Vascular News 85 – January 2020 US Edition

“Do not be an island”: Teamwork prescribed to tackle major demographic trends in vascular disease “Caring for vascular patients is going to take a team,” concluded Marc Bonaca (Boston, USA) at the 2019 Vascular Interventional Advances (VIVA) conference in Las Vegas, USA (4–7 October). Bonaca opened the conference with a presentation on the major demographic trends in vascular disease “from head to toe”, as part of a session on the most controversial clinical challenges of 2019. He argued that physicians “as a community” need to tackle continuing issues with health disparities and increasing costs, and urged delegates: “Do not be an island.”

Marc Bonaca

B

onaca began by highlighting an “important trend” in cardiovascular mortality, which he noted rose steadily until the 1970s and 1980s, when the level plateaued. “We have made progress in cardiovascular mortality,” he said, “until recently.” He remarked that there has been a recent uptick in mortality attributable to diseases of the heart. “[Cardiovascular mortality] is slightly increasing and it is poised to increase more as our population ages,” he told delegates.

“It is still the leading killer.”

Bonaca also mentioned diabetes and obesity as “key drivers” of vascular disease. He detailed that the majority of men and women are either obese

or overweight and that there is a trend towards this becoming more common. He also commented that, while there is a geographic heterogeneity with regards to diabetes and obesity, “there is really nowhere safe”.

On a more positive note, Bonaca acknowledged that there are now better preventive therapies available for patients with vascular disease. For example, the recognition that LDL cholesterol is a toxin and that it can be modified has led to progressively lower rates of cholesterol in the population with drugs such as statins.

In addition, public health efforts recognising the harms of smoking have led to lower rates of cigarette use.

Continued on page 4

January 2020 | Issue 85 Dittmar Böckler:

Dreiländertagung 2019

Page 20

Ronald Dalman:

Profile

Page 30

Hotly-contested meta-analysis suggests a higher risk of death or amputation at one year when paclitaxel-coated balloons are used in infrapopliteal arteries A new meta-analysis, just published in the Journal of Vascular and Interventional Radiology (JVIR), suggests significantly worse amputation-free survival at one year with the use of paclitaxel-coated balloons in arteries below the knee to treat chronic limb-threatening ischaemia (CLTI). However, some experts advise cautious interpretation of results and question whether these data will impact practice. The new systematic review and study-level meta-analysis of eight randomised controlled trials was conducted by Konstantinos Katsanos (School of Medicine, University of Patras, Patras, Greece) and colleagues.

Definitive debate on PCB below the knee at CX 2020 Continued Continued on on page page 62

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January 2020 | Issue 85

Top stories

“Do not be an island”: Teamwork prescribed to tackle major demographic trends in vascular disease Continued from page 1

He did, however, remark that there has been a recent increase in e-cigarettes “of unknown significance”.

Bonaca detailed geographic trends here too, with the use of tobacco products, for example, being more widely used in the South and South East of the USA. After establishing that people are in general smoking less and have better cholesterol control, but acknowledging at the same time there is more diabetes and more obesity, Bonaca posed a number of questions: “How do these trends drive vascular events and what are we going to see in our vascular patients?”. Considering the issue from a “head to toe” perspective, he began by remarking that there have been reductions in stroke and stroke mortality. “We have seen a 13% reduction in the incidence of stroke in high-income countries,” he noted, however, the same cannot be said for low- and middle-income countries. Again, however, while there have been reductions in stroke mortality due to better prevention techniques and better treatment, “there is significant geographic heterogeneity,” he asserted.

Bonaca mentioned that, as a result of the lower rates of stroke and stroke mortality, the field has also seen lower rates of carotid procedures and endovascular approaches. Similarly, the incidence of acute coronary syndrome is decreasing, as is the mortality for this disease. “More importantly,” he commented, “I think that we see the type of acute coronary syndrome shifting.” For example, “in the setting of diabetes we see fewer young patients coming in with their first STEMI [ST-elevation myocardial infarction] but we are now seeing older patients with multi-vessel disease, and multiple comorbidities”.

Furthermore, Bonaca noted that venous thromboembolism (VTE) is increasing and that “this is intuitive if you think of the relationship between VTE and obesity, age, and the inflammatory milieu associated with diabetes”. He posited that this trend may shift as we see better long-term preventive options, but, for now, “VTE is on the rise”.

He mentioned that atrial fibrillation (AF) is also increasing, adding that, “not only is the prevalence [of AF] expected to increase, but there may be a logarithmic increase, because AF is now increasingly detected and there is an increased incidence of the risk factors”. He detailed that AF is closely associated with body mass index (BMI) and diabetes, which are both increasing in

prevalence.

“We are also seeing more peripheral arterial disease [PAD],” he informed delegates. Bonaca referenced data from Fowkes and others, published in The Lancet in 2017, which shows that, between 2000 and 2010, there was a 23.5% increase in the prevalence of PAD. “There are over 200 million cases of PAD globally and this number is expected to rise, particularly in the setting of diabetes,” he commented. However, he noted that we must recognise that what PAD looks like may shift from younger smokers to obese patients with diabetes and more comorbidities.

Bonaca then made some observations about demographic trends in critical limb ischaemia (CLI).

“We do not see reductions in the number of CLI cases and perhaps that is because of the increasing prevalence of diabetes,” he posited. “Stable CLI admission rates show that we are not doing enough to prevent CLI, but we see decreasing rates of amputations and decreasing mortality,” he added. However, he noted that the demographics of the patients presenting with CLI suggest that this cohort are “sicker than they used to be”. He detailed that, in CLI patients today, there has been an increase in hypertension; a threefold increase in obesity; more diabetes, while over a third have chronic kidney disease, and almost one in five has had a prior amputation.

In addition, chronic kidney disease—what Bonaca described as “a form of microvascular disease closely associated with diabetes and hypertension”—is steadily increasing. He remarked that, “with vascular disease, whether it is VTE, PAD, stroke, or any cardiovascular disease, we are going to see a lot of chronic kidney disease, which adds complexity and risk”.

Moving beyond demographic factors, Bonaca also briefly discussed economics, suggesting that cardiovascular disease will “drive up costs” as the population ages. “That is going to be a challenge in our space,” he speculated. He considered the development of novel therapies: “We are lucky to live in an age where we not only have statins but we have PCS-K9 inhibitors; we have rivaroxaban for CAD [coronary artery disease] and PAD, and we have new diabetes drugs.” Despite all these, however, Bonaca believes there are many unanswered questions in the field: “How do we manage all these drugs? How do we manage polypharmacy? And how do we best take care of our vascular patients?”, he enquired.

After delineating the current demographic landscape facing vascular specialists, Bonaca ended his presentation by putting forward the idea that a “key trend” going forward will be the increasing need for multidisciplinary care teams in integrated systems of care, indicating that teamwork will be the best way to tackle the challenges ahead.

German claims data report higher long-term and amputation-free survival in CLTI patients treated with paclitaxel devices There is no sign of increased all-cause mortality following the use of paclitaxelcoated devices for the treatment of symptomatic peripheral arterial occlusive disease, a new study based on German claims data attests in the European Journal of Vascular and Endovascular Surgery.

T

he study investigators set out to determine the survival of patients after use of paclitaxelcoated devices using a propensity score matched retrospective analysis of German health insurance claims. BARMER is the second largest insurance fund in Germany, and lead author Christian-Alexander Behrendt (University Medical Centre HamburgEppendorf, Hamburg, Germany) and colleagues used this dataset to identify index femoropopliteal arterial interventions between 1 January 2010 and 31 December 2018. To ensure first paclitaxel exposure, patients with prior deployment of paclitaxel were excluded.

As reported in this newspaper, Eva Freisinger (University Hospital Münster, Münster, Germany) also used the BARMER dataset to conduct a real-world safety analysis of paclitaxel-based devices in peripheral arteries, concluding in the European Heart Journal that the use of drug-eluting devices is “safe for endovascular therapy of the lower limbs”.

According to the authors of the present study, their research is differentiated from that of Freisinger et al by restricting the included patients to ensure a more homogenous study population. Behrendt and his co-investigators write: “Aiming to add to the existing evidence, the current approach rested on a rigorous study design involving a more homogeneous study population (only femoropopliteal segment, no prior major amputation), with a lookback period of up to five years and follow-up periods (left and right censoring) of five years.”

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January 2020 | Issue 85

Paclitaxel meta-analysis

Hotly-contested metaanalysis suggests a higher risk of death or amputation at one year when paclitaxel-coated balloons are used in infrapopliteal arteries Continued from page 1

SEVERAL PHYSICIAN THOUGHT-leaders believe that the conclusions are not yet definitive, with multiple vascular surgeons and interventionalists cautioning how these data should be interpreted. Most emphasised the challenge of teasing out scientifically meaningful information from a patient cohort that suffered from CLTI, which is associated with “mortality, amputation, and impaired quality of life”. They also point to the inclusion of unpublished data (which has therefore not gone through the peer-reviewed process); the inclusion of summary-level data; the inclusion of the IN.PACT DEEP data (which used a device that has long since been withdrawn from the market); and the study’s short-term follow-up period.

As reported in JVIR, the eight randomised controlled trials included in this most recent summary-level analysis included 1,420 patients, of which 1,380 (97.1%) had CLTI. The primary safety and efficacy endpoint was amputation-free survival, defined as freedom from all-cause death and major amputation (above the ankle). At one year, there was a 13.7% crude risk of death or limb loss among the 835 patients who had received treatment with paclitaxel-coated balloon—74 deaths and 40 major amputations. In comparison, the crude risk of death or limb loss in the cohort treated with an uncoated balloon was 9.4%—39 deaths and 17 major amputations. For the primary amputation-free survival endpoint, the number needed to harm was estimated to be 22 patients (95% confidence interval [CI] 11–94). The authors claim there was consistent evidence from the randomised studies that freedom from major amputation or death was significantly lower in cases with paclitaxel-coated balloons with a pooled hazard ratio (HR) of 1.52 (95% CI 1.12–2.07; p=0.008).

However, Katsanos et al also report consistent evidence that paclitaxel reduces the need for target lesion revascularisation in below-the-knee arteries by approximately 40%. Target lesion revascularisation constituted the secondary efficacy endpoint. The crude risk of target lesion revascularisation was 11.8% (103 revascularisation events among 875 cases) versus 25.6% (159 events among 620 control patients) for patients treated with a paclitaxel-coated balloon and an uncoated balloon, respectively. The calculated pooled risk ratio was 0.53 (95% CI 0.35–0.81; p=0.004), with a corresponding number needed to treat of eight patients (95% CI 4–25).

The study authors claim there is a dose–response relationship between paclitaxel and amputation-free survival. They compared outcomes with low and high doses of paclitaxel, and found significantly more deaths or amputations (lower amputation-free survival) in cases with high-dose devices, defined as 3–3.5µg/mm2 (HR 1.62; 95% CI 1.16–2.27; p=0.005). In comparison, amputation-free survival was higher (fewer deaths or fewer major amputations) when a low-dose device (2µg/mm2) was used (HR 1.06; 95% CI 0.48–2.34).

This low-dose was found to be safe and effective, the authors report.

The authors of the present study say they performed a “comprehensive literature review” due to the “major concerns about systemic safety of paclitaxel”

prolific in the endovascular community today as a result of their earlier meta-analysis published in the Journal of the American Heart Association (JAHA) in 2018. This concluded that there was an increased association of mortality beyond two years through five years of follow-up when paclitaxel-coated balloons and paclitaxel-eluting stents were used in the femoropopliteal arteries.

Concerns of the medical community: The vascular surgeon perspective Kim Hodgson, president of the Society for Vascular Surgery (SVS); Southern Illinois University School of Medicine, Springfield, USA

“The authors use the most relevant of clinical endpoints for this population, amputation-free-survival, to evaluate for the ultimate goal of an intact living patient. While it took use of this composite endpoint to achieve statistical significance, it is alarming that both mortality and amputation came very close to independently reaching statistical significance (p=0.1; p=0.09, respectively), and I suspect that with a larger sample size one or both may have. If further evidence confirms either that paclitaxel does not decrease the rate of amputation but does increase the mortality, then the prospects for its continued use appear bleak. The possible ray of sunshine in this cloud is the observation that the lowest dose paclitaxel device analysed (Lutonix, BD) appeared to be free of increased mortality yet still effective, perhaps indicating that the dosing sweet-spot has yet to be found while acknowledging that we have no accurate way of measuring actual paclitaxel tissue delivery or systemic release. The complicated nature of paclitaxel delivery and its pharmacology, however, portend that this will remain a complicated mystery to unravel.

“There has been a significant shift towards the use of paclitaxel delivering devices in treating peripheral vascular disease since their introduction several years back. Given this and the ever-growing population of peripheral vascular disease patients being treated, it is critical that physicians know the full risk:benefit profile Kim Hodgson of the therapies they employ and always put the patient’s outcome first. The methodological limitations of this pooled analysis are divulged by Katsanos et al and are similar to those of the group’s previous publication on the use of paclitaxel in the claudication population. Nonetheless, his prior report called attention to a signal that was, in fact, subsequently confirmed, though still not understood, so the findings of this analysis are highly relevant and need further analysis.

My major concern is the inclusion of unpublished data.”

Ramon Varcoe

“When considering a risk like mortality, erring on the side of caution only makes sense, especially considering the multitude of other revascularisation options available to most patients, the irreversibility of death, and the risk of litigation. This is especially true when the effectiveness of the therapy itself is in question, as this analysis has suggested. Until we have greater clarity on the safety and efficacy of paclitaxel devices, I believe that most will opt to use them very

selectively in the small subset of patients at high risk for restenosis and no other reasonable revascularisation options.”

Ramon Varcoe, Prince of Wales Hospital and University of New South Wales, Sydney, Australia

“My first reaction was that it was good to see a group looking to define the risks of paclitaxel devices in the CLTI population. The CLTI group is very different to the claudicants evaluated in the previous meta-analysis and warrants specific attention.

“My reaction to the results was mixed. The authors showed no difference in all-cause mortality or major amputation rates but when they combined the two as the endpoint amputation-free survival, they appeared to find a difference between drug-coated balloons and percutaneous transluminal angioplasty, with better amputation-free survival in the control group. The other positive finding was that they showed a 47% reduction in reinterventions, underlining the wellestablished effectiveness of these devices.

“My major concern is the inclusion of unpublished data. This was the case in three of the eight studies pooled. We must take great care in including data that has not been peer reviewed. It is common that event rates change between presentation and final publication, which may alter the findings of a metaanalysis and its conclusions. This is particularly true for low-frequency endpoints such as amputation-free survival at six to 12 months. It is also very difficult for the reviewers to grade the quality of evidence from a short congress presentation, as opposed to a peerreviewed manuscript. However, including unpublished data is not unheard of, particularly when there are few published studies in the literature. What concerns me most is the glaring omission of the most significant study of drug-coated balloon use in below-the-knee arteries of CLTI patients. The five-year results of the

Ramon Varcoe

Michael Conte

IN.PACT DEEP study were presented by Thomas Zeller at the AMP symposium last year (14–17 August, Chicago, USA). Like the other three studies, it was unpublished in September 2019 when the systematic review was conducted. However, if you include some unpublished data you must include all.”

Michael Conte, Heart and Vascular Center, University of California, San Francisco, San Francisco, USA

“CLTI is a major global health problem and current treatments have significant limitations, contributing to high morbidity and mortality rates in these patients.

Interventions for infrapopliteal arteries, in particular, have high rates of failure and thus there is considerable unmet need for more effective approaches. Thus the interest in various methods to improve the results of angioplasty, such as drug-elution, remains high.

“The limitations of this study relate to both the analysis itself and, more importantly, the state of the field it reflects. The meta-analysis involves pooled data and is not patient-level. Thus it is not possible to evaluate confounders (e.g. unbalanced comorbidities or clinical severity) that may be driving the outcomes.

