of the system would “cease immediately” and that Nellix would “only be available for use under clinical protocol with pre-screened patients that adhere to the current indications”. Further to the statement, Endologix voluntarily recalled all existing inventory and issued a field safety notification. Matt Thompson, chief medical officer of Endologix, said at the time: “We monitor the performance of the Nellix system through clinical trials, our complaint monitoring system, physician interaction and available publications. Our independently adjudicated data from the EVAS1 IDE clinical trial indicates that the Nellix system has performed well when used consistently with the current indications. However, data from recent Nellix publications leave us concerned that outcomes are suboptimal when the system is used outside current instructions for use.”

Last year, in the European Journal of Vascular Endovascular Surgery, Seamus C Harrison (Addenbrooke’s Hospital, Cambridge Hospitals University Trust, Cambridge, UK) and colleagues reported outcomes

for patients who underwent EVAS with the Nellix system at their centre (Cambridge University Hospitals Foundation Trust). They found that the system was associated with “poor outcomes” beyond the first two years following implantation, noting that “of the patients surviving more than three years, approximately half of the grafts have shown signs of failure”.

The authors add: “Diagnosis and management of proximal graft failure is challenging and often requires graft explant. Nellix is no longer routinely used at Cambridge University Hospital because of these problems.”

However, in this study, 29% of patients (161 overall) had anatomy outside the original instructions for use (IFU) for Nellix and another 25% had no other endovascular option (including branched or fenestrated endovascular aneurysm repair). The Endologix statement announcing the voluntary recall decrees that off-label use of Nellix has been occurring at “an unacceptable level, with the consequence of suboptimal results”.

Furthermore, in the statement, John Onopchenko, chief executive officer of Endologix, comments: “Ensuring patient safety and optimal clinical outcomes is our top priority, and the current level of off-label use of the Nellix system cannot continue if we are to protect and preserve the potential for transformative EVAS therapy. Taking these actions aligns

Source: BIBA MedTech Aortic Segmentation Monitor

with clinical practice standards, allows us to control off-label use, and will help us ensure appropriate application of the therapy.”

Nellix was designed to improve the long-term durability of endovascular aneurysm repair (EVAR) by reducing the incidence of endoleaks (all types).

Harrison et al report: “The system is based upon two balloon expandable stents attached to ‘endobags’ that are filled in situ with a soluble polymer that ‘seals’ the aneurysm”. They add that, when first introduced, Nellix had anatomical IFU that “were more liberal than other stent graft manufacturers, thereby increasing the applicability of minimally invasive repair”. Therefore, now that its CE mark has been reinstated, Nellix will be—albeit in a limited way—on the EVAR market.

Infrarenal abdominal aneurysm market in Western Europe

According to the BIBA MedTech Aortic Segmentation Monitor, 59% of all aortic procedures (20,932 overall) performed in Q1 (1 January–31 March) were for infrarenal abdominal aneurysms. Of these, 70% were performed with an endovascular approach. Elective repair was the most common indication for an infrarenal abdominal aneurysm procedure (of elective repairs, 75.5% were endovascular). See Figure 1.

In the overall infrarenal market, in Q1 2019, 8,622 devices were used.

Medtronic was the market leader with a market share of 42.8%. Of note, Endologix (with its AFX and Ovation

BIBA Briefings

ranges) had a market share of 4.9%.

See Figure 2.

How the CE mark for Nellix being reinstated will affect the western European infrarenal abdominal aneurysm market is unknown at present, but Endologix has claimed that it expects neither the suspension nor the reinstatement to “impact its previously communicated guidance for 2019”. In May 2019, Endologix reported that its global revenue for Q1 2019 was US$35.6m—a 15.8% decrease from Q1 2018 (which was US$42.3m). The company added, reaffirming its annual guidance, that it expects to have revenue of at least US$140m this year. Onopchenko comments: “Our first quarter financial and operational performance provides us with a solid foundation to accomplish our goals for the rest of 2019, as we continue to execute against our strategic plan and regain credibility and traction in the marketplace. We recently addressed the vast majority of our near-term debt maturities while increasing our liquidity position, allowing us to move forward with a singular focus on maintaining consistent delivery against our commitments. Those commitments include producing compelling evidence that demonstrates improved patient outcomes and supports the introduction of innovative products. I am very proud of what the team has accomplished thus far in 2019, and I strongly believe our evolving culture of accountability will allow us to maintain this level of focus and performance going forward.”

BIBA Briefings is an online platform (www.bibamedtech.com/bibabriefings) that gives an in-depth analysis of the latest market intelligence from BIBA MedTech Insights (www.bibamedtech.com). It also reviews the latest industry news and pipeline developments.

For editorial enquiries, please contact Dawn Powell: dawn@bibamedical.com For sales enquiries (including BIBA MedTech Insights), please contact Merveille Anderson: merveille@bibamedical.com

Issue 83 | September 2019

Complex aneurysms

Multidisciplinary approach to assessment of complex aneurysms is mandated A recent study concludes that the interplay of anatomical and physiological factors in patients with complex aneurysms renders conventional risk stratification tools “unhelpful”, and that a multidisciplinary approach to assessment is mandated. Furthermore, the investigators suggest it is “unusual” that a single major factor ultimately determines treatment modality.

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enjamin Patterson presented the results at the British Society of Endovascular Therapy 2019 Annual Meeting (BSET; 27–28 June, Wotton-under-Edge, UK), on behalf of Michael Jenkins and colleagues at the Imperial Vascular Unit, London, UK. The investigators describe that the interplay of morphology and physiology is “complex” and that these interactions “defy the creation of a standardised algorithm”. They explain that assessment is a continuous process of weighing many factors, and is often based on clinical judgement, concluding that physicians should aim for the “least risky, most durable solution possible”.

At the BSET meeting, Patterson discussed why this topic is important, noting that European guidelines recommend avoiding bias toward a certain treatment modality, and that the UKbased National Institute for Health and Care Excellence (NICE) draft guidelines use “fitness” to determine treatment, suggesting that open repair should be

carried out if the patient is “fit”, and no repair should be carried out if the patient is “unfit”, however there is “no validated way to stratify fitness,” remarked Patterson.

He suggested that aortic networks should provide all options.

While endovascular repair has been increasingly adopted in the treatment of complex aneurysms where previously only open repair was available, the investigators of this study sought to define factors that determine the modality of treatment employed using a retrospective cohort study, conducted at the investigators’ centre, using data from the year 2018–2019.

Patterson and colleagues identified consecutive patients operated on for suprarenal aortic aneurysms and thoracoabdominal aortic aneurysms in the specified time period. Physiological and anatomical data were collected from electronic clinical records and correspondence, and the primary reason for the modality of treatment selected was established. The Chi-squared test was used to examine differences between groups.

The investigators remark that there are four main factors governing the selection of treatment modality for complex aneurysms—physiology, morphology, urgency, and patient choice.

In this patient cohort, across types I–IV thoracoabdominal aortic aneurysms and juxtarenal/suprarenal aortic aneurysms, physiology was the main reason for treatment modality selection, followed by morphology and then urgency. They note that patient choice was never a primary reason for modality in this cohort.

Despite patients in the open and endovascular groups being of similar average age (71 and 73 years, respectively), open repair patients were more likely to have a good exercise tolerance, good pulmonary function, and less likely to have had previous abdominal surgery. Cardiac and renal status was similar in both groups, and anatomical and physiological reasons were equally cited as reasons for choosing treatment modality when the open and endovascular groups were compared.

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Of 136 complex aneurysms, 82 were operated on, of which 59 were I–IV or J/ SRAA. Five patients were turned down for repair by clinicans, three due to patient choice, 14 were awaiting repair, and two died waiting for repair.