The actual event rates in these trials are lower Continued on page 8

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January 2020 | Issue 85

Paclitaxel meta-analysis

Hotly-contested metaanalysis suggests a higher risk of death or amputation at one year when paclitaxel-coated balloons are used in infrapopliteal arteries Continued from page 6

than expected across the board, the overall major amputation rate of 4%, which suggests that the degree of limb threat at presentation may have been modest.

The two larger trials employed a 2:1 randomisation ratio, leading to a significantly larger population with paclitaxel-coated balloon exposure than controls. The results are dominated by the two larger studies, that have only reported short to mid-term outcomes. This is particularly relevant for the death outcome. CLTI itself has a broad clinical spectrum and the need for improved staging systems (e.g. the Society for Vascular Surgery WiFi classification system) is evident to allow for better trial designs and balanced randomisation by limb severity. Finally, one has to ask—where are the five-year data from IN.PACT DEEP and where are the one-year data from Lutonix BTK? The vascular community deserves timely, complete, and honest reporting from the trials.”

Concerns of the medical community: The interventional radiologist perspective

amputation in patients with compromised distal arterial circulation. In addition, it echoes the call after the earlier femoropopliteal publication for more data and an urgent need for adequately-powered multicentre studies with longer follow-up.”

Gunnar Tepe, Klinikum Rosenheim, Rosenheim, Germany

“I have two immediate remarks: it is very important to look into safety issues of devices in general. Therefore, all data have to be taken seriously; and compared to the first publication from Katsanos et al, the statistical part is much more solid.

“Nevertheless, there are several major limitations of the recent publication. Firstly, in order to achieve a certain number of patients, the follow-up time was mixed—some studies follow the patients for six months while others have a 12-month followup. Secondly, Katsanos et al state that they did a meta-analysis based on eight studies. In fact, the meta-analysis is driven by two high-volume studies only. These are the Lutonix BTK study with a six month endpoint, and the IN.PACT DEEP study with a 12-month endpoint. The finding that amputation-free survival is worse in patients who received paclitaxelcoated balloon angioplasty below the knee is driven by the IN.PACT DEEP study, which has high patient numbers. This is nothing new and has been published.

Nevertheless, even the data available to Katsanos et al do not discuss that. For the IN.PACT DEEP study, we know from data presented at conferences that at five years, patients who received drug-coated balloons had a better amputation-free survival. Thirdly, there is a dose issue: Katsanos et al state that a higher dose is associated with more amputations. This is a wrong statement. All below-the-knee drug-coated balloons are low-dose applications compared to what is given

Michael Dake, president-elect of the Society of Interventional Radiology (SIR); University of Arizona Health Sciences, Tucson, USA “Aside from The Godfather Part II, sequels are rarely as compelling as the original version, often with an impact that is a mere ripple of the force produced by the initial statement. Predictably, I suspect this will be the case for the current report, although its contribution to the medical literature will be of interest to many stakeholders in the field of vascular disease.

“The results of this meta-analysis of randomised controlled trials focused on patients with CLTI are more difficult to interpret than the earlier femoropopliteal publication. The medical complexity of the underlying disease and the vulnerability of CLTI patients contribute to a greater heterogeneity in the population studied. Consequently, added caution must be exercised when attempting to make conclusions from this meta-analysis.

“In terms of the methodology used, the current study shares some of the frequently noted limitations of the original femoropopliteal meta-analysis. The lack of patient-level data available to the authors from the randomised studies included in the meta-analysis restricts evaluation of the total dose of paclitaxel used in individual patients and any correlation with mortality. In addition, the relatively small number of patients analysed and [the] short follow-up (46% of the patients had only six-month follow-up) make any conclusions problematic. Unlike the first meta-analysis, however, an additional limitation is noted. The current report of pooled trials includes unpublished data. Results from three of the eight trials used in the analysis have not been published. This represents onequarter of the patients included.

“Nevertheless, the paper raises interesting points about the effect of drug-coated balloon treatment for patients with CLTI, and questions the possible association of downstream drug embolisation and

Michael Dake

Gunnar Tepe

in the superficial femoral arteries. We know from several studies that patients with CLTI and drug-coated balloon treatment in the superficial femoral arteries do fine. There were fewer target lesion revascularisations, but no increase of amputations or deaths. It is totally misleading the Katsanos et al ignore this fact. Katsanos et al do not take into account that most likely almost all patients have received paclitaxel-coated balloons in their history—either in the same leg, in another location, or for target lesion revascularisation. It is not OK that he just states in the discussion that this is unknown.

In summary: Katsanos et al unfortunately increase the uncertainty in the safety of drug-eluting technology.

Aside from The Godfather Part II, sequels are rarely as compelling as the original version.”

Michael Dake

This could lead to fewer patients will get drug-coated balloons and more target lesion revascularisations and [consequently] more amputations may occur.”

Concerns of the medical community: The interventional cardiologist perspective Thomas Zeller, UniversitätsHerzzentrum Freiburg, Bad Krozingen, Germany

“In five of the eight studies, data from congress reports are included in the meta-analysis. The primary endpoint of the study is amputation-free survival.

Secondary endpoints are all-cause death, major amputation, and target lesion revascularisation rates.

Amputation-free survival was significantly worse for the drug-coated balloon group (HR 1.52, 95% CI 1.12–2.07, p=0.008), whereas all-cause mortality and amputation rates were not statistically significantly different. The target lesion revascularisation rate was significantly lower after drug-coated balloon treatment (HR 0.53, 95% CI 0.35–0.81, p=0.004). Again, same as for drug-coated balloon application in femoropopliteal arteries, the authors postulate a dose-dependent increase of risk of mortality and amputation rate with ‘high-dose’ drug-coated balloon devices.

“Katsanos et al conclude: ‘There appears to be an increased risk of death or major limb loss during the first year when paclitaxel-coated balloons are applied in the infrapopliteal arteries for CLTI treatment.

Actual causes for this detrimental clinical outcome remain largely unknown, but downstream and systemic paclitaxel embolisation is a plausible mechanism.’

“First of all, the conclusion is wrong. The study does not show an increased risk of ‘death or major limb loss’: all-cause death rate does not significantly differ between the study groups (HR 1.39, 95% CI 0.94–2.07) nor does major amputation rate (HR 1.63, 95% CI 0.92–2.90). It is the combination of both endpoints—amputation-free survival—that is favouring the percutaneous transluminal angioplasty strategy.

“Are the findings real?

The review includes study data derived from study-level data published or presented on recent congresses. Three out of eight studies are singleThomas Zeller centre studies without independent clinical events committee adjudication of the safety events, three out of eight studies analysed are not yet published congress reports and the data may be subject of change during the publication process.

“The ‘trend to an increased all-cause mortality risk’ following drug-coated balloon exposure in this study is not in line with the finding of the same study group for the treatment of femoropopliteal disease with drugcoated balloon.”

“These data will not impact practice because, as a result of the JAHA publication in 2018, drug-coated balloons are, in general, already used with caution.

In addition, until the recent congress presentations of ACOART II (Guo et al, LINC 2019) and ACOART BTK (Liistro, VEITH 2019) no clear evidence existed regarding the technical efficacy of drug-coated balloons in below-the-knee lesions. Both studies for the first time demonstrated a patency benefit of a drug-coated balloon over percutaneous transluminal angioplasty. Therefore, the use of a drug-coated balloon in below-the-knee disease in daily practice was limited to ‘drug-coated balloon believers’ that will not be changed by the present publication.

Full coverage on vascularnews.com Definitive debate on PCB below the knee at CX 2020

10

January 2020 | Issue 85

Endovascular aneurysm repair

For ruptured AAA, data and experience confirm “EVAR is better” “Endovascular is the best treatment for ruptured abdominal aortic aneurysms [AAA]. Is it settled or not?” was the topic of a headline talk given by Benjamin Starnes (Regional Vascular Center, Harborview, Seattle, USA) at the 2019 Vascular Interventional Advances (VIVA) conference in Las Vegas, USA (4–7 November). “The answer to this question, in my mind, is yes,” began Starnes, going on to detail trial data and “pragmatic experience” in support of his view.

S

tarnes outlined that there have been several randomised controlled trials looking at endovascular repair versus open repair for ruptured AAA, with the “most notable” being the IMPROVE trial

by Janet Powell (London, UK) et al. He referenced an editorial from 2017 from the British Medical Journal (BMJ), in which Martin Björk (Uppsala, Sweden) stated that the three-year results of the IMPROVE trial will change clinical practice of endovascular repair for patients with suspected ruptured AAA. “There is a true survival benefit at three years, better quality of life in the survivors, better overall cost-effectiveness, and similar reintervention rates,” Starnes explained.

Turning away from randomised trial data and towards grafts before the patient is even in our facility and have “pragmatic experience” with EVAR for AAA, “I would them in the room and ready to go,” he remarked. ask you to look no further than Seattle, Washington,” He went on to describe some other key features of the said Starnes, pointing to the positive results achieved protocol at Harborview: “An ID band awaits the patient at the Regional Vascular Center at Harborview. He and is affixed to the wrist on the way to the operating explained that the centre’s success can be attributed to room, our medics transfer the patient directly on to the a protocol for managing patients with ruptured AAA, operating room table, and each patient has a massive implemented over a decade ago. Looking transfusion protocol activated”. at mortality pre- and post-protocol, they He added: “We try and identify those went from a mortality rate of 57.8% to patients who have a 100% mortality 25.3% overall, and for those patients risk. The four predictive factors are age who received an endovascular repair the greater than 76 year, creatinine greater mortality rate was only 16.3%. “This is than 2.0, serum pH of less than 7.2, and the result of a team effort, and my team hypotension at any time of less than 70ml in Seattle are all in alignment with the mercury. If you have all four of those management of these patients and every factors, you have a 100% mortality risk one of our members is endovascularly and we will not offer repair”. trained,” he commented.

For patients with challenging anatomy, Starnes elaborated that his team treats Starnes noted that they will perform a Benjamin Starnes between 30 and 40 patients a year with cone-beam or Dyna-CT at the end of ruptured AAA because they are “the every procedure to assess for type 1a only Level 1 trauma centre serving five large American endoleak. “We have learned that those can be rapidly states”. fatal in the postoperative period,” he explained.

A decade of lessons learned

Starnes noted that he and his team have “learned quite a few lessons” over the last decade, one being that systems and protocols “make a difference”. He pointed out that algorithms, or “structured protocols,” serve as surrogates for an organised approach, adding that if one looks at the studies where a protocol is in place, the mortality rate is 18% versus 32% in those without.

Starnes commented in particular on the importance of prehospital image transfer, which he believes has “revolutionised” patient care. “We are able to choose the

Technical success when treating persistent type II endoleak is significantly higher with translumbar embolisation than with transarterial embolisation A meta-analysis of translumbar embolisation versus transarterial embolisation for type II endoleak after endovascular repair of abdominal aortic aneurysm (AAA) found that “the translumbar route was more successful in obliterating the endoleak on followup imaging”. Results of the meta-analysis were reported by Giang Guo (West China Hospital, Sichuan University, Chengdu, China) and colleagues in the Journal of Vascular Surgery.

THE MAJORITY OF AAAs are treated with endovascular aneurysm repair (EVAR), which—according to Guo and colleagues—is a safer method than open surgical repair. However, a common complication following this procedure, occurring in 22% of cases, is type II endoleak, caused by retrograde blood flow into the aneurysm sac from the collateral arteries. Guo and colleagues write that persistent type II endoleaks can increase the risk of AAA rupture so any that last beyond six months with the AAA increasing in size >5mm will require reintervention.

Embolisation is used to prevent type II endoleaks and enlargement of the aneurysm sac. The most common methods are translumbar direct embolisation of the aneurysm sac and

embolisation of the aortic branches via the superior mesenteric artery or lumbar arteries. Accessing the aneurysmal sac is challenging with either method and there is limited evidence about which is the more effective technique. Guo et al therefore sought “to gather the available evidence and to compare the clinical outcomes between transarterial and translumbar approaches”. They also aimed to “investigate the mid-term to long-term clinical outcomes of open repair for persistent type II endoleaks”.

The authors conducted a systematic review to identify eligible trials which evaluated the outcomes of translumbar versus transarterial embolisation in patients with type II endoleaks after EVAR. The primary outcome was clinical success, which was defined

Team approach is “key”

“I think the team approach is key,” commented Sean Lyden (Cleveland, USA), who then asked how the hospital got all the outlying hospital and the emergency room physicians on the same page. Starnes explained the workings of a system he and his team use in Seattle called Medic 1—a system of medics, paramedics, and prehospital personnel that have routine conferences and teleconferences about protocols, how to stabilise the patient, and how to get them to Harborview for treatment.

as the absence of endoleak on the last examination, and secondary outcomes were technical success (successful deployment of embolisation material to the endoleak cavity) and complication rate. They estimated odds ratios with 95% confidence intervals.

Guo et al write that nine of the 904 studies identified met the inclusion criteria and were assessed as being of high quality. A total of 354 patients underwent 449 procedures: 190 translumbar and 259 transarterial embolisations. None of the studies reported aneurysm rupture or mortality.

Eight studies gave details about clinical success rate. Meta-analysis indicated that there was a relatively higher clinical success rate in patients treated with translumbar embolisation than with transarterial embolisation but the result was not statistically significant (OR=2.29, 95% CI=1–5.25, p=0.05).

However, there was a significant difference in heterogeneity between studies (I2=52%).

Five studies gave details about technical success rate. This was found to

We suggest translumbar percutaneous sac puncture embolisation as first-line treatment of persistent type II endoleak.”

be significantly higher in patients treated with translumbar than with transarterial embolisation (OR=13.32, 95% CI=3.41– 52.07, p=0.0002) with no heterogeneity (I2=0).

Five studies gave details about complication rate. There was no significant difference in complication rate between the two treatments (OR=1.15, 95% CI=0.26–4.96, p=0.85) and no heterogeneity (I2=0). Non-target embolisations were more common with transarterial embolisation, while puncture site haematomas were more common with translumbar embolisation.

Five studies gave details about patients treated with open repair (n=60). All 60 patients were technically treated with this method and 58 patients had clinical success. One patient died of colonic ischaemia after surgery.

The authors noted some limitations.

A small number of studies meeting the inclusion criteria and small sample sizes in the included studies may cause potential publication bias. Only retrospective observational studies were included. Guo et al remarked that “a long-term prospective study to specifically compare these two techniques would be instructive”.

Further, various materials that were used for embolisation and different follow-up periods across the studies might have affected the results.

Guo and colleagues concluded: “Based on the results of this study, we suggest translumbar percutaneous sac puncture embolisation as first-line treatment of persistent type II endoleak and transarterial or transcaval embolisation could be considered alternatively.”

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January 2020 | Issue 85

Circulation Foundation

Update on the Circulation Foundation Michael Jenkins Comment & Analysis Michael Jenkins talks to Vascular News about the Circulation Foundation, outlining the history of the charity and also giving an update on recent activities.

THE HISTORY OF the Circulation Foundation (CF) dates back to the original British Vascular Foundation, the function of which was fund raising for vascular causes. When the Vascular Surgical Society of Great Britain and Ireland changed names to The Vascular Society (VS) in 2004, the charity became more closely aligned and changed its name to the Circulation Foundation in 2006.

I took over the stewardship of the CF three years ago following a rocky patch for the charity with major changes to admin staff of the VS. As my term of office as chair comes to an end, I want to congratulate Rachel Bell, who has been appointed as my successor together with Meryl Davies as deputy chair.

Both are keen to develop the patient facing aspect of the CF, to continue the website improvements and bolster the charity and fundraising aspects. I also want to thank all committee members and representatives from the Society of Vascular Nurses (SVN) and Society of Vascular Technologists (SVT) who

have given their time and energy to the CF over the last three years, all on a voluntary basis.