On the type of surgery conduction, Patterson commented: “For extensive aneurysms, such as type I and type II thoracoabdominal aneurysms patients were much more likely to receive an endovascular treatment because of the extent of surgery required and the fact that they would be more likely to be rejected for surgery based on certain physiological parameters. In the type III group, there is more of an even split. This is explained by the fact that the type III group happen to be slightly fitter than the type I and type II group, which might be a function of the fact that patients with more extensive aneurysms have more extensive disease. If we look at the type IV thoracoabdominal aneurysms we can see that the majority were repaired open, and, looking at the notes for these patients, we can see that a lot of these have been turned down locally for endovascular treatment and had to be sent to our Vascular Unit at Imperial.”

Regarding the relatively small study cohort, Patterson outlined the benefits of the chosen sample size for this particular study: “If you look on a big data level, then what you miss is the complexities invovled, and you miss the constant and often subtle weighing up process between factors during the decision making process”.

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September 2019 | Issue 83

Advertorial

SPONSORED ADVERTORIAL

First patient enrolled in global CERAB study for the treatment of aortoiliac occlusive disease The first patient to be entered into the Covered Endovascular Reconstruction of the Aortic Bifurcation (CERAB) global study has undergone aortic bifurcation reconstruction stenting by using the CERAB technique as a preferential alternative to open surgery in the treatment of extensive vascular occlusive disease.

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he 56-year-old male patient was treated by Michel Reijnen, in the Rijnstate, Arnhem, The Netherlands. The patient was suffering from severe intermittent claudication due to a complete occlusion of the distal aorta and iliac arteries. Data on the CERAB technique and related patient outcomes will be entered into the study for this specific indication.

“The patient was suffering from a severe lesion from the aorta extending all the way into the common femoral artery on both sides,” Reijnen explained.

“He was offered an aorto-bifemoral bypass in another hospital but preferred minimally invasive surgery. We performed a bilateral endarterectomy of the common femoral artery followed by a CERAB procedure that went without events.” Two days after the procedure, the patient was discharged with normalised anklebrachial index, and at two-month follow-up with duplex ultrasound showed a patent reconstruction, with no symptoms.

The CERAB technique was first introduced by Peter Goverde (senior vascular surgeon at the ZNA hospital in Antwerp, Belgium) in 2009 to reconstruct the aortic bifurcation in a more anatomical and physiological fashion than the more conventional kissing stents that have been commonly used to treat aortoiliac occlusive disease (AOID).

Occlusive disease is one of the predominant diseases of the vascular system, and the aortic bifurcation is one of the main points where occlusions occur. In the past, a patient with AOID underwent major open surgery involving laparotomy and this is related to significant risk for morbidity and mortality, according to Reijnen who was the co-developer of the CERAB technique alongside Goverde.

Describing the CERAB technique, Reijnen said: “It is a minimally invasive alternative, because we work in the vessels themselves, in an endovascular manner. We recanalise the iliac arteries, and reconstruct the aortic bifurcation using balloon expandable covered stents.

With these stents, we are able to reconstruct the entire aortoiliac bifurcation in a tailor-made solution in the most optimal anatomical and physiological manner.”

At least three stents are used for CERAB. One BeGraft aortic (Bentley) balloon expandable covered stent of 12mm diameter is placed in the distal aorta, and is flared proximally according to the diameter of the healthy aorta for good wall apposition, and then two BeGraft peripheral stents, usually 8mm in diameter, are positioned in the distal 12mm portion of the aortic stent, and together these make a tight connection. “It is really a very tight connection of these three stents eliminating radial mismatch, and in this way we reconstruct the aortic bifurcation without inducing flow disturbances. Sometimes we extend distally to reach out over the diseased area,” said the vascular surgeon, adding that, “with the Bentley BeGraft stents, this is more feasible than with some alternative stents. The stent is made of cobalt chromium and its flexibility is impressive.”

CERAB is minimally invasive and avoids laparotomy and associated major complications,

Pre CERAB

Post CERAB

minimising admission time and time spent in Intensive Care. “Effectively, the CERAB technique involves all the advantages of an endovascular approach over open surgery,” added Reijnen.

Reijnen has extensive experience in performing the CERAB technique and his centre in Arnhem has now started an investigator-initiated prospective

New Zealand, Australia, Poland, Italy, France, The Netherlands, England, and Mexico. Previous studies have supported the CERAB technique in terms of high stent conformation. A study comparing kissing stents with the CERAB technique, published in the Journal of Vascular Surgery, concluded that, “although nitinol self-expandable stents have a high stent conformation, the lowest radial mismatch was found in the CERAB configuration using covered stents, supporting the hypothesis that the CERAB configuration is the most anatomical and physiological reconstruction of the aortic bifurcation.

Within the CERAB configuration, the two limbs are ideally positioned inside the tapering portion of the aortic cuff, minimising mismatch.” Another study that looked at three-year outcomes of CERAB for the treatment of extensive aortoiliac occlusive disease found that the technique is a safe and feasible option for the treatment of extensive aortoiliac occlusive disease with good three-year results regarding patency and clinical improvement. Thanks to these initial publications, and the data to be collected by the global study, Bentley hopes to show that the CERAB technique in combination with Bentley BeGraft stents is a mature and safe treatment option for patients with AOID.

The CERAB technique involves all the advantages of an endovascular approach over open surgery.” global study in order to gain more robust real-world data on the efficacy of these stent grafts for the aortic bifurcation indication. The study will document all CERAB procedures from participating centres using the Bentley BeGraft aortic and BeGraft peripheral stents.

The primary endpoint of the registry study is technical success and primary 12-month patency.

Secondary endpoints are patency rates, periprocedural morbidity, clinical improvement, quality of life, clinically-driven target vessel revascularisation and reintervention-rate.

The study will include 145 patients enrolled over two years who will be followed up post-procedure using medical imaging for five years. The study will include patients from the following countries:

References 1. G root Jebbink E, Grimme FAB, Goverde PCJM, et al. Geometrical consequences of kissing stents and the Covered Endovascular Reconstruction of the Aortic Bifurcation configuration in an in vitro model for endovascular reconstruction of aortic bifurcation. J Vasc Surg 2015;61:1306–11.

2. T aeymans K, Groot Jebbink E, Holewijn S, et al. Three-year outcome of the covered endovascular reconstruction of the aortic bifurcation technique for aortoiliac occlusive disease. J Vasc Surg 2018;67:1438–47

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September 2019 | Issue 83

Multidisciplinary care

The reactive and repetitive multidisciplinary CLI team Jihad Mustapha Comment & Analysis It is imperative that every medical institution has an interdisciplinary CLI team, argues Jihad Mustapha. Here, he exhorts the benefits of working in such a multidisciplinary team, and outlines how the circle of care concept can be applied to reduce rates of unnecessary major amputation.

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he most effective critical limb ischaemia (CLI) multidisciplinary team structure is comprised of multiple layers or groups of providers from a variety of areas, including surgical and endovascular revascularisation, podiatry, wound care, endocrinology, primary care, orthopaedics, cardiology, infectious disease and physical medicine.

The action of each group is reactive to the immediate need of the CLI patient.

The course of action in the treatment cascade is not linear; instead, it is both

repetitive and reactive. To transform the potentially catastrophic event of a CLI diagnosis into a patient with a successful outcome, the team must act in harmony and initiate the reactive cycle of therapy when a CLI patient receives treatment at the level that is most critical at any single point in time (Figure 1).

A provider will refer the CLI patient to the next most critical continuum for the secondary issue to be addressed (cascade of care). The CLI team must always be aware of and acknowledge that the CLI

patient’s therapy is not conclusive, and that the chance of recurrent disease is high. Therefore, heightened awareness and strict follow-up evaluation are required. Once a recurrent CLI event is discovered, the repetitive cycle must be initiated. For a patient with active CLI disease, there should never be a period of time where no form of therapy is being delivered. The average time it takes for a CLI patient to receive any type of first treatment or diagnostic testing has been reported to be nine days. This is unacceptable. Too much can happen in nine days to result in a poor outcome for a CLI patient. Therefore, the repetitive phase must be initiated as early as possible.

Any member of the CLI team can and should trigger the repetitive treatment cascade in the presence of: Recurrent rest pain Absent doppler pulse Occluded target vessel and lack of progression of wound healing Regression of wound healing Infection or sepsis. Note: Amputation is not always the answer here. Revascularisation and intravenous antibiotics must be tried first, unless the patient is in shock and the limb is not salvageable. Only then should amputation be performed without an attempt at revascularisation.

Once a CLI patient has been treated and has reached a stable form of the disease, such as wound healing, rest pain resolution and/or return to activity, the preventive phase of CLI therapy (in the circle of care) should be initiated by the CLI team. The CLI team members must

each provide their recommended medical treatment based on their specialty. Most importantly, the circle of care (preventive phase) should never be stopped. In fact, prevention should be started in the pre-CLI phase for patients who are Rutherford 1–3. Any form of peripheral arterial disease (PAD) should be preventively treated as early as possible to prevent the catastrophic outcomes that we know can happen to those patients that reach the CLI phase. Hence, there is an extreme need for a multidisciplinary CLI team to exist in every institution in the USA and around the globe.

CLI centres are a new concept, and have adopted the strategies discussed above. The success of any CLI centre is dependent upon the harmony of the members of the multidisciplinary CLI team. CLI centres’ outcomes have been shown to produce excellent outcomes with impressive reductions in major amputation.1,2 The future of effective CLI therapy lives in a cohesive and functional multidisciplinary team.

Jihad A Mustapha is the associate clinical professor of Medicine at Michigan State University COM, E Lansing, USA. He is also the CEO of Advanced Cardiac and Vascular Centers for Amputation Prevention, Grand Rapids, USA. References 1. Mustapha JA, Saab FA, Diaz-Sandoval LJ, Beasley R, McGoff T, Finton S, Heaney C, Adams G. The Peripheral RegIstry of Endovascular Clinical OutcoMEs (The PRIME Registry): Interim Analysis of the First 328 Subjects With Critical Limb Ischemia.

Vascular Disease Management. 2017;14(3): E55-67.

2. Raymond Dattilo, Alexandra Dattilo, Shawn Colby.

Outcomes of Patients Treated for Critical Limb Ischemia in an Outpatient Endovascular Center.

Vascular Disease Management 2018;15(6):E49-E52.

New West London Vascular and Interventional Centre opens, highlighting the importance of specialty centralisation The new West London Vascular and Interventional Centre at Northwick Park Hospital (Harrow, UK) has officially been declared open.

As of 25 June, 2019, patients who require vascular treatment will be able to benefit from the modern facilities and integrated approach, undergoing treatment in one location.

WITH BOTH VASCULAR surgeons and interventional radiologists working together under one roof, the hope is that patients will receive seamless and efficient care for a range of complex conditions, including specialist venous and aneurysm clinics, varicose vein care, diabetic foot care and minor treatments. The centre has been funded primarily by the London North West Healthcare Charity, which gave its largest single donation to date, at £1.5 million.

At the grand opening, Simon Crawford, deputy chief executive, London North West University Healthcare, said, “The reason we are here is down to professor Martin Malina, for championing the importance of vascular surgery, and for being a great advocate for the speciality.” He adds, “The new vascular and interventional centre will allow us to serve our patients locally and stop them being referred out. It also helps repatriate some patients, keeping them closer to home.”

“The work undertaken here underlines the importance of patient care, as it brings all cohort teams together in a more modern, fit-for-purpose environment,” concludes Crawford. Touching on why the Trust’s charity gave their single, largest donation, Vineta Bhalla, chair of the Charitable Funds Management Committee, said, “This new innovative vascular unit will help improve patient experience, providing an innovative one-stop-shop for

care, treatment and recovery. We are not a big charity, but we are grateful we can support projects such as these.”

The importance of modernised approaches to patient care was further emphasised by Martin Malina, clinical director of the vascular unit. “The important message is that with new evolving techniques and vascular centres comprised of high tech minimally invasive procedures, patients can be discharged the next day. We need centralisation, including an integration of vascular surgery and interventional radiology into a single unit to improve patient safety and welfare.”

Highlighting the importance of the geography of the department, he said, “This is a very clever choice of location in order for it to become an efficient integrated unit.” He added, “The unit is comprised of a blood flow lab, an imaging facility, a clinical and recovery centre, a angio-suite, as well as an educational centre.”

In terms of the venous centre, Malina estimated that 1,300 patients are to be treated there per year. He said that while the line service offers access to the blood vessels, the blood flow lab will process around 6,000 patients per year.

Before handing over to Henrik Sillesen, president of the European Vascular Society, Malina ultimately concluded, “We need to come together, not just as

surgeons or radiologists; we need to get truly integrated, and learn from the angiologists. In the future, we need vascular specialists [in order] to offer the best treatment, by moving away from the previous model to an integrated, modern approach.”

Alluding to his own experiences in the vascular field, Sillesen put forward the benefits of a large department leading to more opportunities for specialisation within the department, and less on-call frequency—which is important, he said, given the rising issue of physician burnout currently plaguing Europe. Lastly, Sillesen said that with a large department comes more opportunities for research, while it is easier to attract good commercial and public funding.

Speaking to Vascular News, Lorenzo Patrone, consultant interventional radiologist, reiterates the unique qualities of the new West London Vascular and Interventional Centre, “Of course, we have high-volume centres providing high quality care, but the team is key.

Both specialities are under the same roof and part of the same unit. This gives the interventional radiologists the possibilities to follow their patients clinically, while the vascular surgeons can improve their endovascular skills. It is the only one in Europe that properly merges each speciality, with a hybrid team working together to provide efficient care.”

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September 2019 | Issue 83

Transcarotid artery revascularisation

Final results of the ROADSTER 2 post-market approval study of TCAR Vikram S Kashyap, co-principal investigator of the ROADSTER 2 trial, presented the final 30-day outcomes of the post-market approval study in a late-breaking trial session at the Society for Vascular Surgery (SVS) Vascular Annual Meeting (VAM; 12–15 June, National Harbor, USA). The data show the sustained safety and efficacy of transcarotid artery revascularisation (TCAR) with Silk Road Medical’s Enroute system. In this interview, Kashyap speaks to Vascular News about the procedure, and how TCAR trialists are hoping to make an impact for patients needing carotid revascularisation.

What is the idea behind TCAR, and how does it differ from other treatment strategies?

Transcarotid artery revascularisation is very different to other treatment strategies, such as carotid endarterectomy [CEA] or stenting [CAS]. This is a carotid stenting procedure, but it is via a different approach—a transcarotid approach—and the critical issue is that there is a protection mechanism to prevent cerebral embolisation which is using an extracorporeal reversal flow system, and importantly, clamping of the carotid artery below the sheath insertion that leads to obligate reversal flow in the carotid system during the intervention. So, this is very different to transfemoral CAS in that one does not have to navigate the aortic arch and the carotid arteries to get the devices there.

Secondly, and probably more importantly, there is absolute protection before any intervention is done; before a wire even crosses the lesion, reversal flow is accomplished so that debris is caught and removed via the system, and the blood is given back in the femoral vein. CEA, which has been our gold standard for decades, is an operation that requires a longer incision and the interruption of blood flow temporarily. It is a longer

procedure and a procedure that is a bit more intricate.

Following the initial ROADSTER 1 trial, what was important when considering the study design and endpoints of this post-market approval study?