With help from VS members (most of whom are now generous regular donors) the financial position of the CF is much improved. If any have yet to complete Gift Aid please consider this as it provides a further important income stream. Donations also continue to come in from those who have run, cycled or swum in events throughout the year on behalf of the CF. Other ways anyone can help and promote the CF are by using the Savoo search engine, Amazon Smile (both organisations donate for free with no additional cost to users) and Just Giving (details below). These are excellent ways for patients, clinicians, colleagues and friends to help the CF by allowing small (but completely free) regular donations to add up.

Patient needs and expectations are not always easy to gauge and feedback from patient groups through lay members is vital to shape the direction of the information provided via the CF website.

I am very pleased that our new lay member, Sara Pittack is incredibly keen, resourceful and energetic in her approach to the patient perspective. You will see that there are new “risk checkers” and patient blogs on the website, the feedback from which has been excellent. We have raised the profile of our social media presence and this is paying dividends in raising the profile of the website via search engines.

As well as funding various research fellows outright, we have recently joined forces with the Royal College of Surgeons of England to collaborate in joint funding of posts which I believe is the right direction for us, both in terms of governance and helping our precious funding streams to go further.

We have also supported the new lower limb ischaemia quality improvement framework as we felt this was important to members, and a new fellow starts early next year to take this forward. Over the last few years, we have brought the VS and CF closer together, both from an organisational perspective (sharing

We have raised the profile of our social media presence and this is paying dividends.”

Spinal cord problems with frozen elephant trunk are a “potential concern” At the recent VEITHsymposium in New York, USA (19–23 November), Joseph S Coselli (Division of Cardiothoracic Surgery, Baylor College of Medicine, Houston, Texas) gave an update on the value and limitations of frozen elephant trunk repairs and the Thoraflex hybrid graft for complex aortic arch lesions, considering in particular whether or not spinal cord ischaemia is an issue. He concluded that spinal cord problems, such as paraplegia, with the frozen elephant trunk approach are a “potential concern” and that the procedure should only be carried out in patients who have active or potential problems with the descending thoracic aorta.

C

oselli explains that the frozen elephant trunk technique was developed because “one of the problems with the classic technique is that the completion rate is only around 50% or so, and there is an interval mortality between the first and the second operation which is not insignificant and runs at about 10%”. The frozen elephant trunk procedure enables one-stage repair using a preassembled or custom-made hybrid prosthesis that facilitates a combined open and endovascular repair. The proximal part consists of a Dacron graft to be used as part of an open aortic replacement procedure while the distal part consists of a stent-graft to be deployed endovascularly.

Although spinal cord problems are rare after a classic elephant trunk repair, a major problem associated with

the frozen elephant trunk procedure is an increased risk of paraplegia, with “paraplegia rates from early reports ranging from 9% to 25%”. More recent studies, however, have found a smaller but “not less inconsequential” risk of paraplegia associated with the procedure.

Coselli described the results of a meta-analysis of >3,000 patients undergoing a frozen elephant trunk procedure presented by Preventza at the 99th Annual Meeting of the American Association for Thoracic Surgery (AATS) in Canada in May 2019. The metaanalysis, which included 35 studies, aimed to determine the rates of adverse neurological events and mortality associated with the procedure. The procedure was associated with spinal cord ischaemia (4.7%), stroke (7.6%) and mortality (8.8%). Importantly, the study

the same office staff) and financial perspective which leaves the charity in a much stronger position going forward.

In recognition of these stronger links and indeed the alliance between the VS, SVT and SVN, I am delighted to announce a series of small regular grants which will be available for finite projects and accessible to members from all three societies. Please see the website for details.

Finally, I want to give thanks for the support and generous donations from our patrons and major benefactors. George Davies continues to remain involved and interested in all aspects of both the Foundation and things vascular in general and gives valuable time from his busy schedule to meet, advise and hear about our latest projects, many of which he has funded. I am very pleased that Professor Roger Greenhalgh has agreed to be a Patron and continue his interest in the CF. He was a founding patron of the original British Vascular Foundation prior to the relaunch of the new charity—the Circulation Foundation in 2006—and it is fitting that we now renew this relationship.

Text CIRC10 £5 to 70070 to donate to the Circulation Foundation and make a difference today. www.savoo.co.uk—sign up and nominate the CF to ensure that 1p goes to the CF for every internet search you perform. Repeat on your mobile, tablet and home computer and tell family and friends. www.smile.amazon.co.uk—sign up and nominate the CF. 0.5% of the purchase price of anything you buy (excluding VAT and shipping) is then donated to the charity of your choice.

Michael Jenkins is a consultant vascular surgeon at St Mary’s Hospital in London, UK and is chairman of the Circulation Foundation.

found that a stent length ≥15cm, or coverage to T8 or beyond, was associated with an increased incidence of paraplegia that was statistically significant. Preventza et al therefore recommended that when using the frozen elephant trunk technique, a 10cm stent length is advisable and coverage to or beyond T8 should be avoided to reduce the likelihood of a spinal cord injury.

Coselli gave details of the Thoraflex trial: “It included 12 US sites, with 65 patients and nine in the ruptured group. There were no acute dissections in the primary group, which included many with chronic dissections.

The rupture group included acute aortic dissections in seven of the nine patients. There was an almost even split across the 10cm and 15cm lengths. In the primary group, 5% had all-cause mortality, 5% had permanent stroke and 6% had spinal cord deficit. All three patients had 15cm-length frozen elephant trunk. In the rupture group, there was only one spinal cord injury—this was also with the 15cm length.”

Coselli concluded: “If you are going to do a frozen elephant trunk, it ought to be in patients who have descending aortic problems, or will soon develop descending problems. Additionally, younger patients with connective tissue disorder are going to need repair extended to the distal aorta. Spinal cord problems with a frozen elephant trunk approach are a potential concern, particularly if the stent is 15cm in length or placed distal to T8, so stage the repair and extend after a period of recovery.”

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January 2020 | Issue 85

Regulation

International collaboration will promote “transparency and predictability” in regulatory pathways Misti Malone (Silver Spring, USA), assistant director of cardiovascular devices at the US Food and Drug Administration (FDA), gave an update on the regulatory landscape at the 2019 Vascular Interventional Advances (VIVA) conference in Las Vegas, USA (4–7 November), outlining the importance of international collaboration “to promote both transparency and predictability”.

“I

hope you do not consider the FDA the most challenging and controversial aspect in clinical care,” Malone began, speaking during VIVA’s opening session on the most controversial clinical challenges of 2019. Aiming to set the record straight, she clarified: “We are here to interact and be collaborative with you, and we appreciate the hard work that you are doing.”

Malone then moved into a discussion of the “evolving” regulatory pathways across the world.

Firstly, Malone considered the US FDA 510k pathway, which is required for most Class II, medium-risk, devices, including guidewires, introducers, balloon catheters, and peripheral atherectomy devices. She detailed that this pathway requires demonstration of “substantial equivalence” to a legally-marketed predicate device, meaning that the device design, performance, and intended use must be similar to a Class II device that is currently on the market.

She then reported that on 20 September 2019, the FDA released a new guidance regarding an alternative 510k process, called the Safety and Performance-based Pathway, or SPP. While this is based on the predicate device equivalence benchmark that underlies the current pathway, there must also be performance testing, involving FDA-specified methods and criteria that may be based on recognised standards and historical performance of comparable devices, rather than side-byside testing with a specific marketed devices.

Malone admitted that due to the “complex and evolving” nature of cardiovascular device technology, identifying performance criteria may prove challenging and “it is not our goal to reduce innovation, it is to help support it by allowing the process to move as efficiently as possible”.

“One of the goals of this new pathway is that it will be more similar to regulatory paradigms in other countries,” Malone remarked, addressing the potential benefits of the recently-released guidance update.

Malone referenced, in particular, the third party certification in the Japanese system, which relies on performance criteria set by the Japanese government, but includes few cardiovascular devices. “This may be a pathway that will be valuable for some of our simpler devices in which we can set these performance criteria,” she concluded. She posited that the new pathway “may facilitate global regulatory decision-making”.

Malone reported that, in the European Union (EU), adoption of the Medical Devices Regulation (MDR) is likely to take effect in May 2020, however there is “continued discussion” on the topic. She outlined one goal of this update being to reinforce provisions for clinical evidence so that clinical evaluation will be required premarket for some devices, and that this will continue in the post-market with regular updates, surveillance, and analyses. Two additional goals will be to encourage transparency, using UDI traceability, and also data availability for both clinicians and patients.

“The EU hopes that this will provide more information to support clinical decision-making and patient decisionmaking,” Malone concluded.

According to Malone, devices that are most likely to

require clinical investigation under the MDR are those that are implants and high-risk devices, devices that may be Class II or lower where the technology has little or no experience, or a device for which the intended purpose is being extended or if there is a new indication for use.

For Class III and implantable devices, she detailed that a post-market clinical follow-up report “may be required”.

Addressing how these changes may affect device availability, Malone commented: “I think this is more of a question for industry, however we look to clinicians to help us understand the ramifications of some of

market authorisations in one place may be supported in another country.

Malone also mentioned that the USA collaborates closely with Japan due to the “similar regulatory environments and patients”. She described that there have been a number of recent developments in Japan, including the Sakigake (pioneer) device scheme, shifts in pre- and post-market balance similar to the FDA, the use of non-domestic data, the establishment of registries, and the use of “real-world” evidence and pathways for early feasibility studies.

Malone summarised that many regulatory jurisdictions are establishing different regulatory approaches for medical devices. In the USA, new processes have been developed that “may be appropriate to follow in some cases” but are “not the only options,” Malone detailed. “[The FDA] continues to work interactively with our companies and our clinicians to create an efficient and predictable pathway,” she added. Malone closed the presentation by urging VIVA delegates: “Please consider global strategies when appropriate.”

“We do hope that more companies will come to the US in the future”

Ravish Sachar (North Carolina Heart & Vascular, Raleigh, USA) commented: “It was really helpful to get an understanding of where we are right now and where we might be heading, not just [in the USA], but

Misti Malone

[The FDA] continues to work interactively with our companies and our clinicians to create an efficient and predictable pathway.” the regulatory decisions and also to involve a global consensus so the process can be efficient”.

Harmonisation through collaboration

Malone mentioned that there are a number of global groups, such as the International Medical Device Regulators Forum (IMDRF), in which regulators cooperate with numerous countries across the globe.

“This is a voluntary effort among medical device regulators to harmonise various regulatory requirements across their jurisdictions,” she explained, concluding that the forum is “driving global cooperation at the device level”. The FDA consider collaborations like the IMDRF as part of their “strategic priority” to put in place the foundations for creating a Medical Device Single Review Programme, Malone reported, with the potential goal that, once this has been established, some

also in Europe and Japan”. He then asked whether, in the context of higher thresholds for device approval in Europe, we might expect more first-time devices coming to the USA for approval via either the 510k or PMA pathway? “While I cannot predict the future,” said Malone, “we do hope that more companies will come to the US in the future.” She then detailed a number of ways in which the FDA collaborate with companies in order to speed up the process. The early feasibility study, for example, allows testing to be done in parallel to the study “to help promote both innovation and bringing these devices to clinicians and to patients”.

Looking forward, Peter Schneider (San Francisco, USA) asked Malone if she could provide any details on the upcoming breakthrough pathway. “We are hearing a lot about it but we do not really know exactly what it means and how it is supposed to work, but we are excited about it,” he commented. Malone responded that there are two pathways currently in draft form.

She explained that one—the breakthrough devices pathway—is for life-threatening or irreversibly debilitating devices that may be more effective than the devices that are currently available. The second pathway is for devices that are not life-threatening or irreversibly debilitating but may be a safer option that what is currently offered. She elaborated: “If devices meet these criteria there will be a more efficient process in place and speedier discussions.”

Issue 85 | January 2020

US Preventive Services Task Force releases new recommendations on AAA screening The US Preventive Services Task Force (USPSTF) has released a new recommendation statement on screening for abdominal aortic aneurysms (AAA) in asymptomatic adults 50 years or older.

The recommendation, published in the Journal of the American Medical Association (JAMA), incorporates new evidence and replaces the 2014 USPSTF statement. In the new recommendation, family history of AAA has been added as a risk factor for screening decisions in women, but otherwise the recommendation is consistent with the 2014 USPSTF statement.

A

s of 10 December 2019, the USPSTF suggests one-time screening in men aged 65–75 years who have ever smoked, selective screening for AAA in men aged 65–75 years who have never smoked, against routine screening for AAA with ultrasonography in women who have never smoked and have no family history of AAA, and concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for AAA in women aged 65–75 years who have ever smoked or have a family history of AAA. In a more detailed summary of the recommendation that clinicians selectively offer screening for AAA in men aged 65–75 who have never

smoked, rather than routinely screening all men in this group, the USPSFT elaborate: “In determining whether this service is appropriate in individual cases, patients and clinicians should consider the balance of benefits and harms on the basis of evidence relevant to the patient’s medical history, family history, or other risk factors, and personal values.”

The statement details that the prevalence of AAA has declined over the past two decades among screened men aged 65 years or older in various countries such as the United Kingdom, New Zealand, Sweden, and Denmark, with the reduction in prevalence being attributed to the decrease in the incidence of smoking over time. In the USA, however, current prevalence of AAA

Abdominal aortic aneurysms is unclear because of the low uptake of screening.

To update its 2014 recommendation, the USPSTF commissioned a review of the evidence on the effectiveness of one-time and repeated screening for AAA, the associated harms of screening, and the benefits and harms of available treatments for small AAAs (3–5.4cm in diameter) identified through screening.

Based on a review of the evidence, the USPSTF concludes with “moderate

Family history of AAA has been added as a risk factor for screening decisions in women.” certainty” that screening for AAA in men aged 65–75 years who have ever smoked is of “moderate net benefit” and that screening for AAA in men aged 65–75 years who have never smoked is of “small net benefit”. They also conclude that the evidence is “insufficient” to determine the net benefit of screening for AAA in women aged 65–75 years who have ever smoked or who have a family history of AAA, and finally that they conclude with “moderate certainty” that the harms of screening for AAA in women aged 65–75 years who have never smoked and have no family history of AAA outweigh the benefits.

Guidelines director at NICE faces questions on AAA uncertainty Paul Chrisp, the director of the Centre for Guidelines at the National Institute for Health and Care Excellence (NICE), spoke at the annual meeting of the Vascular Societies’ Annual Scientific Meeting (VSASM; 27–29 November) about what the institute does, and how they do it. Chrisp detailed the core principles of NICE, addressed the challenges they face, and considered the “bigger picture”, in keeping with the theme of the President’s Symposium during which he spoke—safe, sustainable vascular services for 2020 and beyond. While some delegates noted that the talk provided useful insight as context to the guideline on diagnosis and management of abdominal aortic aneurysm (AAA), many had specific questions and concerns regarding the draft of the guidelines, with one delegate remarking: “We still do not know”.

CHRISP BEGAN BY outlining that NICE is “an independent organisation responsible for providing evidence-based guidance on health and social care in England”. He specified that they use evidence that is “relevant, reliable, and robust,” and also take into consideration many other factors, such as population benefits, cost effectiveness and implementation issues.

“We ask our committees to produce guidance that will benefit the most people while also taking into account fairness and respecting individual choice and preferences,” going on to emphasise the challenges facing its advisory committees in balancing “all that complexity”.

Following the presentation, several delegates had questions and comments for Chrisp. Michael Jenkins (London, UK) remarked: “It was great to get a broader view of NICE,” which—in the eyes of “many in the vascular community”—has been “synonymous” with aneurysm draft guidelines over the last 18 months. He asked if Chrisp could give any “upfront knowledge” on any progress on the AAA repair guidelines.

Chrisp responded: “It takes time to get to a point where the committee is happy and satisfied, NICE is happy and satisfied, and you as clinicians and commissioners are able to take those recommendations and put them into practice,” concluding that “triangulating those three aspects is hard”.