There are a couple of important things to consider in terms of ROADSTER 1 and 2. Firstly, the pivotal study had a small group of patients, while ROADSTER 2 had a much bigger cohort, and with a considerable number of new operators. ROADSTER 1, for which I was also an investigator, consisted of a very small group of investigators, while the second trial includes 87 investigators—with 80% of them being new to TCAR, and they provided 70% of patients enrolled. This postapproval study was mandated by the US Food and Drug Administration (FDA), to see what the outcomes would be in a broader group of individuals, so that was part of how we designed the study. Secondly, there was concern that we could not replicate the data of ROADSTER 1 because it was such a select group of proceduralists, and so I think all of us are excited that the outcomes of ROADSTER 2 were as good, if not numerically better. I think therefore it is important to acknowledge the ROADSTER 2 investigators, who were phenomenal.

How do the final 30-day outcomes of ROADSTER 2 compare to the results of the previous trial?

I would suggest that the data are analogous, but it is not necessarily fair to compare the two studies and outcomes directly, as that was never the purpose of ROADSTER 2.

Nevertheless, I think one can say that in a raw group of investigators with a fairly diverse group of patients, that we did get broadly similar results to ROADSTER 1.

I am impressed that we continued to have a very low event rate. Initially we thought that our good early results were due to the experienced investigators doing the early cases and getting great results. It actually turned out that even as we progressed and had more sites come on board with their patients, we still had outstanding outcomes. In ROADSTER 1 there was a total stroke/death rate in the pivotal group of 1.4%, and now in ROADSTER 2 this is 0.8%, which I think is very compelling. If you look at stroke death and myocardial infarction, it was 3.7% in ROADSTER 1 and now in ROADSTER 2 with 632 patients in the per-protocol group, the total number is 1.7%—11 patients. This number includes four strokes, one death and six with myocardial infarction, and the death importantly was not stroke-related but rather the patient had a ruptured aneurysm a few weeks after the procedure.

So, neurological death rate was 0, in these 632 patients, and I think for any carotid revascularisation trial that is very impressive, especially a trial using carotid stenting.

The reported success rate was high, despite the majority of operators being new to this procedure. Why do you think that is, and do you think this adds particular value to your outcomes?

Firstly, one has to credit Silk Road and their training programme, where there was a very carefully thought-out plan on how to get new surgeons comfortable and expert at this technique—I think that is important to mention.

Also relevant to that fact is that many of my colleagues who were co-investigators on ROADSTER 1 proctored new surgeons and gave them our best practices that we had learned in the pivotal trial and in the continued access. Thirdly, I think you can also say that perhaps this technique is pretty resilient, meaning this novel technology allows a new adopter to get pretty good fairly quickly.

The learning curve is in other words short, and steep, as people get good within five cases or so, and are able to get outstanding outcomes.

Will ROADSTER 2 continue to follow up its patients in order to report on longer-term outcomes?

Yes, a one-year follow-up study is already in the works, that I am leading along with a couple of my coinvestigators. We hope to report on this next year, and give some insight into the durability of TCAR. It is interesting that—as opposed to stenting in other locations—after the first 30 days, if there is not a significant problem the issue of restenosis in the carotid bifurcation has not come up in other carotid stenting trials.

So if a patient does not have an early deleterious outcome, it is likely that they will not have any. This is the thing that is maybe most exciting about this follow-up study: that there hopefully will be a very low rate of reintervention, as opposed to when you are talking about the femoral artery or the renals, or even the coronaries.

In terms of next steps, I believe we are at the point now where we need to do a prospective controlled trial. We have shown in a pivotal trial and a single-arm registry that TCAR is safe, technically feasible and adoptable by new surgeons, so I think a head-to-head comparison is the next step. Obviously, the narrative has now changed a bit. Three or four years ago, that comparative trial would have been TCAR versus CAS via transfemoral approach, and now I think we are at a point where we are instead thinking about TCAR versus carotid endarterectomy.

Large real-world dataset finds TCAR compares favourably with CEA for carotid artery disease patients

Mahmoud Malas (San Diego, USA) presented, for the first time, updated results from the TransCarotid Artery Revascularisation (TCAR) Surveillance Project at the Society for Vascular Surgery (SVS) Vascular Annual Meeting (VAM; 12–15 June, National Harbor, USA). Malas distilled the data highlights for Vascular News, providing “strong evidence” on the safety and effectiveness of TCAR, which showed lower odds of composite in-hospital stroke, death and myocardial infarction compared to carotid endarterectomy (CEA), as well as lower odds of one-year mortality.

What is the TCAR Surveillance Project?

The TCAR Surveillance Project is sponsored by the Society for Vascular Surgery’s Vascular Quality Initiative, or VQI. The main objective of this trial is to monitor the safety and effectiveness of TCAR and compare it to the gold standard carotid endarterectomy in a real-world setting. The main outcome measures are stroke or death at one year, while the secondary outcome measures

are myocardial infarction, stroke and death at 30 days.

TCAR is a hybrid procedure inspired by carotid endarterectomy. A small cut down is made at the base of the neck, and a stent is directly placed into the carotid artery while reversing the blood flow to protect the brain from potential embolic events. The main benefit of this procedure are avoiding the tortuous and potentially atherosclerotic arch, providing a carotid endarterectomy-like

protection by clamping the common carotid artery, performing all parts of the procedure under robust flow dynamic reversal protection, and by easing the procedure by having a direct access, shorter wires, catheters and stent delivery systems.

What were the key highlights of the analysis?

This is the largest study to date evaluating the outcome of TCAR,

performed in a little over 5,700 patients, in comparison to the gold standard carotid endarterectomy. Patients undergoing TCAR were older, more likely to be symptomatic, were more likely to have severe co-morbidities, and also had higher rates of anatomical risk factors. In matched analyses, there was 64% odds ratio reduction in mortality as well as 53% odds ratio reduction in the composite outcome of stroke, death and myocardial infarction in the TCAR group in comparison to carotid endarterectomy. There was also a 23% reduction in hazard ratio of one-year mortality in the TCAR group.

How do you think these data will impact the treatment of carotid disease?

I believe the study provides strong evidence on the effectiveness and safety of TCAR. Larger studies with longer follow-up are needed to confirm our findings and evaluate the indication of this procedure in normal risk patients.

Issue 83 | September 2019

CX 2019: A Medical Student’s Perspective

This year at the Charing Cross Symposium (CX; 15–18 April, London, UK), a student essay competition was open to delegates attending the session focused on recruitment to vascular management: An Introduction to Vascular Surgery. Here, medical student Lucy Belk (University of Leeds, Leeds, UK) gives her report of this event in the essay that won the competition.

W

ith the introduction of vascular surgery as an independent specialty from General Surgery in the UK in 2013, there has been a significant reduction in the number of candidates applying to the specialty. Perhaps partly attributable to the limited exposure to the specialty during medical school and throughout foundation and core training, the impact that this may have on the shape of vascular surgery in the future is a very real concern. The Rouleaux club, the UK Vascular trainee’s society and The Vascular Society of Great Britain and Ireland set about reversing the trend of falling application numbers by increasing exposure to and involvement in the specialty. In a combined initiative between the Rouleaux club, The Vascular Society of Great Britain and Ireland and the Charing Cross Symposium, “An Introduction to Vascular Surgery” was established. Born out of a need to address the lack of exposure to vascular surgery amongst medical students, foundation doctors and core trainees, the one-day event is hosted annually at the renowned Charing Cross Symposium, held at Olympia London.

This year the course proved so popular that it ran twice over two days at the symposium, with over 50 delegates from all over the globe in attendance across both days. The course aimed to give hands-on training in surgical techniques, practical demonstrations and advice from current trainees—and this year’s course did not disappoint.

Sophie Renton, consultant vascular surgeon whose accolades include sitting on the Specialist Advisory Committee for Vascular Surgery which oversees vascular surgery training in the UK, chaired the day and delivered the opening address. Delegates heard her speak openly about her journey to vascular surgery, including addressing aspects such as having a family alongside a career—often a concern to students and young doctors, despite recent campaigns in social media from the Royal College of Surgeons to #changethenorm surrounding women in surgery. She went on to give an overview of the programme for the day, sparking excitement and quashing any trepidation of being a medical student or junior doctor at such a large and prestigious conference and setting the tone for a really great day.

Vascular surgery trainee and academic clinical fellow George Dovell, who was responsible for much of the organisation behind the programme, extended the warm welcome before the day was underway with a talk from Ellie Atkins, ST4 in the East of England.

She gave an overview of what exactly vascular surgery is and what it encompasses, highlighting the unique breadth of the specialty.

Delegates then heard about vascular surgery from a junior’s perspective from Claire Dawkins, a vascular surgery trainee and surgeon in the Royal Air Force, with an opportunity to ask questions about all aspects of the training programme, and for those who were interested, questions about military medicine too.

Hands-on activity

Trainees Dovell and Atkins performed a step-by-step demonstration of vascular anastomosis using surgical models. Delegates spent time honing their suturing skills in pairs and getting valuable feedback from the surgical trainees, with all participants successfully completing their first vascular anastomosis. With some naturals amongst the delegates, Atkins and Dovell took us

through suturing a patch onto a vessel—making it look deceptively easy. With not quite so much ease as the vascular anastomosis, all delegates rose to the challenge to produce some impressive patch angioplasties. Very often, students are spoon-fed steps of a procedure without knowing the reasoning behind, so it was nice for Dovell and Atkins to address some of the ‘why’s’ behind the techniques used in vascular surgery, particularly with regards to longitudinal incisions to avoid stenosis.

With vascular anastomoses proving hungry work, food and a chance to network with other delegates and exhibitors arrived at just the right time; with offers of macaroni cheese and bangers and mash lining the stomachs of the cohort of future surgeons.

The afternoon session began with a talk from surgical trainee Dennis Lui, who addressed all things portfolio

Lucy Belk

Delegates spent time honing their suturing skills, [...] successfully completing their first vascular anastomosis.” related. He gave essential tips on what to include in a surgical portfolio and how best to practically compile it, inspiring me to determine the whereabouts of all those certificates from my early undergraduate years that I thought I would never need. Lui addressed delegates questions surrounding formatting of the portfolio and preferred methods of keeping logs of surgical procedures. In my experience, portfolios tend to be something that medical schools are poor at mentioning until late on in the undergraduate curriculum, by which time myself, like many others have misplaced certificates or failed to keep logs up to date, so it was refreshing to have someone take time to explain the importance of a well-kept portfolio.

For those delegates who were not already sold on vascular surgery as a career from the morning’s activities, an Association of Surgeons in Training

Vascular surgery training

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communications representative and ST3 Leanna Erete continued the afternoon with a compelling talk entitled “Why choose vascular surgery”, highlighting her favourite aspects of the specialty.

The delegates then undertook a tour of the symposium, under the guidance of Atkins. For many delegates, CX was a completely new experience, so the tour was a privilege. Students and trainees are readily encouraged to attend conferences and symposia, yet too often the medical community fails to recognise what a daunting prospect this can be for those whom it is their first experience. Which stands can I approach? Which talks should I attend? Can I take this brochure away with me? Atkins encouraged us to get involved and ask questions, settling that inner Imposter Syndrome feeling. The first stop was a station showcasing basic venous duplex skills offering a chance to get hands-on with the equipment, with human volunteers under the guidance of experienced vascular scientists from the Imperial College Healthcare NHS Trust. These newly acquired duplex skills were then put to good use in an ultrasound-guided cannulation workshop using handheld portable ultrasound scanners—a great opportunity for students and trainees to be hands-on with innovative new technologies and to speak to some of the exhibitors at the symposium.

A particular highlight of the event for myself was a talk on Thoracic Outlet Syndrome by senior surgeon John Thompson. I particularly enjoyed his interpretation of the syndrome as one with either an arterial, venous or nervous cause rather than just a syndrome alone. The talk was really brought to life with some case studies

Above: A first attempt at vascular anastomosis completed during the surgical skills workshop.

and illustrated by some interesting radiology.

With the afternoon’s activities drawing to a close, there was just enough free time for us to visit other stands, exhibitors and talks at the symposium. It was a really great opportunity to get hands-on with technology and hear about breakthroughs that could easily be integrated into clinical practice within my career. The course finished with closing remarks from Renton and a chance for any final questions.

Overall, the course was a resounding success and I am pleased to say that I have made contacts with other like-minded students and junior doctors from across the UK. I especially enjoyed the hands-on opportunities with a chance to gain feedback from professionals. As an aside, and although perhaps not directly intended by its organisers, I was really pleased to see the number of female surgeons facilitating the course and at the symposium as a whole. This really promoted the message of women in surgery. It was a privilege to be a part of one of the largest vascular meetings in the world, showcasing the very best of vascular surgery. I left the course feeling even more inspired to pursue a career in vascular surgery and with much more guidance on how to achieve this. Thank you very much to all that were involved in this unique and successful programme—I sincerely look forward to seeing you all next year at the 42nd Charing Cross Symposium.

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September 2019 | Issue 83

Market watch

Product News MagicTouch PTA sirolimus coated balloon granted breakthrough device designation by FDA

Concept Medical has been granted breakthrough device designation from the US Food and Drug Administration (FDA) for its MagicTouch percutaneous transluminal angioplasty (PTA) sirolimus drug-coated balloon (DCB) catheter, used in the treatment of peripheral arterial disease (PAD) in infra-popliteal lesions. The first breakthrough device designation received by Concept Medical was on 30 April 2019 for its MagicTouch sirolimus-coated balloon, for the treatment of coronary arterial disease (CAD) in patients with in-stent restenosis.

Concept Medical has pioneered the sirolimus drug delivery platform technology (Nanolute Technology) which has been used in more than 30,000 patients worldwide. The MagicTouch PTA sirolimus-coated balloon is developed using this Nanolute Technology for use in PAD. In an ongoing clinical study (XTOSI), associate professor Edward Choke, principal investigator of the trial and chief of Vascular Surgery, Sengkang General Hospital, Singapore, said, “XTOSI study is the world’s first pilot study to investigate the safety and efficacy of novel MagicTouch PTA sirolimus drug-coated balloon in the treatment of below the knee arterial lesions in addition to femoropopliteal lesions. The majority of patients enrolled had major comorbidities (diabetes and end stage renal failure) and the indication for angioplasty was for severe critical limb ischaemia (more than 90% had the most severe Rutherford scores of 5 or 6). The extent of peripheral arterial disease treated was also severe, and about 80% of patients did not have any patent below the knee arteries before angioplasty.

“I am very encouraged by the excellent results so far in these challenging cohort of patients. Device and technical success were both 100%.

Freedom from device and procedure related mortality was 100%. Limb salvage rate at 30 days was 97%. At six months, freedom from clinically driven target lesion revascularisation (TLR) was 91%; and primary patency, independently and blindly assessed by duplex ultrasound, was 82%. I did not encounter any distal embolization or ‘slow flow phenomenon’ after application of sirolimus-coated balloon in below the knee vessels.”

Sahil Parikh, an interventional cardiologist and associate professor of Medicine and director of Endovascular Services at the Columbia University College of Physicians and Surgeons (New York, USA) says, “The breakthrough designation demonstrates

how important it is for us to have new technologies for below the knee intervention. Patients with critical limb ischemia (CLI) represent an enormous burden to our healthcare system and comprehensive care for these patients begins with effective revascularisation.

The MagicTouch PTA will hopefully bring us closer to our goals of reducing amputations in the USA and the world.”