The discussion largely focused on concerns

We do use different types of evidence when it is appropriate to answer the question that is in front of us.” surrounding the draft guidelines for AAA repair. Ross Naylor (Leicester, UK), for example, remarked that he has previously been involved in the process of putting together stroke guidelines, noting that “part of the

15

“Recommendations should be expanded” In a press release, it is noted that Marc Schermerhorn, chief of the Division of Vascular and Endovascular Surgery at Beth Isreal Deaconess Medical Center (BIDMC; Boston, USA) recently authored two perspective pieces on this topic—one in the journal JAMA Surgery and another in the journal Circulation.

According to Schermerhorn, screening should be expanded to two populations in particular: women with one risk factor and patients over the age of 75 years who are in good health. The cost of screening is low and those populations have sufficiently high prevalence of the disease.

“Although AAA is less common in the overall population of women, the prevalence in select subgroups such as smokers and those with heart disease is comparable to men,” says Schermerhorn.

“Similarly, patients older than 75 years have the highest risk of aneurysmrelated mortality, but are not eligible for screening under the current guidelines, despite excellent life expectancy.”

problem we faced was that it is preferred that most of the evidence is based on randomised trials,” many of which are “very historical”. According to Naylor, NICE was described as a “spoilt child” in a comment made at VEITHsymposium (19–23 November, New York, USA) for not referring to modern evidence and instead relying “solely” on randomised trials. “NICE relies heavily on randomised trials but when [they] are so old, how do you move on?” Naylor asked Chrisp. “We recognise that and we do use different types of evidence when it is appropriate to answer the question that is in front of us,” replied Chrisp, to which Naylor responded, “It does not always seem like that”.

Continuing with the theme of evidence, to which Chrisp referred many times during his presentation, Roger Greenhalgh commented on the importance of context: “I think we should have the perspective that endovascular repair is a stage, a step towards the future,” urging NICE to “keep your minds open”. “We always have open minds,” replied Chrisp, adding that NICE “always responds to significant changes in the evidence base” and that they update their recommendations in accordance with evidence changes.

One final comment to Chrisp considered possible variance between the decision of the patient and the physican on the one hand, and the recommendations of NICE on the other, to which Chrisp noted that “guidelines are not mandatory, however they do reflect what the committee think is the best evidence and they should be taken into account”. President of the Vascular Society, Ian Loftus, ended the discussion with a comment that NICE has been “very engaged” with the vascular community and has listened to their concerns and continues to do so. “We still do not know what the final outcome and wording [of the AAA guidelines] will be,” he added, addressing the fact that there is still the potential for change before the guidelines are published.

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January 2020 | Issue 85

Collaboration

Vascular surgeons and vascular scientists pledge to advance aortic care together At the most recent Vascular Societies’ Annual Scientific Meeting (VSASM), which took place 27–29 November 2019 in Manchester, UK, vascular surgeons from London, UK, discussed plans for the upcoming DETECT Study (Detection of EVAR sac expansion using ultrasound surveillance). This study aims to optimise the follow up of elective endovascular aneurysm repair (EVAR) patients by investigating the possibility of managing follow up in the community under certain clinical circumstances. DETECT is under the auspices of the Vascular Society and at their collaborators’ meeting it was appreciated that the study will be impossible to conduct without the involvement of Society of Vascular Technologists (SVT) members. Mari Murumets (Imperial College London, London, UK), vascular scientist for the DETECT study, duly attended the ad-hoc meeting with SVT the following day and reported similar concern that the two societies were not collaborating as they might.

TO DISCUSS THIS further, the DETECT team organised a meeting with the SVT, during which Dominic Foy, president of the SVT, Lee Smith, vice president of the SVT, Murumets, and Florence Prior-Evans (study manager of DETECT) discussed the potential for

collaboration with then VS president Ian Loftus, VS secretary Sophie Renton and VS council members, Michael Jenkins and Rachel Bell, who all supported the initiative.

Murumets summarised the aim: collaboration between vascular scientists

and vascular surgeons to advance treatment in the interest of the patient.

An opportunity for further discussion was offered for six months’ time at the Charing Cross (CX) Symposium in London (21–24 April). Subsidised registrations will be offered to encourage further discussion on this topic.

Discussion will then be brought back to the Annual Scientific Meeting in November 2020. It is already appreciated that SVT members and specialist vascular nurses are so committed to NHS output that Continuing Professional Development (CPD) for these crucial professional colleagues is as important as Continuing Medical Education (CME) if proper collaboration is to be achieved for best patient management.

Despite this forward-looking step, it was acknowledged that it will take time to ensure that interdisciplinary

Advance in patient care will only happen if we come together and speak in a language that everyone understands.” collaboration is the norm in medical research. Murumets pointed out to Vascular News that, across Europe, the situation is “even more complicated” and engaging allied health professionals with research is “very challenging”.

Murumets also acknowledged the fact that the profession of a clinical

New Zilver PTX data presented at autumn 2019 meetings At this year’s Vascular Interventional Advances (VIVA) conference (4–7 November, Las Vegas, USA), Michael D Dake presented data on Zilver PTX that supports the device’s benefits across different patient groups.

DAKE PRESENTED THE latest data regarding Zilver PTX, Cook Medical’s paclitaxel-coated stent that is used to treat peripheral arterial disease (PAD). His presentation focused on findings that Zilver PTX shows benefits for a variety of patients.

“Our ultimate goal is to help patients suffering from PAD. That is why these data are so important—behind each one of these data points is a real person. As we continue this discussion on paclitaxel-coated devices, we will keep providing as much information on Zilver PTX as we can so that patients and physicians can make the best decisions,” said Mark Breedlove, vice president of Cook Medical’s Vascular division.

In Cook Medical’s ongoing review of data relating to the Zilver PTX peripheral arterial stent, patient-level data for Zilver PTX were evaluated to determine if there was an increased mortality risk due to paclitaxel and the impact of risk factors on outcomes. Data presented at VIVA were collected from a five-year randomised controlled trial. In the trial, patients with PAD were initially randomised to be treated with either Zilver PTX or angioplasty. When the data were analysed, it was discovered that patients assigned to the Zilver PTX group had more risk factors than the control group, despite the trial’s randomisation of patient assignment.

The trial had a study design that allowed for patient crossover to treatment with Zilver PTX within the first year. Taking actual treatment into account, analyses

vascular scientist “does not exist” in many European countries, where instead, scans are performed by medical doctors, nurses, and/or other healthcare professionals, e.g. vascular assistants.

Murumets commented that performing an ultrasound is “often an add-on” to the main duties of these practitioners, whereas in the UK, vascular labs are “fully dedicated” to vascular scanning.

Murumets emphasised that the lack of standardised training and regulations in Europe has led to “great disparity of skill and knowledge” available for ultrasound practitioners, many of whom “struggle to access resources needed for specialist training”.

“Vascular scientists need to feel that they are part of the bigger picture and that their input is crucial,” Murumets pointed out that advances in vascular technology are “moving fast” and that

of the complete five-year data for Zilver PTX show no increase in long-term mortality for the paclitaxeleluting stent. When evaluating potential risk factors for freedom from target lesion revascularisation (TLR), data continue to support the benefit of Zilver PTX across a variety of patient risk factor groups.

When considering treatment options for PAD, the US Food and Drug Administration (FDA) recommends that physicians discuss both risk and benefit possibilities with their patients.

At this year’s VEITHsymposium (19–23 November, New York, USA), Marc Bosiers presented data showing that patient treatment with the Zilver PTX stent has several benefits when compared to traditional bypass surgery.

The data, which were gathered from a randomised controlled trial, show that treatment with Zilver PTX results in fewer complications and shorter hospital stays for patients with PAD. To better understand the impact of Zilver PTX, Cook Medical funded a five-year physician-sponsored study called ZILVERPASS that compared the effects of treatment with Zilver PTX to traditional open prosthetic bypass surgery. The study was a randomised, multicentre trial that involved 220 patients in four countries.

The data presented at VEITHsymposium show that the procedure with Zilver PTX takes about half the time

this progress should not be happening in isolation, but deserve a chance to be integrated.

She concluded: “Advance in patient care will only happen if we come together and speak in a language that everyone understands,” urging future collaboration for patient benefit.

as a bypass procedure. Patients who were treated with Zilver PTX had a hospital stay that was on average five days shorter. Thirty days after the procedure, patients who were treated with Zilver PTX for long and complex lesions were 60% less likely to have complications than patients who had bypass surgery. In addition, other clinical outcomes of Zilver PTX were comparable to those of bypass surgery, according to the two-year data.

This study is continuing to collect results through five years.

“Our mission with Zilver PTX—and with every product we make at Cook Medical—is to try to improve people’s lives. Cook Medical has released extensive data around Zilver PTX, and this device continues to show benefits across a wide spectrum of patients. We hope that by continuing the conversation around paclitaxel, physicians and patients can make more informed decisions,” said Mark Breedlove, vice president of Cook Medical’s Vascular division.

Zilver PTX (Cook)

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January 2020 | Issue 85

Artificial intelligence

How artificial intelligence can be used for aneurysm follow-up Stéphan Haulon Dominique Fabre Comment & Analysis In the Aortic session at this year’s CACVS meeting (23–25 January, Paris, France), Stéphan Haulon and Dominique Fabre discussed the rise of artificial intelligence (AI), informing delegates how this technology could be the solution for aortic aneurysm follow-up.

Here, they give a summary of their key points.

ARTIFICIAL INTELLIGENCE (AI) applied to medicine has been growing exponentially in recent years, according to the number of scientific publications in the field. Its efficiency at characterising and learning from large amounts of data makes it well suited to tackle the challenges of medical imaging.

And challenges, there are many: Aging population, systematic use of imaging at every step, new generation equipment with a 40 fold increase of output images over the last 30 years.

Overwhelmed Radiologists are asked to read thousands of images daily while everything suggests that a very needed revolution is coming: a large volume of digital data, unprecedented computing powers and detection or characterization

questions that are often well defined. The training of high-performance machine learning models has become a reality.

Aortic aneurysms diameter measurements fit as an ideal candidate to benefit from more data-driven automatisation: it is a tedious and timeconsuming task with high inter- and intra-operator variability.1 While there are several commercially available tools to assist on these measurements, none provide full automatization. Most are efficient in segmenting the lumen of the aorta but often fail at capturing the full diameter of the thrombus (less contrasted on CT scans). Aneurysm measurement is performed to decide whether to intervene and during follow-up after open and endovascular repairs.

To address this challenge, we initiated a partnership with a young startup specialised in AI in Medical Imaging (Incepto Medical, Paris, France) using Machine-Learning-based solutions.

In this project, we first retrospectively collected a large number of CT scan examinations from patients who benefited from an abdominal or thoracic aortic aneurysm endovascular repair at Marie Lannelongue Hospital, France. All preand post-operative images available were included, providing a large variety of cases, with various segments of the aorta, various lesion sizes, in the presence of endografts or not, evolving or not, and from different hospitals, and therefore CT manufacturers and models. On all of these examinations, hundreds of contrasted CT scans were segmented manually to constitute a large segmented aorta database with their outer maximum diameters. We then built a pipeline of algorithms. A first one, on the localization of the aorta area in chest and / or abdominal CT scan. A second one, on the segmentation of the localized aorta. These two algorithms are 3D Fully Convolutional Networks models.

A third one, on the computation of the central line of the segmented aorta. And finally a last one, on the measurement of the maximum external diameter perpendicular to the central line, the smallest axis.

The results, although preliminary, show a good performance in segmentation of the aorta by including the outer wall of healthy zones and dilated zones with the thrombus. The results are also quite high in cases with the presence of stents.

Usual next steps of this work will include an increase of the training database, by manually segmenting more

aortas, internal and finally external validations. For internal test set, two experienced operators will manually measure on a large variety of cases (with and without endograft, on normal and aneurysmal aortas), external aortic diameters at 8 levels of the vessel. This ground truth will be used to assess the algorithmic pipeline performance, inter and intra-reader variability.

Several recent works have been published around automatic aortis segmentation. But to our knowledge, our database of hundreds of exams is by far the largest and the only one to address the entire aorta, from the ascending aorta down to the iliac arteries, when others have only addressed the abdominal portion of the aorta.2–4 Another originality of our approach was to consider a large amount of exams (80% of our database) where a graft was present in the aorta, against only six cases out of 40 in Lareyre et al and none in Le et al.

Finally, the close collaboration between surgeons and data scientists allowed us to elaborate a tool specifically designed to fit smoothly into the clinical workflow.

References 1. Mora et al. Eur J Vasc Endovasc Surg. 2014 2. Lu, Jen-Tang, et al. “Deep AAA: clinically applicable and generalizable detection of abdominal aortic aneurysm using deep learning.” International Conference on Medical Image Computing and Computer-Assisted Intervention. Springer, Cham, 2019.

3. López-Linares, Karen, et al. “Fully automatic detection and segmentation of abdominal aortic thrombus in post-operative CTA images using Deep Convolutional Neural Networks.” Medical image analysis 46 (2018): 202–214.

4. Lareyre, Fabien, et al. “A fully automated pipeline for mining abdominal aortic aneurysm using image segmentation.” Scientific reports 9.1 (2019): 1–14.

Stéphan Haulon and Dominique Fabre are vascular surgeons at the Aortic Centre, Fondation Saint Joseph Marie Lannelongue, Paris, France.

LimFlow announces positive sixmonth data from PROMISE I US early feasibility study LimFlow SA today announced the presentation of positive six-month data from the full patient cohort in its PROMISE I early feasibility study of the LimFlow percutaneous deep vein arterialisation system. Results were presented on the podium at the 2019 Vascular InterVentional Advances conference (VIVA; 4–7 November, Las Vegas, USA) by Daniel Clair, PROMISE II principal investigator and chair of the department of surgery at the University of South Carolina (USC) and Palmetto Health-USC Medical Group.

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indings from this early feasibility trial are very promising,” said Clair. “They show that the LimFlow system is a novel, safe and reproducible approach for improving wound healing and reducing amputation rates in a patient population for whom amputation would otherwise be considered inevitable. It is very encouraging to be able to offer hope to patients that cannot be treated with any current technology today.”

PROMISE I is a multicentre, prospective, single-arm study conducted at seven US centres encompassing 32 end-stage—or “no option”—chronic limb-threatening ischaemia patients, 100% of whom had non-healing wounds on the target foot, 69% of whom had diabetes, and 34% of whom had renal insufficiency.

At six months, the LimFlow system achieved an amputation-free survival rate of 74%. A strong trend

of successful wound healing was also demonstrated, with 67% of wounds classified as healed or healing at six months and 100 percent healed or healing at nine months. Technical success was 97%.

When all other therapeutic options have been exhausted and a CLTI patient is facing major amputation, the minimally-invasive LimFlow system is designed to bypass blocked arteries in the leg and deliver oxygenated blood back into the foot via the veins. For many patients, restoring perfusion in the lower limbs resolves chronic pain, improves quality of life, enables wound healing and prevents major amputation.

“We are enthusiastic about the exceptional results for the LimFlow System,” said LimFlow CEO Dan Rose. “Our goal with the technology is to fully heal previously non-healing wounds and save more patients

LimFlow

from amputation, improving their quality of life and preventing the downward spiral that comes from losing a limb. With the recent FDA approval of our pivotal trial, we look forward to shortly commencing enrolment in the USA and continuing to build evidence for the therapy.”

CLTI is the most severe form of PAD and often occurs in patients suffering from coronary artery disease, diabetes, obesity, high cholesterol and high blood pressure. Patients with CLTI often experience profound, chronic pain and develop festering wounds or infections that lead to major limb amputation, an event closely associated with increased mortality and reduced quality of life. To relieve the symptoms of CLTI, patients today are treated primarily with angioplasty or open bypass surgery. In many late-stage patients, however, neither option is feasible due to extensive disease in the target arteries or other anatomical constraints.