Under the programme, the FDA will provide Concept Medical with priority review and interactive communication regarding device development and clinical trial protocols, through to commercialisation decisions.

agency’s mission to protect and promote public health.

An acute type A dissection is a life-threatening condition that requires emergent repair. Today’s standard surgical treatment is associated with a high rate of mortality and reintervention rates due to malperfusion and continued growth of the aorta. The AMDS complements the current surgical repair without adding significant time or complexity to the procedure.

It’s designed to reduce the risk of mortality and reoperations by treating malperfusion and inducing positive aortic remodeling.

Ali Shahriari (West Palm Beach, Florida, USA), CEO of Ascyrus Medical, said: “Receiving Breakthrough Device Designation will accelerate our efforts and partnership with the FDA to secure a US approval for the AMDS.”

Ascyrus Medical Dissection Stent

Ascyrus dissection stent receives breakthrough approval from FDA

Ascyrus Medical has announced that it has received Breakthrough Device Designation from the US Food and Drug Administration (FDA) for its Ascyrus Medical Dissection Stent (AMDS) to treat acute Type A aortic dissections. This designation underlines the clinical importance of the AMDS and continues the advancement of the technology globally.

Ascyrus Medical conducted the largest prospective, monitored, type A dissection trial (DARTS) with patients enrolled in Canada and Germany. The results have shown a significant reduction in mortality and re-interventions along with effective malperfusion management, without any device related adverse events.

The FDA’s Breakthrough Devices Programme is intended to accelerate the regulatory review process for certain medical devices and device-led combination products that provide a more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases and conditions.

The goal of the programme is to provide patients and healthcare providers with timely access to important breakthrough medical devices by accelerating their development, assessment, and review, while preserving the statutory standards for premarket approval, 510(k) clearance, and de novo marketing authorisation, consistent with the

Endologix receives FDA approval for chEVAS IDE study and signs distribution agreement with Boston Scientific

Endologix has announced the investigational device exemption (IDE) approval from the US Food and Drug Administration (FDA) to commence a new pivotal study to evaluate the safety and effectiveness of the Nellix Chimney EndoVascular Aneurysm Sealing System (chEVAS) for the endovascular treatment of complex abdominal aortic aneurysms (AAA). The company also announced an exclusive distributor agreement with Boston Scientific, to distribute Endologix products in China.

The chEVAS system is an endovascular abdominal aortic aneurysm therapy designed to combine the Nellix 3.5 endograft with parallel visceral stents to enable treatment of patients with juxtarenal, pararenal, and suprarenal AAA. The application of endovascular aneurysm sealing (EVAS) for patients with complex aneurysms will offer innovative new technology to a group of patients that are underserved by the current standard of care.

John Onopchenko, Chief Executive Officer for Endologix, commented, “We are pleased to receive IDE approval from the FDA to begin this study, which will recruit 120 patients with complex AAA in up to 50 centres, both in the USA and internationally. This approval marks another step forward on our path to reestablishing durable, predictable growth through a continued focus on execution

and evidence-driven differentiation.”

An agreement announced by Endologix names the Boston Scientific Corporation as the exclusive distributor for Endologix products in China. The long-term agreement includes distribution rights to Endologix’ current endovascular aneurysm repair (EVAR) and endovascular aneurysm sealing (EVAS) products, as well as the right of first negotiation for future product offerings.

“We are excited to partner with Boston Scientific to bring next-generation abdominal aortic aneurysm solutions to patients in China,” says Onopchenko.

“China is one of the largest and fastest-growing EVAR markets in the world, representing an exciting market opportunity. We look forward to building our brand in this important market by leveraging the Boston Scientific team’s extensive experience introducing new products for patients suffering from vascular disease.”

As part of the agreement, Boston Scientific plans to invest in building a dedicated sales team to commercialise the Endologix products and drive adoption.

Additionally, Endologix will provide commercial and clinical support and training to the Boston Scientific team, with the goal of ensuring that the best possible clinical outcomes are realised.

Boston Scientific expects to begin selling these products upon local regulatory approval and subsequent commercial launch of the first product, anticipated in 2021.

The current portfolio of Endologix products includes the Ovation iX Abdominal Stent Graft and the AFX2 Endovascular Abdominal Aortic Aneurysm System, both of which are minimally-invasive solutions to repair aortic aneurysms and have received US FDA clearance and CE mark.

FDA notifies BD that Lutonix paclitaxel balloon PMA application for below the knee “not approvable in current form”

The US Food and Drug Administration (FDA) have denied BD premarket approval (PMA) for the company’s Lutonix drug-coated balloon (DCB) in the treatment of peripheral arterial disease (PAD).

Speaking in the company’s third quarter conference call on 6 August, BD CEO Vincent Forlenza told analysts: “Regarding our FDA, PMA submission for Lutonix below the knee [BTK], as you are all aware, we have been working with the FDA in a collaborative review process. Subsequent to the FDA Advisory Committee meeting on paclitaxel, the statutory review time for our BTK PMA submission concluded, and the FDA notified us that our PMA was not approvable in its current form.

“While this determination was based on the clinical evidence provided todate, we continue to review, collaborate and align with the FDA on the path forward regarding our submission, including the need to potentially provide additional clinical data.

“As a result, the approval process

Issue 83 | September 2019

Market watch

Product News timeline has extended out from our previous expectations and we no longer expect approval this calendar year. We will keep you informed as we work with the FDA and make further progress.”

Paclitaxel devices have come under regulatory scrutiny in the last eight months, following the publication of a meta-analysis in the Journal of the American Heart Association (JAHA) by Konstantinos Katsanos (Patras, Greece) and colleagues reporting an increased association of death when paclitaxel devices are used in the lower leg. The FDA analysed all available clinical randomised controlled trials or singlearm registries conducted with agencyapproved devices with at least two year follow-up. The investigation compared drug-eluting or coated devices with noneluting or coated devices.

At two years, the observed mortality rates for the paclitaxel-coated device group were higher for the Zilver PTX (Cook Medical) trial, Levant 2 (evaluating BD’s Lutonix DCB), and IN.PACT SFA I and II trials (looking at Medtronic’s Admiral DCB) in the FDA’s own analysis.

On the same call, the company reaffirmed its full-year revenue and earnings forecasts, and reported quarterly revenues of US$4.35 billion for the third fiscal quarter (which ended 30 June this

year). According to a BD press release, this represents an increase of 1.7% over the prior-year period. The company state that on a comparable, currency-neutral basis, revenues increased 5.7% over the prior-year period.

Rivaroxaban recommended

by NICE for peripheral and coronary artery disease patients

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

Publication of this NICE draft is based on evidence from the COMPASS study, the largest Phase III study with rivaroxaban (27,395 patients). This study showed that rivaroxaban vascular dose, 2.5mg twice daily combined with aspirin 100mg once daily, statistically significantly reduced the risk of the

composite of cardiovascular (CV) death, stroke or myocardial infarction (major adverse cardiovascular events; MACE) by 24% (relative risk reduction, ARR: 1.3%) compared with aspirin 100mg once daily alone amongst patients with stable atherosclerotic vascular disease (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; p<0.001).

In the COMPASS trial, for patients with stable CAD, addition of rivaroxaban 2.5mg twice daily with aspirin 100mg once daily lowered major adverse cardiovascular events compared with aspirin once daily (347 [4%] of 8313 vs. 460 [6%] of 8261; HR 0·74, 95% CI 0·65–0·86, p<0·0001). Moreover, patients with PAD who received rivaroxaban 2.5mg twice daily combined with aspirin 100mg once daily, also had fewer major cardiovascular events compared with the aspirin 100mg once daily alone group (126 [5%] of 2492 vs. 174 [7%] of 2504; HR 0·72, 95% CI 0·57-0·90, p=0·0047).

Rivaroxaban is an anticoagulant that targets Factor Xa, an enzyme which acts at a key point in the blood clotting process, inhibiting its ability to generate thrombin. NICE are recommending use of rivaroxaban as part of a dual pathway approach (in combination with aspirin) to prevent atherothrombotic events in patients who are at high risk of such events. Coronary artery disease patients who are at high risk of ischaemic events are defined by NICE as those aged 65 or over, patients with atherosclerosis in at least two vascular territories, or those

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presenting risk factors such as smoking, diabetes, kidney dysfunction, heart failure or a history of stroke.

Derek Connolly, COMPASS trialist, consultant interventional cardiologist and honorary senior clinical lecturer at Birmingham City Hospital (Birmingham, UK) said: “The COMPASS trial showed that adding rivaroxaban vascular dose to low-dose aspirin significantly reduced vascular events. The large reduction in events [such as strokes], outweighed the increase in major bleeding events seen.

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

“Rivaroxaban vascular dose in combination with aspirin is the first treatment of its kind for this patient population and this recommendation from NICE provides clinicians with an important additional option for treating patients at risk of major adverse cardiac events such as cardiovascular death, stroke or myocardial infarction.”

Publication of the NICE draft for rivaroxaban follows approval by the European Commission (EC) in August 2018 for the regimen of rivaroxaban 2.5mg twice daily plus aspirin 75– 100mg once daily for the prevention of atherothrombotic events in adult patients with CAD or symptomatic PAD at high risk of ischaemic events.

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September 2019 | Issue 83

Market watch “These products are advertised as not harmful, and many e-cigarette users are convinced that they are just inhaling water vapor,” Caporale says. “But the solvents, flavorings and additives in the liquid base, after vaporisation, expose users to multiple insults to the respiratory tract and blood vessels.” Caporale adds that further studies are needed to address the potentially adverse long-term effects of vaping on vascular health.

Clinical News BASIL-3 resumes randomisation

The BASIL-3 study, which was halted in response to findings reported in the Journal of the American Heart Association (JAHA) that paclitaxelcoated and –eluting devices were associated with an increased mortality signal when used in the femoropopliteal arteries, is on course to resume in September 2019.

Following the announcement that the trial is set to continue, the Vascular Society for Great Britain and Ireland have provided an update on the trial’s progress. In a news release, the society state: “Based on the aggregate data we have so far on the 411 patients who had been randomised at the time we paused recruitment in December 2018, our statistical colleagues tell us that, maintaining 90% power and a minimum of two-year follow-up (as per the original protocol), we will probably need just short of 500 patients to answer the original question.

“In addition, in concordance with advice from MHRA [Medicines and Healthcare products Regulatory Agency] (and FDA [the US Food and Drug Administration]), we are discussing with NIHR HTA [National Institute for Health Research Health Technology Assessment], and other stakeholders, the possibility of extending follow-up to a minimum of five years (to look at the late mortality).”

The FDA has been in touch “very recently” with the British Society of Interventional Radiology (BSIR) regarding a data sharing agreement. The news release on the Vascular Society for Great Britain and Ireland’s website states, “We will be discussing their approach and proposals at our next TMG [trial management group] meeting in September”.

US e-cigarette study confirms impact of vaping on vascular function Inhaling a vaporised liquid solution through an e-cigarette, also known as vaping, immediately impairs vascular function, even when the solution does not include nicotine, according to the results of a new study published in Radiology.

E-cigarette use is on the rise.

According to the Centers for Disease Control and Prevention, more than nine million adults in the USA use e-cigarettes, and vaping has become especially popular among teenagers.

In addition, the 2018 National Youth Tobacco Survey reported that in 2018, more than 3.6 million middle and high school students were using e-cigarettes.

“The use of e-cigarettes is a current public health issue because of widespread use, especially among teenagers, and the fact that the devices are advertised as safe despite uncertainty about the effects of long-term use,” says

International Cardio begins first-in-human trial of its highintensity ultrasound system

Alessandra Caporale (Philadelphia, USA), a post-doctoral researcher in the Laboratory for Structural, Physiologic and Functional Imaging (LSPFI), which is directed by senior author and principal investigator of the study, Felix W Wehrli (Philadelphia, USA). The research was funded by the National Heart, Lung, and Blood Institute (NHLBI).

The authors revealed that e-cigarette inhalants, upon vaporisation of the e-cigarette solution, contain potentially harmful toxic substances. Once inhaled, these particles can reach the alveoli of the lung, from where they are taken up by the blood vessels, thereby interfering with vascular function and promoting inflammation.

To study the acute effects of vaping on systemic vascular function, the researchers performed a series of MRI exams on 31 healthy non-smoking young adults (mean age 24; 14 women) before and after nicotine-free e-cigarette inhalation.

The e-cigarette liquid contained pharmagrade propylene glycol and glycerol with flavouring, but no nicotine.Using novel multi-parametric MRI protocols developed

by Michael C Langham (Philadelphia, USA), one of the co-authors of the study, scans of the femoral artery in the leg, the aorta and brain were performed before and after a single vaping episode equivalent to smoking a single conventional cigarette.

For the femoral artery MRI, blood flow in the upper leg was constricted using a cuff and then released; the brain MRI was conducted in the sagittal sinus, during a series of thirty-second breath holds and normal breathing.

Comparing the pre- and post-MRI data, the single episode of vaping resulted in reduced blood flow and impaired vascular reactivity in the femoral artery, in which a 34% reduction in flowmediated dilation—or the dilation of an artery mediated by blood flow increase— was found. There was also a 17.5% reduction in peak flow and a 25.8% reduction in blood acceleration.

These findings suggest impaired function of the endothelium (inner lining of blood vessels). Moreover, a 20% reduction in venous oxygen saturation is indicative of altered microvascular function. The researchers also found a 3% increase in aortic pulse-wave velocity, a measure of arterial stiffness, or the rate at which pressure waves move down the aorta.

International Cardio Corporation (ICC) announced that it has achieved the first human use of its high-intensity focused ultrasound (HIFU) system designed to treat peripheral vascular disease (PVD).

The Minneapolis-based company said its HIFU Synthesiser system is undergoing a 15-patient safety study in The Netherlands to investigate its feasibility and safety for the treatment of atherosclerotic plaques. The system uses high-intensity ultrasound to noninvasively treat vulnerable and occlusive plaques in peripheral arteries to reduce stroke mortality and improve the quality of life for those suffering from PVD. “The potential for noninvasively ablating and stabilising vulnerable vascular plaques is a compelling opportunity to both reduce stroke risk and deliver better outcomes with higher patient safety than current treatment options for patients suffering from PVD,” says ICC chief operating officer David Lee in a news release.

The safety study is the first step toward achieving the CE mark and FDA approval of the HIFU Synthesiser.

On The Netherlands Trial Register website, the investigators summarise their study: “Current treatment of lower extremity peripheral arterial disease consists of risk factor modification, exercise therapy and pharmacological treatment initially, but intervention is frequently needed when patients are significantly disabled. Interventional treatment is invasive, either surgical or endovascular. This study investigates a new non-invasive technique that uses high-intensity focused ultrasound to treat atherosclerotic arterial disease.”

The primary endpoint of the study is the 30-day major complication rate, which is a composite endpoint that includes the 30-day major adverse limb event rate and the 30-day mortality rate.

Secondary outcomes assessed include a range of technical, MRI, echo-duplex, clinical, and quality of life parameters.

Reflow Medical enrols first patients in DEEPER OUS Spur stent trial

Reflow Medical announces the first patients have been enrolled in its DEEPER OUS clinical trial using the Temporary Spur Stent System.

DEEPER OUS is a 100-patient prospective, non-randomised, multicentre trial designed to assess the safety and efficacy of the Temporary Spur Stent System compared to a meta-analysis of published data for percutaneous

transluminal angioplasty (PTA) in treating patients with infrapopliteal disease.