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January 2020 | Issue 85

Dreiländertagung 2019

Highlights of the 2019 Dreiländertagung Dittmar Böckler Comment & Analysis Dittmar Böckler talks to Vascular News about the recent Dreiländertagung meeting, outlining its history and highlighting key sessions, including an anniversary meeting of the founding fathers of the German Vascular Society, a look at the future of vascular surgery and vascular medicine, and a session on recently published guidelines.

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rom 16–19 October 2019, the ninth so-called “Dreiländertagung” took place in Mannheim, Germany.

The three German speaking Societes of Vascular Surgery, from Germany, Austria and Switzerland (abbreviated as DGG, ÖGG and SGG) celebrated their annual meeting together. This joint meeting goes back to an old tradition starting in Salzburg, Austria in the year of 1979. Since then, every three years his huge meeting takes place alternately in Germany, Austria and Switzerland.

The scientific programme in Mannheim included 34 sessions with over 200 presentations and was expanded by workshops, lunch symposia and a separate nursing conference.

A special programme for medical students was embedded and introduced

the fascination of vascular medicine and surgery to the young and next generation of physicians.

More than 1,850 attendees participated in this three-and-a-half days meeting, in which three sessions must be highlighted: On the occasion of the 35th anniversary of the foundation of the Germany Society of Vascular Surgery (DGG), which took place on 7 December 1984 in Munich, Germany, the “founding fathers” of the DGG got together in Mannheim and told attendees “on stage” about the circumstances to practice vascular surgery and their motivation and necessity to separate from general surgery into an individual society of vascular surgery. At that time, surgical department covered all surgical disciplines, in which vascular played

The “founding fathers” of the DGG

a minor role. The majority of leading professors at university departments considered this act as a revolt or mutiny and threatened them with contract termination. The “founding fathers were nevertheless courageous and convinced enough to move ahead.

An international session in English, with simultaneous translation, highlighted the “Future of Vascular Surgery and Vascular Medicine”.

A famous international faculty with pioneers in the field (Alison Halliday, Oxford; Roger Greenhalgh, London; Frank Veith, New York; Barry Katzen, Miami; Stéphan Haulon, Paris; Joseph Bavaria, Philadelphia; Michel Makaroun, Pittsburgh; John Matsamura, Madison and Jos van den Bergh, Lugano) shared their vision of the near future of vascular disciplines with a final panel discussion.

In a joined session which was called the “ESVS meets DGG”, current published guidelines were presented by prestigious speakers and representatives of both societies. The ESVS guideline on

Core outcome sets developed in UK for patients undergoing lower limb amputation In the area of lower limb amputation, core outcome sets “should be adopted on all future studies recruiting patients” said Graeme Ambler (University of Bristol, Bristol, UK), who was speaking at the Vascular Societies’ Annual Scientific Meeting (VSASM; 27–29 November 2019, Manchester, UK). Developed in a four-stage process, Ambler discussed how the core outcome sets address a range of concerns involved in the care of amputees.

“AMPUTATION IS A feared complication of vascular disease and diabetes, but there are also many stakeholders, so it was not clear to us whose opinion on the most important issues should be listened to,” Ambler noted at the beginning of his presentation.

It was further explained by the speaker that the purpose of developing core outcome sets is to aid comparability between studies and allow for additional meta-analysis, as well as directing focus towards the issues most important to patients, carers and medical professionals.

The process of developing new core outcome sets for lower limb amputations “began with a systematic review looking at all outcomes that had previously been reported in research on amputees,” Ambler revealed, before reiterating that 440 studies on lower limb amputations—most of which were observational—were found.

In addition to this, a huge number of different outcomes were reported by these various studies; Ambler highlighted that “281 outcomes reported in these 440 studies derived from just one of the investigations,”

demonstrating poor research efficiency in this area.

Results of this systematic review were supplemented by consultation with focus groups, which involved all key stakeholders and ensured that no outcome was missed due to not being covered by previous research.

Each of the groups, which were divided into patients and carers, allied healthcare professionals and a group of medically trained healthcare professionals, in accordance with the previous development of core outcome sets, had six to 10 participants.

After pooling results from the systematic review and focus group sessions, a total of 50 key domains were established to take forward to a three-round Delphi survey, “which was again completed by all

We think these sets should be adopted on all future studies recruiting patients.”

graft infection, which will be published soon in the European Journal of Vascular Surgery (EJVS), was presented “first on podium” from Holger Diener, Hamburg Germany, one of the leading writing commitee members.

In a special ceremony, Barry Katzen, from Miami, USA; Michael Jacobs, from Maastricht, The Netherlands; Takao Ohki, Tokyo, Japan; and Thomas Hupp from Stuttgart, Germany, were given the award of honorary membership of the German Society of Vascular Surgery.

These personalities were honored for their lifelong commitment, dedication to support of vascular surgery in Germany This year’s annual meeting of the DGG will take place from 23–26 September in Bremen, Germany and the next 10th Dreiländertagung in Vienna, Austria from 19–22 October 2022.

Dittmar Böckler is professor of vascular surgery at the University of Heidelberg, Germanty, and is past president of the German Society of Vascular Surgery.

key stakeholders”. About the survey, Ambler said: “Outcomes were rated twice, because we felt that outcomes might be different between studies focused on short-term outcomes, where perioperative issues might be most important, and medium-term studies out to a year or two where issues around mobility and independence might come to the fore.” In the end, 91 people completed all three rounds of the survey.

According to the survey, the key short-term outcomes were death, pain and stump-related complications, as well as hospital care, readmissions and re-amputation.

Effective communication between a healthcare team, and patients and carers, was also considered to be incredibly important.

“With regard to medium-term outcomes”, Ambler outlined that “somewhat as expected, problems with mobility, independence, social reintegration and quality of life also came up”.

The speaker then explained that core outcome sets were taken to a consensus meeting, held in April 2019 and attended by all key stakeholder groups. While this meeting ratified the findings of the Delphi survey, it was also expressed that issues related to psychological morbidity and deterioration of the other leg were also important.

Summarising the project and its endpoint, Ambler commented: “In conclusion, although we have developed these core outcome sets, there is still a lot of work to do; this is because we need to establish the best way to measure these outcomes, especially factors such as communication which have not been studied at all.

That being said, we think these sets should be adopted on all future studies recruiting amputee patients.”

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January 2020 | Issue 85

New guidance

ESC/ESVS consensus document gives clear recommendations for patient follow-up after revascularisation for peripheral arterial disease New guidance on monitoring patients after revascularisation for peripheral arterial disease (PAD) has been produced by the European Society of Cardiology (ESC) Working Group on Aorta and Peripheral Vascular Diseases and the European Society for Vascular Surgery (ESVS) to enable “optimal surveillance of revascularised patients beyond the perioperative period”. The consensus document was published by Maarit Venermo (Department of Vascular Surgery, Helsinki University Hospital and University of Helsinki, Finland) and colleagues in the European Journal of Vascular and Endovascular Surgery.

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hile ESC/ESVS guidance produced in 2017 advises about the indications of PAD requiring revascularisation, there is a lack of good evidence about optimal surveillance after treatment. The authors therefore sought to “systematically review the literature addressing followup after revascularisation and to propose a consensus document as a complement to the recent guidelines.”

Venermo et al explain: “The opinion of the authors of this interdisciplinary consensus document is that the proposed surveillance strategy may be appropriate while awaiting better quality data to be acquired. Importantly, the regular follow-up of revascularised patients does not systematically imply the use of imaging techniques. Clinical assessment and implementation of preventive measures remain the pillars of the follow-up programme. These could either be performed by general practitioners or cardiovascular specialists (cardiologists, vascular physicians, or vascular surgeons) according to the management of patients in different countries.

The recommendations here apply irrespective of the healthcare systems.”

The document elucidates the optimal surveillance required to prevent local and general adverse events taking place in the mid-term (one to 12 months) and long-term (>12 months) after revascularisation. General cardiovascular prevention is an important aspect of follow-up alongside imaging when needed. Venermo and co-authors describe the most appropriate follow-up according to the indication for revascularisation, namely, extracranial carotid artery disease, upper extremity artery disease, mesenteric artery disease, renal artery disease, and lower extremity artery disease.

The regular followup of revascularised patients does not systematically imply the use of imaging techniques.”

Ultrasound before angioplasty for BTK lesions may improve outcomes without the need for a drug-eluting device Low-frequency, high-intensity ultrasound energy delivery followed by percutaneous transluminal angioplasty (PTA) may improve clinical outcomes in below-the-knee (BTK) lesions without the need for a drug-eluting device, but a larger randomised study is needed to confirm these results. This was the main conclusion presented by Costantino Del Giudice during the ULYSSE registry late-breaking trial presentation at the 2019 Vascular Interventional Advances conference (VIVA) in Las Vegas, USA (4–7 November).

THIS REGISTRY IS A retrospective, nonrandomised, single-centre study evaluating the safety and the efficacy of ultrasoundplasty before angioplasty to treat below-the-knee (BTK) lesions in 22 critical limb ischemia (CLI) patients (35 BTK lesions). All patients were Rutherford category 4–6 and had moderate to severe calcification.

Ultrasoundplasty was performed using the Kapani catheter (Apani Corporation), which delivers a local, low-frequency, high-intensity ultrasound energy to the lesion.The objective of the study was to demonstrate that locally delivered ultrasound energy may modify plaque structure using microcavitational effects and change plaque compliance without risk of vessel dissection and rupture.

Modifications of plaque structure may

potentially improve the outcome of a simple balloon angioplasty.

The primary safety outcomes were the major adverse events at 30 days, recurrence of CLI, and surgical or endovascular revascularisation at six months. The primary efficacy endpoint was angiographic restenosis and target lesion revascularisation at six months.

Immediate outcomes showed good results, with 100% technical success and no major adverse events. At six-month angiographic control, primary patency was 97.1%, with 100% ulcer healing and no target lesion revascularisation and no CLI recurrence. At 24 months, freedom from restenosis was 91.4% as evaluated

by Doppler ultrasound control, with no target lesion revascularisation and no CLI recurrence.

Major mid-term complications following revascularisation are acute thrombosis of the revascularised site despite antithrombotic therapy, and embolism to the arteries distal to the revascularised site.

Intimal hyperplasia can lead to restenosis, with intimal hyperplasia lesions being detectable from a few weeks up to two years after the procedure. Complications directly resulting from the revascularisation procedure can occur after a year, but most long-term complications are related to disease progression and general cardiovascular events, many of which may be avoided with optimal cardiovascular prevention and medical management.

Clinical follow-up should include assessment of symptoms or signs that may suggest revascularisation failure or other cardiovascular condition, and ensuring that the patient is following optimal cardiovascular prevention and drug adherence advice. The authors explain that success of revascularisation in the long-term depends on the patient’s concordance with secondary prevention and exercise training, and an understanding of the symptoms that may indicate revascularisation failure and need them to seek immediate help from vascular specialists. The document provides a checklist of the items that should be assessed regularly during patients’ follow-up visits in terms of cardiovascular prevention, hypertension, diabetes, cholesterol, symptoms and signs related to revascularisation site, and other cardiovascular conditions.

The main imaging technique used to identify revascularisation failures is duplex ultrasound scanning (DUS), which can be repeated over time either to detect abnormalities or to confirm whether symptoms are caused by revascularisation failure or disease progression. Other imaging tests available are ankle brachial index or toe brachial index for the lower limbs, and computed tomography angiography and magnetic resonance angiography for confirming or further investigating DUS findings.

Perivascular temsirolimus could be “viable alternative” to prevent restenosis in BTK lesions It was announced recently that results of the TANGO low-dose cohort compared to controls are positive, both for primary and secondary endpoints. These latest findings were presented by Ehrin Armstrong at the 2019 Vascular Interventional Advances conference (VIVA) in Las Vegas, USA (4–7 November).

According to Armstrong, perivascular temsirolimus is being developed as a “viable alternative” to prevent restenosis after below-theknee (BTK) peripheral artery interventions, and TANGO highdose data are “forthcoming”.

THE TANGO TRIAL is a phase II, dose escalation, double-blinded trial comparing the delivery of temsirolimus to saline control in patients with severe claudication or critical limb ischaemia.

This is the first US trial to investigate a sirolimus analogue to improve the durability of peripheral revascularisation procedures. Armstrong commented that the present results warrant a move to Phase III trials.

The purpose of the trial is to limit neointimal hyperplastic tissue growth into the artery after endovascular BTK revascularisation procedures, where paclitaxel-coated balloons have had limited success.

Results are now available comparing Bullfrog micro-infusion device (Mercator MedSystems) delivery of either low-dose temsirolimus treatment (0.1mg/mL; n=20) or saline control (n=20) into the perivascular tissue around lesions subsequent to revascularisation. Patients (Rutherford category 3–5) with up to 30cm-long BTK lesions were enrolled in the study.

The primary safety endpoint was 30day freedom from major adverse limb event or postoperative death, and no events were observed.

The primary efficacy endpoint was improvement in six-month transverse view vessel area loss, an angiographic measure that uses the opacified area of the lesion to approximate the neointimal volume.

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January 2020 | Issue 85

Education

VIVA keynote: Medical education needs a reboot in the digital age Introduced as “a pioneer in the vascular arena”, Michael Dake, senior vice president of the University of Arizona Health Sciences, Tucson, USA, addressed the audience at the 2019 meeting of Vascular and Interventional Advances (VIVA; 2–5 November, Las Vegas, USA) in a keynote lecture entitled “The future of medicine and medical education: How do we prepare the next generation?”

Responsible for the integration of undergraduate and graduate education at his institution, Dake enumerated the lessons he had learned from personal experience concerning physician training.

this big data certainly is not as expensive to process as it was years ago,” he said. “That is good for us.”

Exemplifying the uses of big data, he continued: “Everyone in any healthcare centre or academic community is aware of the buzzwords around precision medicine. There is a lot of emphasis on deep phenotyping: taking large-scale datasets, predicting complex traits and disease risk, whether it is by a variety of ‘omics’ that take large cohorts of individuals and stringently control for clinically phenotyped outcomes, or by mapping genetic overlap between different diseases involving shared pathogenic elements and comorbidity risks.”

Illustrating the idea of genetic phenotype mapping with an example, he cited a study published in Nature Genetics in 2018 by Rainer Malik (Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany) et al that identified a genetic overlap between stroke and related vascular traits at 32 genome loci in 521,612 people. Twenty-two of these loci were new to the designation “stroke risk”.

This is one example of the “tremendous opportunities” afforded to researchers with access to large datasets, Dake opined.

However, he did enumerate several challenges presented by the emergence of big data. “The problem with real world data,” he said, “is that it is, indeed, real

“BIG BIOLOGY AND big medicine is meeting big data,” he began, elaborating: “Some have called it the fourth industrial revolution, where we have an accelerated, exponential convergence of data science, physical science, and life sciences. These are creating enormous opportunities, but also challenges, for all of us. Our main task as educators is to figure out how to integrate large scale, multidisciplinary datasets into our education.”

The convergence of precision medicine and digital medicine

He is enthusiastic about the prospect, fervently anticipative of the future he is advocating: “We are in a period of great innovation. There are tremendous opportunities, and these will continue to grow with technological advances that promise to impact clinical practice and transform medicine and medical education.

The pace of change is rapid; thinking outside the box is essential. The potential impact on medical education and medical care is enormous.”

“How do we drive precision medicine and datadriven healthcare into routine clinical practice?”

Dake asked. He believes the answer lies with artificial intelligence (AI). “Where AI can really help in the future of healthcare,” he said, “is with merging these two dominant trends: precision medicine and digital medicine.”

Dake detailed how new technology platforms that use profiling, automation, and computing to provide deep phenotyping and risk profiling will interact with the “expanded care space”—wearables, sensors, telemedicine, social media and lifestyle metrics, data on consumer patient engagement—to enable remote monitoring of patient health status. This interaction will be mediated by machine learning algorithms. The “potential power” of AI in this context, Dake explained, is to provide analytics for improved decisions and clinical outcomes at lower cost.

Indeed, the cost of big data has decreased dramatically over the last decade. Showing a graph plotting the cost of data relative to speed versus data consumption, Dake demonstrated that the cost of data per second has dropped from nearly US$3 per Mbps in 2004 to less than US$0.1 per Mbps by 2013, while data consumption per subscriber per month rose from less than 10MB a month in 2006 to 225MB a month in 2013. “We can feel confident that at least computation comes cheaply. All

Understanding data structure and application to improve decisions and outcomes will become a critical institutional competency.” world.” Elaborating, he explained how people analytics and large scale databanks had blurred the boundaries between medical research, clinical care, and daily life, rendering every monitored event as a potential data point, every individual as a data node and research asset.

Social spaces are also becoming quantifiable, and with sufficient data, investigators could reveal increasingly predictable behaviour and individual risk patterns.

“This blurring of private and public spaces could lead to complex ethical and legal issues,” Dake commented, noting that consent, privacy, security and surveillance were factors society was “only beginning to address”, and that they would be “increasingly important as areas of focus”.

One of the key benefits of AI, though, is the fact that it can overcome the “bandwidth” limits of humans, Dake enthused. “There is currently a data deluge,” he

said. “Our cognitive bandwidth is certainly challenged and overwhelmed, but I think there is great promise in decision support, and ways that we really can impact the future of medical education for the better.”

He informed the VIVA audience that society was at the cusp of the “era of cognitive computing and decision–support systems”. Using AI algorithms can help draw patterns and sense from such large datasets.

“Clearly we have limits to individual expertise,” Dake said. “We have limits to our individual abilities to multi-dimensionally evaluate data, we have limits to our sensory systems, cognitive experiences and perceptions, and limits to our objective decision-making. This is where AI, deep learning, and machine learning can come to help us.”

Envisioning the future of medicine as made possible

by AI and big data, Dake predicted: “As we evolve from qualitative, descriptive information of variable quality and provenance to quantitative data of known provenance and validated quality, [we will] change from a complex ecosystem of largely unconnected data sources to an evolving, interconnected network of data sources for robust decisions and improved care.”

Digital Darwinism: A looming data divide in medical education

“If you are teaching today what you were five years ago, either the field is dead, or you are,” Noam Chomsky (University of Arizona, Tucson, USA) said. Sharing this quote, Dake added: “Noam Chomsky is 95 years of age, and he is aware of this—so should we be”.

Dake highlighted a shift in medical education, from being science-centric in the 20th century, to becoming more data-centric between 2000 and the present day.

Extrapolating this trend, he said that education will next become network-centric, stressing the importance of students gaining mastery of escalating complexity and massive data.

“There is a digital Darwinism looming,” Dake warned. “Understanding data structure and application to improve decisions and outcomes will become a critical institutional competency. With major skill gaps and predicted personnel shortages, we are going to have to train a new cadre of data scientists, both medical and non-medical, and institutions that lack adequate computation infrastructure and are not committed to this training are going to suffer ‘cognitive starvation’ and relegation to competitive irrelevance.”

So how will medical education adapt to this demand?

Dake outlined his thoughts on curricular emphasis in the 21st century, believing that knowledge capture and creation, not information retention, should be the priority, and that students should be taught to distinguish between information and knowledge. He said that he would like to see future physicians have a deep understanding of probabilistic reasoning, as well as collaboration with and management of AI applications.

Lastly, he underlined the importance of cultivating empathy and compassion in the next generation of doctors, emphasising the “very real” issue of physician burnout, and advocating for a more holistic curriculum prioritising students’ mental health.

The University of Arizona has implemented a programme to “future-proof” its graduates, Dake recounted, taking all of these factors into account.

The institution is following a health sciences strategic plan, comprised of 26 initiatives, which cover a range of topics, from reducing student debt, to increasing the number of nurses and primary care physicians, to creating more flexible learning pathways. While every institution will need to explore ways of tackling its own specific challenges, Dake said, his keynote lecture serves as a blueprint for building a comprehensive medical curriculum capable of reimagining the physicians of the future.

He concluded: “The ultimate goal is the creation of a real-time learning health system, in which the practice and teaching environments learn from each other and are informed by research.”

Issue 85 | January 2020

Conference coverage

False lumen occlusion with candyplug devices improves outcomes for patients after TEVAR for TBADs Complicated type B aortic dissections (TBADs) in the descending thoracic or thoracoabdominal aorta are associated with high levels of morbidity and mortality. Thoracic endovascular aortic repair (TEVAR) has significantly improved outcomes for patients with complicated TBADs compared with open repair, and is first-line therapy for suitable patients alongside optimal medical therapy.

T

EVAR acts to induce false lumen thrombosis and stabilise the aortic diameter. Aortic remodelling after TEVAR, which involves regression of the false lumen and expansion of the true lumen, is associated with better outcomes. However, when complete false lumen thrombosis is not achieved after TEVAR, continuing false lumen patency increases the patient’s risk of aortic rupture and requires treatment with endovascular false lumen occlusion. According to Tilo Kölbel (German Aortic Center Hamburg, Department of Vascular Medicine, University Cardiovascular Center Hamburg), endovascular flase lumen occlusion using e.g. the candy-plug is a simple treatment option obviating the need for complex fenestrated/branched EVAR in patients with chronic TBAD and appropriate anatomy.

Kölbel provided an update on false lumen occlusion techniques at VEITHsymposium, which took place in New York on 19–23 November 2019. He noted that the reason for a lack of aortic remodeling after TEVAR “is because branch vessels coming from the false lumen prevent occlusions of the false lumen. This is also the case in open surgery and this can be prevented using false lumen occlusion.”

Kölbel described a paper by Liu et al (J Thorac

Cardiovasc Surg 2017;155:21–29) which explains the failure to remodel in chronic dissection: “This paper analyses the number of branch vessels originating from the false lumen and its impact on the remodelling of the false lumen. This is maybe how we should pick our patients who require false lumen embolisation in the primary treatment.”

There are numerous ways of creating a surgically modified candyplug. What we need, however, is an off-theshelf device.”

The two most common techniques used for false lumen occlusion are the candy-plug and Knickerbocker techniques. “The main difference between the two,” explained Kölbel, “is the level at which occlusion can be achieved. Candy-plug devices can be used more distally while Knickerbocker is used more proximally, which is

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probably why we continue to do more candy-plugs.”

The candy-plug occluder “allows the false lumen to regress within a short time frame; after two to three years the candy-plug will be compressed in the false lumen and disappear” he said.

The first 18 cases using candy-plug devices Tilo Kölbel showed “regression or stable diameter in the vast majority of patients”. Kölbel continued: “Subanalyses when we had 41 cases showed a high technical success rate and low rate of spinal cord ischaemia of 2.4%.”

Kölbel outlined a case performed by Andrew Unzeitig in Atlanta, USA, in which a double candy-plug was used in a patient with chronic TBAD and sudden onset of thoracic pain: “The patient received TEVAR first, then in this high-risk case, the false lumens had been growing further and two surgically modified candyplugs were used to occlude those with a very nice result of regression of the false lumen.”

He summarised the general approach to chronic TBADs: “In false lumen aneurysm we usually start with a TEVAR and occlusion of the subclavian artery and nowadays we also do the false lumen occlusion plug.

The false lumen regresses in the vast majority of cases and if we see dilatation of the abdominal aorta we do fenestrated and branched TEVAR.” Kölbel concluded: “False lumen backflow limits the success of TEVAR in chronic TBAD. There are multiple techniques to solve this problem, whether we use plugs, coils, glue; candy-plug devices; or the Knickerbocker technique. There are numerous ways of creating a surgically modified candy-plug. What we need, however, is an off-the-shelf device.”

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January 2020 | Issue 85

Conference coverage

Prospective studies are “desperately needed to demonstrate the safety and clinical benefit” of percutaneous pulmonary embolectomy A single-session/single-device therapy has largely been realised for a number of vascular beds, so why not for pulmonary embolism (PE), queried Robert Lookstein (Icahn School of Medicine at Mount Sinai New York, USA) at the 2019 Vascular and InterVentional Advances meeting (VIVA, 4–7 November, Las Vegas, USA).

He described how this type of technology has been broadly adopted for treating ST-elevation myocardial infarction, stroke, and acute deep vein thrombosis as he put forward the case for pharmacomechanical thrombectomy for acute PE. “THERE HAS BEEN a rapid introduction for percutaneous devices, which have been approved for peripheral clot extraction. All have been explored as possible options for percutaneous pulmonary embolectomy,” he said. “We can visualise the problem we are facing as we explore these options when we see the amount of clot that cardiac surgeons can take out—it is truly humbling.”

Lookstein proposed that thromboaspiration has the potential to debulk acute PE in intermediate-risk PE, so reducing/eliminating the need for overnight lysis. He questioned whether the method might also be able to replace surgical embolectomy in high-risk patients and whether this could reduce

the morbidity of open surgery.

He described some of the devices currently available. The first entry into the marketplace was the large-bore 22F AngioVac VORTEX. Not much literature is available about the device, but one paper recommended that further study is needed, along with careful patient selection. The device has been shown to be successful for clots in transit.

The Inari FlowTriever Infusion Aspiration System is a slightly smallerbore 20F device. The device consists of a flow restoration catheter, an aspiration guide catheter, and a retraction aspirator device. It is indicated for the non-surgical removal of emboli and thrombi from blood vessels, and injection, infusion,

and/or aspiration of contrast media and other fluids into or from a blood vessel, and is intended for use in the peripheral vasculature system.

The FLARE study, a prospective, single-arm, controlled, multicentre study, completed enrolment “just over a year ago where up to 168 patients were enrolled. It led to a successful premarket approval (PMA) and ultimately US Food and Drug Administration (FDA) approval for use of the FlowTriever device in the pulmonary circulation,” stated Lookstein.

The technology “clearly demonstrated improvement in RV/LV ratio at 48-hour follow-up and demonstrated clinical efficacy.”

He described how the greatest benefit was seen in patients presenting with acute right ventricular (RV) hypertension and pulmonary artery (PA) hypertension, while patients with relatively normal PA blood pressures “did not see clinical benefit”.

Another study used the FlowTriever thrombo-aspiration device in 38 patients who had an intermediate risk of PE and found “only a modest average drop in PA pressure and 30-day mortality was not

We need a single-session therapy—but there is a lot of work yet to do.”

Penumbra Indigo Aspiration system IDE trial for acute PE meets primary safety and efficacy endpoints Penumbra has announced that the EXTRACT-PE trial successfully met its primary endpoints, demonstrating the safety and efficacy of the Indigo Aspiration System for aspiration mechanical thrombectomy in patients with acute pulmonary embolism (PE). The data were presented in one of the late-breaking clinical trials sessions at the Vascular Interventional Advances (VIVA) annual meeting in Las Vegas, USA (4–7 November).

“T

he positive results of the EXTRACT-PE trial, the first prospective safety and efficacy study of the Indigo Aspiration System, are a step forward in building needed clinical evidence around catheter-based embolectomy in patients with acute pulmonary embolism,” said Akhilesh Sista, EXTRACTPE national principal investigator, chief of Vascular and Interventional Radiology at NYU-Langone School of Medicine, and vice chair of the recently published Interventional Therapies for Acute Pulmonary Embolism guidelines from the American Heart Association. “New AHA [American Heart Association] guidelines state that catheter-based embolectomy may have an important role in severe PE, but that more study is needed. EXTRACTPE is an important first step in determining how and when we should employ promising and innovative catheter-based technologies such as the Indigo aspiration device.”

EXTRACT-PE was a prospective, single-arm, multicentre trial conducted under an Investigational Device Exemption (IDE) from the US Food and Drug Administration (FDA) that evaluated the safety and efficacy of the Indigo Aspiration System in the treatment of acute pulmonary embolism (ClinicalTrials.

gov Identifier NCT03218566). The study enrolled 119 participants across 22 US study centres.

The primary efficacy endpoint was met with a significant mean reduction in right ventricular (RV)/left ventricular (LV) ratio of 0.43, corresponding to a 27.3% reduction at 48 hours after intervention. The primary safety endpoint was reached with a low major adverse event composite rate of 1.7% within 48 hours.

The major adverse event composite included devicerelated death, major bleeding, and device-related serious adverse events as measured by the clinical events committee. Additional data reported included median time of Indigo System usage (37 minutes) and median ICU stay (one day). No thrombolytic drugs were used in 98.3% of patients.

“From a pulmonologist’s perspective, the results of the EXTRACT-PE trial are another important dataset that help broaden the mechanical treatment options for patients

eliminated”.

The latest device to enter the market is the small-bore 8F Penumbra Indigo thromboaspiration system and “has gained traction in acute ischaemic stroke”. Lookstein described how multiple single-centre case reports and case series have demonstrated safety and efficacy with the use of this technology.

EXTRACT-PE, a prospective, multicentre trial to evaluate the safety and efficacy of the Penumbra thromboaspiration system in acute submassive PE, has recently completed and has successfully demonstrated safety and efficacy of the system.

Lookstein noted that “Across the country, there has been an increase in the last decade in the incidence of PE and a rapid increase since the turn of the decade in the use of catheter-based technologies—almost a 500% increase.

Clearly, there is a perception that there is a need for percutaneous approach in treatment of acute PE.” He concluded: “Numerous devices currently exist for aspiration of PE. All have been used clinically and have demonstrated feasibility at being able to be delivered to the pulmonary circulation and aspirate pulmonary embolus. At present, there is no clear consensus regarding appropriate use and which device is most appropriate for which specific clinical presentation. Prospective studies are therefore desperately needed to demonstrate safety and clinical benefit.

We need a single-session therapy—but there is a lot of work yet to do.”

with pulmonary embolism,” said Victor F Tapson, pulmonary critical care specialist at Cedars-Sinai Medical Center in Los Angeles, USA, and EXTRACTPE steering committee member. “The safety profile of the Indigo System and the low rate of bleeding events, combined with the significant reduction in RV/LV ratio seen in the EXTRACT-PE trial, can positively impact the emerging field of acute pulmonary embolism intervention.”

“The Indigo Aspiration System has demonstrated tremendous potential to address patients with clots in other parts of the body, and today’s data show its specific potential in the pulmonary arteries,” said Adam Elsesser, chairman and chief executive officer of Penumbra.

He continued: “Pulmonary embolism is a deadly disease where we see an unmet clinical need and patient opportunity, and we commend the dedication of physicians who are focused on addressing this area. We are excited about the excellent results of this trial and look forward to working together with physicians in the field to bring better treatment options to patients.”

According to EJ Benjamin et al, on behalf of the AHA Council on Epidemiology and Prevention Statistics, PE affects roughly 300,000 Americans per year. In 2014, Penumbra introduced the Indigo System, a continuous aspiration mechanical thrombectomy system designed to remove clot from arteries and veins in the peripheral vasculature.

The Indigo System utilised the Penumbra ENGINE aspiration source to deliver nearly pure, continuous vacuum suction to the Insigo System Aspiration catheters to address thrombus in vessels of various sizes.

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January 2020 | Issue 85

Conference coverage

There may be a link between aneurysm sac exclusion methods and risk of mortality Having an aneurysm is very bad for your health, even if it is repaired, argued Ian Loftus (St George’s University of London, UK) at the 2019 Vascular Interventional Advances meeting (VIVA, 4–7 November, Las Vegas, USA). He described how the size of an aneurysm dictates a patient’s chances of survival, and how even having an aneurysm larger than 5.5cm that has been successfully repaired is an independent risk factor for decreased survival.

“T

he reason is there is an excess of cardiovascular (CV) events and CV mortality in patients with aneurysms,” Loftus said.