Andrew Holden, director of Interventional Radiology at Auckland City Hospital in New Zealand, was “delighted to perform the first three cases treating below-the-knee peripheral arterial disease using the Temporary Spur Stent System. All three cases were technically successful and all patients were discharged home safely the following day, with an excellent clinical result. We look forward to gaining more experience with this new technology as the trial continues.” Occlusive disease affecting below-the-knee (BTK) arteries is a common and often serious consequence of peripheral arterial disease (PAD).

The Temporary Spur Stent System is a novel retrievable stent designed to treat severely calcified infrapopliteal disease by enhancing the uptake of anti-restenotic drugs and minimise vessel recoil without leaving anything behind.

“This milestone demonstrates our commitment to collecting verifiable clinical data in developing innovative technology like the Spur Stent System.

Guided by real data, the team at Reflow Medical, along with our world-class physician partners, continues to address the unmet needs of patients with peripheral vascular disease,” comments Teo Jimenez, VP of Research and Development for Reflow Medical.

Reflow anticipates opening DEEPER OUS in European sites later this year, and additional studies of next-generation Spur technologies in the near future.

TARGET BP I trial enrols its first patient

The first patient has been randomised in the TARGET BP I trial at the Piedmont Heart Institute in Atlanta, USA, to investigate the use of the Peregrine System Kit (Ablative Solutions) in renal denervation.

Target BP I is a blinded, randomised, sham-controlled study that is evaluating the safety and efficacy of the system in the treatment of patients with uncontrolled hypertension who are taking two to five anti-hypertensive medications.

The company announced the trial’s commencement in a press release, which explains that the TARGET BP I trial and the ongoing European TARGETBP OFF-MED trial are part of the TARGET BP clinical trials programme and are designed to evaluate the safety and efficacy of the Peregrine System Kit when used to treat patients with uncontrolled hypertension. The system is comprised of a patented infusion catheter and dehydrated alcohol.

David Kandzari (Piedmont Heart Institute, Atlanta, USA), co-principal investigator of the TARGET BP I trial, comments in the release: “It is exciting to initiate this important trial to evaluate the Peregrine System Kit for the treatment of patients with uncontrolled hypertension.

More than half of those treated with antihypertensive medications do not achieve their target blood pressure, so there is a great need for improved therapeutic options.”

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September 2019 | Issue 83

Events

Calendar of events 7–11 September CIRSE: Cardiovascular and Interventional Radiological Society of Europe

10–11 October 2019 Pacific Northwest Vascular Society Annual Meeting

17–18 November EVTM: Endovascular Trauma Management Symposium

23–25 January CACVS: Controversies and Updates in Vascular Surgery

30 October–2 November Controversies in Dialysis Access (CIDA)

27–29 November The Vascular Societies’ Annual Scientific Meeting

28–31 January LINC: Leipzig Interventional Course

Vancouver, Canada www.pacificnwvascular.org

Barcelona, Spain www.cirse.org

13 September i-VAS: International Vascular Access Symposium

San Diego, USA www.dialysiscontroversies.org

Paris, France www.i-vas.org

31 October–2 November Aortic Summit 2019

Lugano, Switzerland www.aorticassociation.org

23–27 September ESVS: European Society for Vascular Surgery annual meeting

Hamburg, Germany www.esvs.org

31 October–3 November CEC: China Endovascular Course

Beijing, China www.topcec.com

25–29 September TCT: Transcatheter Cardiovascular Therapeutics

4–7 November VIVA: Vascular Interventional Advances

San Francisco, USA www.crf.org/tct

2–4 October The Amputation Prevention Symposium (AMP)

Lugano, Switzerland www.europe.amptheclimeeting.com

Las Vegas, USA www.vivaphysicians.org 19–23 November VEITHsymposium

New York, USA www.veithsymposium.org

Denver, USA www.jevtm.com/evtm-symposium

Manchester, UK www.vascularsociety.org.uk

Paris, France www.cacvs.org

Lepzig, Germany www.linc2020.com

4–6 December 9th Munich Vascular Conference

21–23 February American Society of Diagnostic and Interventional Nephrology: ASDIN

5–7 December The Verve Symposium

12–13 March LINC Asia-Pacific

5 December Vascular Anomalies Special Interest Group Forum 2019

22–24 March EVC: European Vascular Course

Munich, Germany www.Mac-conference.com

Sydney, Australia www.vervesymposium.com

London, UK www.bsir.org

12–14 December 44th Annual Northwestern University Vascular Symposium

Chicago, USA www.cme.northwestern.edu

Las Vegas, USA www.asdin.org

Singapore www.linc2020.com

Maastricht, The Netherlands www.vascular-course.com 21–24 April Charing Cross Symposium (CX)

London, UK www.cxsymposium.com

June 2015

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Janet Pow Profile

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94.4% primar a the 12-mo the open repair d a strong benefit for liteal artery and aged them showed a agreed that months, s showe trial results in women nine VE trial encour y analysi at The at the strateg IMPRO erthe often. scular with Eluvia tion rate the charact EVAR more the endova , patency rate at baseline, revascularisa Continued on page 2 to perform similar with men. the fact that , Imperial College data target lesion compared groups were 3.6% two latest Janet Powell the the nt in each istics of presented three-quarters idual patie diate manLondon, UK, with almost VE (Imme aneurysms Pooled indiv : s men. “The from the IMPRO with rupture large with outcome the 12-month group being the patient trial that were also very group being data agement of presented in this trial scular repair) from the Ron Balm ers in each Open vs. endovaar outcomes followmeta-analysis average diamet said. The principal outcomes from the she reported one-ye ty and endovascular patient data over 8cm,” trials of strategy of individual e was mortali controlled of ruptured ing either a one-year outcom es were reintervenrandomised or open repair The Dutch AJAX outcom repair first related three d aneurysms; the sm. secondary ge, healthaortic aneury rupture y 2013), the l benefit abdominal hospital discharquality-adjusteds of Surger no surviva tions, (Annal strate 2015) S trial , costs, for ruptrial (EJVE results demon ess. quality-of-life scular strategy er, French ECAR trial. cost-effectiven for the endova at one year. Howev IMPROVE life-years and Powell noted that were sm and the UK for the all trials that tured aneury l At CX 2015, rst strategy answer the “These were s with a clinica designed to aneurysms an endovascular-fi on patient In the trial was with a patient of ruptured performed d aneurysm. what to do management discharge ncy room of rupture question of mortality patients faster and it is suspicion s to the emerged abdomidoes offer trial the 30-day imately who present quality of life the AJAX sis of rupture was approx with better these factors with a diagno sm. “What we had ective. Both in both groups it was 22% and in also cost-eff and clinical nal aortic aneurythat using an endory for patient heard.

25%, in ECAR had a slightly was es are necessa ated which was it er VE, delegat anticip 35% ng, in IMPRO y, wherev design, it was decision-maki published in April vascular strateg feasible, we could were different study(BMJ 2014), but all l (EHJ). ty These data ologically Journa of group mortali morph ve Heart an in each operati to Hülsbeck multicenstrate the benefit the Europe reduce 30-day open repair group a pragmatic, Stefan Müllerfailed to demon setting. “The in the IMPROVE, ) trial ranemergent repair was from 47% and one Canadaa clinical EVAR in the by the fact endovascular tre (29 UK hampered 33% where said. patients with sm, 316 ed so much results were vely,” she domised 613 repair perform ed on page 2 used extensi ruptured aneury rst strat“At one year, that open Continu diagnosis of Powell added: was 41.1% for VN App an endovascular-fi ity was suitable patients to all-cause mortal strategy group and morphology lishing open aortic to (if scular 297 egy @VN_pub the endova if not) and and open repair drew attention to also rNews cula repair. Powell /Vas

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