Long-term results of the EVAR1 trial, which compared endovascular aneurysm repair (EVAR) with open repair, showed that “EVAR in the long term is not really working. This is related to aneurysmrelated mortality.”

Recently published data from the EVAR1 trial cohort indicate that the aortic size predicts the risk of rupture and the risk of aneurysm-related mortality. Loftus summarised the results of this study: “If you have a decrease in aneurysm sac size, you are unlikely to die from your aneurysm and extremely unlikely to need a rupture-preventing

reintervention (RPR). Aneurysm regression is the key to better aneurysmrelated survival. However, if you have a continuing increase in aneurysm size after repair, you are at increased risk of reintervention, rupture and aneurysmrelated death.”

“While this should not necessarily surprise us,” continued Loftus, “it is important when we start to consider long-term aneurysm-related outcomes.”

Loftus described how the New England group in the USA have shown that aneurysm sac expansion is an independent factor for predicting mortality after EVAR. Among a large cohort of patients with sac regression “there was a clear relationship between the degree of aneurysm sac regression and survival”, he noted, “while,

conversely, there was a relationship between the degree of aneurysm sac expansion and an increasing risk of mortality.”

“Aneurysm sac behaviour is therefore key when we start to consider outcomes with long-term CV risk,” stated Loftus.

Problems with EVAR are topical in the UK, with draft guidelines suggesting that we should not be using EVAR at all in patients with aneurysm, Loftus commented. “Essentially, this is because we are not really seeing all-cause or aneurysm-related mortality benefits from EVAR. It is clear that failure to exclude the aneurysm sac leads to poor outcomes.

EVAR is associated with higher reintervention rates and rupture risk.

Patients are living longer so they need durable repair. Essential to this, however, is cardiovascular risk management,” Loftus explained.

Open aneurysm repair completely removes or obliterates the aneurysm sac.

However, EVAR leaves “a biologically active aneurysm sac with a large amount of thrombus”.

Loftus outlined how this problem might be overcome: “We have seen attempts to perhaps replicate what we get with open repair by using an endovascular aortic sealing (EVAS) graft and filling the aneurysm sac with a polymer-filled bag, which might alter the biological behaviour of the aneurysm sac. This method also has the benefit of obliterating and eradicating type 2 endoleaks.”

In studies comparing patients treated

with EVAR and with EVAS using sacfilling techniques, those treated with EVAS appear to have benefits in terms of CV and all-cause mortality. There appear to be biological and physiological reasons for this, noted Loftus: “Sac filling alters the inflammatory response of the body in the patient treated with the EVAS device.”

I think it is vital that we do, however we do it, tackle this longterm CV risk for our patients with aneurysms.”

Two studies from Europe have demonstrated a marked change in postoperative inflammatory response.

Patients treated with EVAR have high spikes in C-reactive protein inflammatory markers in the postoperative period, while patients treated with EVAS do not.

It therefore appears that there may be some physiological reasons for this.

Loftus concluded: “It is really important when we consider our modality of treatment going forwards that we think about this increase in risk of CV mortality and the potential benefit of obliterating and altering the biological response of the aneurysm.”

Four-year data from the IN.PACT Global study highlight durable performance and safety of IN.PACT Admiral DCB Medtronic has announced four-year data from the IN.PACT Global study, which reinforce the long-term durability and safety of the IN.PACT Admiral drug-coated balloon (DCB) in patients with peripheral arterial disease (PAD) in the superficial femoral (SFA) and popliteal arteries. The data were presented in a late-breaking clinical trial session at the Vascular Interventional Advances (VIVA) 2019 conference in Las Vegas, USA (4–7 November).

THOMAS ZELLER, DIRECTOR of the Department of Angiology at Universitaets-Herzzentrum, FreiburgBad Krozingen, Germany, presented the new, four-year results from the full clinical cohort of the IN.PACT Global Study. The results are the first four-year, realworld, fully adjudicated DCB data to be presented in a scientific congress. The IN.PACT Admiral DCB demonstrated durable effectiveness and a strong safety profile in a real-world population.

“The IN.PACT Global study is the largest independently adjudicated real-world evaluation of any peripheral intervention undertaken and includes patients with the most complex lesions observed in any existing DCB clinical study, many of whom have commonly known risk factors for progressive PAD,” said Zeller.

“Even in this real-world patient population, including those with critical limb ischaemia (CLI), we continue to see durable treatment effect through four years. These data further demonstrate the clinical benefit of the IN.PACT Admiral DCB and its ability to be a first-line therapy for patients with challenging lesions.”

Kaplan-Meier estimates demonstrated a freedom from clinically-driven target lesion revascularisation (CDTLR) rate of 73.4% (n=1,406) in a large, real-world

patient population through four years. Of the subjects enrolled, the mean lesion length was 12.09±9.54cm, 18% had in-stent restenosis, 35.5% had occluded lesions, 39.9% had diabetes, and 68.7% had calcified lesions. Overall, the average time to first CD-TLRs in this complex patient population was approximately 570 days.

Based on the Kaplan-Meier estimate, IN.PACT Admiral demonstrated a solid safety profile through four years with a low major target limb amputation cumulative incidence of 1.1% through four years. The freedom from all-cause death through four years was 83.5%, which is comparable to what would be expected in this patient population. This rate is based on data from all subjects enrolled in the IN.PACT Global study, among which 98% had known vital status.

Furthermore, an additional analysis was conducted to evaluate the performance of IN.PACT Admiral through four years in patients with intermittent claudication and CLI based on Rutherford Classification (RCC). The Kaplan-Meier estimated freedom from CD-TLR was 74.5% (n=1,246) in the intermittent claudication (RCC 2/3) patient cohort and 64.8% (n=156) in the CLI (RCC 4/5) patient cohort respectively.

IN.PACT Admiral DCB

“The body of evidence on paclitaxel-coated devices continues to mature with recent significant publications and presentations, including the IN.PACT Global four year data, adding to the totality of evidence generated,” said Mark Pacyna, vice president and general manager of the Peripheral Vascular business, which is part of the Cardiac and Vascular Group at Medtronic.

He continued: “Outcomes from the IN.PACT Global study specifically show that the IN.PACT Admiral DCB, which has now been used to treat approximately 500,000 patients worldwide, can prolong the time between reinterventions in a very challenging patient population by over a year and a half. Long-term and real-world data continue to demonstrate both the safety of these devices and the overall treatment benefit to the patient.”

According to a press release, Medtronic—in collaboration with clinicians, researchers and scientists worldwide—offers the “broadest range of innovative medical technology for the interventional and surgical treatment of cardiovascular disease and cardiac arrhythmias”. It states: “The company strives to offer products and services that deliver clinical and economic value to healthcare consumers and providers around the world”.

Issue 85 | January 2020

Advertorial

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THIS ADVERTORIAL IS SPONSORED BY LOMBARD MEDICAL

“It changes the game”: A novel application of the Altura Endograft System One of the novel applications of the Altura Endograft System is use in the revision of previously placed endovascular grafts or previous abdominal aortic surgery. Jörg Tessarek (Bonifatius Hospital Lingen, Lingen, Germany) has performed a number of such cases, and will be presenting data on his series at the Leipzig Interventional Course (LINC; 28–31 January, Leipzig, Germany). Here, Tessarek discusses the benefits of Altura in this type of revision surgery, details a notable case, and finally considers how this novel application of Altura might be of interest to the wider vascular community.

What are the main challenges of relining aneurysms that have been treated with other devices or by open repair in the past, and which are now failing?

The challenges for relining are located at different levels: coming from below, navigating through the existing device can be difficult, especially in narrow and tortuous anatomies. Maximum overlap of graft components is mandatory really, to achieve reliable fixation of the distal component to prevent further migration. Cannulation of fenestrations or target vessels, which can sometimes be covered by suprarenal fixation bare stents adds further time to the procedure and increases radiation dose, and as such, can put the patient at risks of complication.

In my opinion, Altura changes the game. The device has a low-profile flexible introducer, which enables exact and fast placement. The device relines and excludes the whole aneurysm and the failing endograft, not only parts of it. As a result, the migration forces are no longer applied to already migrating components.

Telescoping of the main body and limb over the same wire makes extensive fluoroscopy use unnecessary.

hich types of devices have you relined W with Altura?

To date, we have relined single tube, double tube and bifurcated grafts successfully. All of these grafts had bare stents for suprarenal fixation and contraindications for fenestrated cuffs and anchors. In one case an iatrogenic infrarenal dissection after aorto-iliac stent placement with rapid growth of the false lumen and intramural hematoma was treated successfully using the Altura device. The residual stent lumen was 4.5mm, which required robust post-dilatation of the endograft.

Have you used Altura to reline surgical grafts?

Not as yet, but with the low profile introducer and the device characteristics, I anticipate that there is likely to be real benefit to this treatment option, particularly in cases where there is evidence of aneurysm expansion, or anastomotic compromise at either end of the grafts.

What do you see as the benefits of using Altura for relining in these cases?

The characteristics of the Altura device enable its use as a complete substitute for failing grafts, or as a reliable repair component for procedural failure at the distal end. By placing the D-shaped graft components inside the lumen with sufficient overlap, this mimics a standard bifurcated graft. Additionally, the unique deployment technique of the limb allows an exact placement at the level of the hypogastric artery, thereby achieving a maximum distal landing zone.

Are there any particularly notable cases that you can share with us?

The most challenging case so far was an Altura relining of a type Ib endoleak after initial placement of a

As this is a novel use of Altura, can we expect any data on it in the near future?

Altura is being used for relining in several centres around Europe and I am aware that some encouraging outcomes are being reported anecdotally.

Hopefully, we can collect data from all over Europe to look at this further; colleagues with known experience in this challenging field have already been contacted.

Disclaimer The Altura Endograft System has not been evaluated in patient populations involving revision of previously placed endovascular grafts or previous AAA surgery.

Refer to the Altura Endograft System Instructions for Use for all Indications, Contra-Indications, Warnings and Precautions.

Jörg Tessarek

Altura is being used for relining in several centres around Europe and I am aware that some encouraging outcomes are being reported anecdotally.”

100mm tube graft and coiling of a distal endoleak.

The graft migrated sideward with the distal end sitting perpendicular to the aortic wall, and coils lying distal to the fabric edge.

After cannulation over two 90° angulations and stiff wire placement, the graft could be slowly moved into the middle of the sack. The two Altura main body components were advanced under local anaesthesia in a routine manner with ballerina position and long overlap, resulting in a complete sealing without any migration of the coils.

How might this novel application of Altura be of interest to the wider vascular community?

The concept of siting a complete independent new endograft inside a failing graft without the need for complex manipulation at renal or visceral target vessel level might be a game changer.

Given an appropriate infrarenal landing zone, deployment of the graft components can be successfully achieved inside any bifurcated graft, independent from its main body length.

Graft overlap is not an issue here because the Altura device excludes the aneurysm and the failing graft by covering the whole diseased or failing segment.

Altura Stent

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January 2020 | Issue 85

Interview

Profile

Ronald Dalman

President-elect of the Society for Vascular Surgery, Ronald Dalman, talks to Vascular News about various aspects of his career. He also considers future development in the field and offers advice to aspiring surgeons.

What led you to become a vascular surgeon?

Experience with mentors and role models—in medical school, Professor Gerald Zelenock at the University of Michigan was my advisor and confidant. He, along with future vascular surgeons Robert Zwolak and Timothy Kresowik and vascular section chief James Stanley inspired me by their example: knowledgeable, capable, confident, and compassionate leaders in their respective domains. During residency in the vascular surgery division faculty at the University of Washington (UW) in Seattle, D Eugene Strandness and Alec Clowes, were equally inspirational in their own way—always asking questions, striving to understand the natural history of vascular disease, leveraging the (then) new abilities of medical ultrasound and physiologic testing to increase diagnostic precision, guide intervention and optimise care. It did not hurt that Kaj Johansen, chief of vascular surgery at Harborview Medical Center and a pioneer in protocolised regional management acute aortic emergencies, also served as the surgery residency program director. Of all the surgical subspecialties represented at UW in the 1980s, vascular and trauma surgery were at the forefront of their respective areas of research and innovation. During fellowship with John Porter, Lloyd Taylor and colleagues in Portland, Oregon, I learned the true meaning of the term “highquality vascular surgery” based on their example and uncompromising standards.

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

Well, the endovascular revolution, now in its third decade, and its integration into mainstream vascular practice, is the most obvious answer. But quality vascular practice today has benefited from so many landmark accomplishments: the development of evidence-based practice, as enabled by the Vascular Quality Initiative and similar registry initiatives; the blossoming of effective medical management options to improve longevity and quality of life in vascular patients; the initiation and success of direct training pathways worldwide for vascular specialists, and the corollary recognition of vascular surgery as a distinct and primary medical specialty; the convergence of vascular specialists worldwide into highly influential writing and consensus committees such as the Lower Extremity Global Guidelines Writing Group… far beyond any one procedure, device or outcome assessment metric, the recognition that quality vascular care is an essential element of good overall health, and deserving of substantial capital and intellectual development by surgeons, healthcare systems, and corporations world-wide is the defining development of my professional lifetime. Keep in mind that the Society for Vascular Surgery (SVS) was founded to champion and celebrate excellence in the technical management of vascular disease by surgical pioneers of the early 20th century. While remaining committed to that ideal, the concept of the “vascular specialist” has come to mean so much more to both the public and our professional colleagues—an extremely validating transition to experience over the last three decades.

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

Acknowledging that predictions are generally a fraught exercise, the societal and financial trends driving the volume to value transition are an undeniable and relentless catalyst for change. We will almost certainly see an ever-increasing emphasis on quality and costeffective outcomes with a framework of populationhealth considerations. Holistic patient, rather than symptom, management is already becoming the norm.

Within a resource-constrained environment, how do we optimise vascular health, function, and quality of life? How do we precisely quantify the benefits that accrue from vascular interventions when necessary?

Technical surgical excellence will always command a premium—where, when, and how can it be delivered in the most cost-effective and sustainable manner possible? The “Medicare for all” controversy roiling political discussions this year in the run-up to the 2020 US Presidential Election is only just the beginning of a much larger health care re-organisation in the USA and most developed nations worldwide. Healthcare resources will flow to those with the best justification for their need—that is our challenge, both individually and collectively—to make the case that vascular care remains a top health care priority.

What do you hope to achieve as president of the SVS?

This question has challenged all my presidential predecessors. For some, the moment was thrust upon them; Peter Lawrence stepped up to address the challenge of overutilisation and ethical practice considerations in response to the seminal New York

If your current situation is not providing you the opportunities you want, look elsewhere.”

Times (NYT) report in 2015, and in doing so defined our speciality and membership as voices of reason and restraint in this critical discussion. For others, such as Michel Makaroun in 2019, championing recognition of the more subtle but no less compelling challenge of maintaining access to quality vascular care at a critical juncture in the evolution of our specialty has been a more planned and predetermined focus. In survey after survey, our members convey pride in the care they provide to some of most vulnerable members of our society, while at the same expressing frustration at the lack of recognition that vascular surgeons receive for the essential role(s) they play in the healthcare system. As a corollary to Makaroun’s access to care focus in 2019, the SVS launched a multi-pronged effort to accurately value and brand the essential services vascular surgeons provide to our society. Both my immediate predecessor Kim Hodgson and I are building off these efforts to ensure that quality vascular care is appropriately

recognised and rewarded by the public and our many partners in health care financing and delivery. Assuming no unanticipated NYT-level disruptive moments this coming year, we plan to leverage the branding, valuation, and wellness initiatives, when they are complete, to proportionately recognise and reward the value that vascular surgeons provide to our healthcare system.

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

Once you are comfortable with your surgical skills, judgement, and practice rhythm (and this usually takes more than a few years), when working in a larger organisation such as a university or employed position, several axioms have served me well. First, know yourself—develop your own career path, be the surgeon/ investigator/partner/mentor you want to be, not who you think others want you to be. This is most important for long-term career and personal satisfaction. If your

Issue 85 | January 2020

Interview

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Fact File

Staff appointments (selected)

2010–present: Walter C Chidester Professor of Surgery, Stanford University School of Medicine (SOM), Stanford, USA 2016–2019: Staff Surgeon, Stanford Health Care/Valley Care, Pleasanton, USA 1991–2005: Primary vascular surgeon, VA Palo Alto Health Care System, Palo Alto, USA

Medical education

2003: Endovascular Fellowship, Texas Tech University, Lubbock, USA 1989–1991: Vascular Surgery Fellowship, Oregon Health Sciences University, Portland, USA 1984–1989: General Surgery Residency, University of Washington, Seattle, USA 1981–1984: University of Michigan Medical School, Ann Arbor, USA (Graduated with Distinction)

Society appointments (selected)

2020: President, Society for Vascular Surgery 2010–2011: President, Western Vascular Society

Journal affiliations (selected)

current situation is not providing you the opportunities you want, look elsewhere. Secondly, strive to understand what is expected of you in all circumstances. This cannot be stressed enough—if your personal goals are not well-aligned with those of your partners or larger organisation, neither you, nor they, will reach them.

Thirdly, collaborate aggressively and ambitiously across disciplines—for myself, the strongest and most powerful collaborations arose from individuals and groups far afield from my department and school. Commercial entities, complementary disciplines such as engineering, health policy and research, implementation science— these relationships have provided me with extraordinary opportunity in my own career. As vascular surgeons we have unique insights into novel solutions for common problems. As you gain experience and success in your own career, those hard-won insights are intellectual bitcoin for powerful collaborations—leverage them to their full extent. Finally, own the problem—we in our specialty are uniquely privileged to provide full

spectrum care for an increasingly common, morbid, and highly expensive spectrum of disease. As emphasised on the #comprehensivevascularcare Twitter thread, our future depends in the breath of our expertise and ability—not mere technicians, diagnosticians, risk-factor experts or public health advocates, but rather all of that, and more: vascular surgeon specialists. Our value is, and should remain, as experts of the disease process we have worked so hard to understand. That expertise provides our patients the ever-improving quality of life they have gained under our care and the success and influence our specialty enjoys today.

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

Time with my wife Jocelyn, a general surgeon, and our two adult children Jessie and Jackson. We love living in Northern California and being part of the Stanford Community. When we have time together outside of work we enjoy playing golf, snow skiing, bicycling (mountain and road), and just being outdoors in and around our home in Portola Valley.

2016–present: Editorial board member, Arteriosclerosis, Thrombosis and Vascular Surgery 1996–present: Reviewer, Journal of Vascular Surgery 2005–2010: Editorial board member, Journal of Vascular Surgery

Recent publications (selected)

n Flores AM, Mell MW, Dalman RL et al. Benefit of multidisciplinary wound care center on the volume and outcomes of a vascular surgery practice. J Vasc Surg 2019. Epub before print. PMID: 31153696. n McFarland G, Tran K, Virgin-Downey W et al. Infrarenal endovascular aneurysm repair with large device (34- to 36-mm) diameters is associated with higher risk of proximal fixation failure. J Vasc Surg 2019;69:385–393.

PMID: 30686336 n External reviewer, Wanhainen et al’s Editor’s Choice – European Society for Vascular Surgery (ESVS) 2019 Clinical Practice Guidelines on the Management of Abdominal-iliac Aortic Aneurysms. Eur J Vasc Endovasc Surg 2019;57:8–93. PMID: 30528142

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Medtronic DCB receives US FDA approval to treat arteriovenous fistula lesions Medtronic has announced US Food and Drug Administration (FDA) approval of the IN.PACT AV drug-coated balloon (DCB), a paclitaxel-coated balloon indicated for the treatment of failing arteriovenous (AV) access in patients with end-stage renal disease (ESRD) undergoing dialysis.

Kidney patients report positive experiences with novel approach to dialysis access

V fistulae are created and used to enable haemodialysis for patients with ESRD. Over time, vessel restenosis limits the ability to use AV fistulae effectively. In order to restore function, patients often undergo one to three maintenance procedures per year, which can result in significant disruptions to critical haemodialysis care and increased costs to the healthcare system. Pivotal randomised trial results from the IN.PACT AV Access trial have shown IN.PACT AV DCB can extend the time between reinterventions by maintaining AV access site patency, therefore maximising a patient’s uninterrupted access to lifesaving dialysis care.

“In many cases, AV fistula are considered lifelines for patients with ESRD as they are the primary access point for life-saving dialysis treatment. When these access sites fail, patients experience delays in their dialysis treatment and require multiple reinterventions to keep the site functioning,” said Vincent Gallo, interventional radiologist at Holy Name Medical Center in Teaneck, USA, and an investigator for the IN.PACT AV Access trial. “With this approval physicians now have access to a safe and extremely effective therapy to slow the progression of restenosis, which results in fewer reinterventions and disruptions in care for these patients.”

The FDA approval is based on data from a prospective, global, multicentre, blinded, randomised (1:1), investigational device exemption (IDE) study, which enrolled 330 subjects, and evaluated the safety and effectiveness of the IN.PACT AV DCB at 29 sites in the USA, Japan, and New Zealand. Early data presented at the Cardiovascular Interventional Radiological Society of Europe (CIRSE) met the primary endpoints in demonstrating the comparable safety and the superior effectiveness of IN.PACT AV DCB compared

A NEW STUDY reports high levels of patient satisfaction with a minimally invasive approach to creating vascular access for kidney patients who require haemodialysis. In addition, the researchers found that nearly all the dialysis access sites, or fistulas, were still functional after two years —a significant improvement over surgically created fistulas.

The study marks the first published two-year data for any endovascular fistula procedure. It was recently published online in the Journal of Vascular Access (JVA).

The multicentre study encompassed 105 US patients who had their fistulas created with the Ellipsys vascular access system (Avenu Medical) and had at least two years of follow-up. Patients’ responses in the study emphasised the avoidance of surgery, a perceived lack of pain and improved body image when compared to patients who underwent surgery.

Haemodialysis requires access to the patient’s bloodstream, which is often created by establishing a permanent connection between an artery and a vein in the arm known as an arteriovenous fistula (AVF).

Instead of an open surgical procedure, the innovative Ellipsys system creates a percutaneous AVF using just a small needle puncture and catheter.

“We knew fistulas created with Ellipsys functioned well in the beginning, but patients wanted to know how long their access sites would last. Our goal was to see how many still worked after two years while capturing patients’ opinions on this innovative procedure,” said Terry Litchfield, a study co-author and president of Access Solutions.

“The results were overwhelmingly positive from both a patient and clinical perspective.”

A

to percutaneous transluminal angioplasty (PTA).

Patients treated with IN.PACT AV DCB maintained patency longer and required 56% fewer reinterventions compared to those treated with standard PTA through six months. Through 12 months the data also showed no difference in mortality rates between the IN.PACT AV DCB group and the PTA control group. Finally, data presented at VIVA 2019 demonstrated superior patency was achieved with IN.PACT AV DCB versus PTA in both de novo and restenotic lesions, and all studied types of AV access.

“Until now, there were virtually no therapies available to treat AV fistulae lesions that had demonstrated an ability to maintain primary patency and reduce reinterventions over time,” said Robert Lookstein, national principal investigator in the USA and professor of radiology and surgery, vice-chair of interventional services, and medical director of clinical supply chain at Mount Sinai Healthcare System in New York, USA. “In the largest AV DCB pivotal study to-date, IN.PACT AV DCB demonstrated the highest primary patency rate through six months and significantly lowered the rate of reinterventions required to maintain patency. With this evidence and approval in hand, we now have a technology that provides a significant clinical benefit of a 56% reduction in repeat interventions, which I believe is a huge win for the haemodialysis community and the patients we treat.”

IN.PACT AV DCB, leveraging technology from Medtronic’s IN.PACT Admiral platform, increases blood flow and reduces thickening of the vessel wall by delivering the proven anti-proliferative drug paclitaxel.

IN.PACT Admiral DCB was expanded for the treatment of failing arteriovenous (AV) access in patients with end-stage renal disease undergoing dialysis.

The results were overwhelmingly positive from both a patient and clinical perspective.”

According to the survey responses, 93% of patients rated their overall satisfaction with the procedure as “excellent” or “very good”. The study authors also reported that nearly 92% of the fistulas continued to function two years after the Ellipsys procedure. In contrast, less than two-thirds of surgically created fistulas are still functional after two years.

IN.PACT AV drug-coated balloon (Medtronic)

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Endovascular arteriovenous fistulas “key part of any dialysis programme” Endovascular arteriovenous fistulas (endoAVF) platforms add additional fistula options for patients and physicians, argues Dheeraj Rajan (University Health Network, University of Toronto, Toronto, Canada, and a paid consultant for BD) at the 2019 Vascular Interventional Advances meeting (VIVA; 4–7 November, Las Vegas, USA). He argues that, due to higher patient satisfaction, good technical success, and low complication rates, as well as the attendant cost savings, endovascular AVF creation will soon be “essential” for any dialysis programme.

T

he first AV fistula, described in 1966 by Michael Brescia, James Cimino, Kenneth Appel, and Baruch Hurwich (all Veterans Administration Hospital, New York, USA), involved the side to side surgical anastomosis of the patient’s cephalic vein and radial artery near the wrist.

“It is important to note,” Rajan said to the VIVA audience, “that over 50 years [since the first AV fistula], we are still talking about the surgical creation of AV fistulas; not a lot has changed in that time. If you think about what kind of innovation has happened in different areas of medicine over those 50 years, and compare it to that in dialysis access, then you can see that we have not really had a lot of innovation in this space.”

He thinks this is changing, however, predicting the mainstream adoption of endovascular AVF creation.

Rajan highlighted the 20–60% failure rate of surgical AVFs to mature, as reported in “meta-analyses and multiple, large studies”—though he did also note that, anecdotally, AVFs may have a higher maturation rate, with several conference attendees reporting a 90% success rate in their own experience. In addition, he told delegates that 80% of patients start dialysis with a central venous catheter (CVC) in place, which he said “is not good for the patient”. Added to these downsides of surgical AVF creation, he commented, “In the world of patient-centred care, it is important to note that 30% of patients do not want to get surgery. It is something we rarely talk about.”

There are two devices currently commercially available for endovascular AVF creation: the 4Fr or 6Fr WavelinQ endoAVF platform, from BD, and the 6Fr Ellipsys vascular access system, from Avenu Medical.

These were both approved by the US Food and Drug

Dheeraj Rajan

Administration (FDA) in 2018, following CE mark approval for Ellipsys in 2016, and WavelinQ in 2017.

The WavelinQ system is a dual catheter system, which uses radiofrequency (RF) energy to vaporise tissue between the artery and the vein, thereby creating an anastomosis between the two vessels.

Describing the commonalities between surgical and endovascular AVF creation, Rajan says screening is “relatively similar”, with both requiring ≥2mm vessels and a perforator. The interventionalist arterialises the deep venous system to the superficial system.

However, he then went on to detail the differences in outcomes between the two methods. The prospective, multicentre NEAT (novel endovascular access) trial, published in the American Journal of Kidney Diseases in 2017 by Charmaine Lok (University Health Network, University of Toronto, Toronto, Canada) et al, concluded than “An endoAVF can be reliably

I think patients will demand this, and they will actually drive a large part of the adoption.” created using a radiofrequency magnetic catheterbased system, without open surgery and with minimal complications. The endoAVF can be successfully used for haemodialysis and demonstrated high 12-month cumulative patencies. It may be a viable alternative option for achieving AVFs for haemodialysis patients in need of vascular access.”

Indeed, primary and secondary patency were better for endovascular AVF creation than outcomes from surgical creation. Primary patency was time from successful AVF creation to the first intervention designed to address thrombosis or stenosis, assist in maturation, or cannulation of AVF abandonment.

Secondary patency was time from creation to the abandonment of AVF. “Maturation rate, with both devices [WavelinQ and Ellipsys], was better than what we see typically with surgery,” Rajan said. Presenting data on WavelinQ from Lok et al’s NEAT trial, he said that the maturation rate in this study for endovascular AVF creation was 91%. In comparison, Rajan showed data from Michelle Robbin (University of Alabama, Birmingham, USA) et al, published in Radiology, that reported a maturation rate of 76% in the upper-arm and 53% in the forearm when using surgical AVF creation.

Patient satisfaction is also superior with endovascular haemodialysis AVF creation, Rajan reported. Indeed, Lok et al found that 96% of patients said they were “satisfied” with endovascular AVF creation. Illustrating this statistic with an anecdote, Rajan recounted: “I will never forget a conversation

I had with a vascular surgeon where he grabbed me, physically grabbed me by my lapel, and said ‘I want in’. I asked him what he meant, and he said ‘You are working on this endovascular fistula thing, I want to invest’. I said ‘We do not know if it really works or not yet or how good our numbers are going to be’, and he said ‘It does not matter, every patient is going to want this first before they want surgery’.”

Another advantage of the endovascular approach listed by Rajan is the reintervention rate. He continued: “In terms of post-creation procedures,” Rajan continued, “the total number of interventions with endovascular access, using WavelinQ specifically, is 0.6 per patient year, compared to surgical, where it is 3.4 per patient year. So looking at our intervention rate, that is six times’ lower than with the surgical approach.” In addition, time to first intervention is longer when the endovascular approach is used.

Rajan also outlined how these factors translate into cost savings: a study by Shuo Yang (Quorum Consulting, San Francisco, USA) and colleagues, published in Journal of Vascular Access in 2017, found that US$11,240 was saved per patient-year following endovascular haemodialysis AVF creation compared with surgically created AVFs, due to the reduced number of reinterventions. “We have follow-up data that shows the cost-savings are even better than that,” Rajan added.

“One of the things to note is, with both devices [WavelinQ and Ellipsys], you are actually not getting rid of traditional surgical options. This actually adds more options for the patient, so you are not eradicating surgical choices. Working distal to proximal, you are adding more sites to create accesses, and these are autogenous fistulas: you are not leaving prosthetic material behind, you are not leaving a stent graft, you are not leaving a stent, there is no suture material here, and that all translates into better outcomes.”

To demonstrate this, Rajan collated the outcomes of major studies published recently, where the technical success rate with endovascular access was consistently above 80%. These studies included the Flex study (2015), the NEAT study (2017), and the EASE study (2019), which all used WavelinQ, as well as the two Hull studies (2017 and 2018), and the Mallios study (2018), which utilised the Ellipsys device. Mean maturation time ranged from 42 days to 118 days, and functional patency was “very high” for both devices, ranging from 87% to 100%.

Adverse events are also rare in endovascular AVF creation, Rajan commented. The number of serious adverse events recorded in these major studies ranged from 0% to 8%, though Rajan noted that events may not always be due to AVF creation. “Depending on the study and how you record adverse events,” he said, “keeping in mind that in studies, when you talk about serious adverse events, this includes strokes, cardiac attacks, car accidents and so on, so there are different adverse events that can be attributed to devices.”

He summarised: “I think this will accelerate and improve patient care. We are talking about not needing pre-operation visits. You could potentially screen patients with ultrasound the day they get a dialysis catheter; you do not need anaesthesia, these are outpatient procedures that can be done with conscious sedation, and this all potentially gets you to getting a fistula on a patient sooner, but also potentially cannulating sooner as well.

“This is coming. I think this adds a different platform for patients, the data suggest technical success and the complication rates are acceptable, there is high cannulation success, high patency with low interventions, and, most importantly, high patient satisfaction. I do think this will be a key part of any dialysis programme going forward, and there have probably been around 2,000 cases performed between both devices globally. I think patients will demand this, and they will actually drive a large part of the adoption.”

January 2020 | Issue 85

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IVUS during haemodialysis access “aids device selection and adequacy of treatment” Narayan Karunanithy Comment & Analysis Narayan Karunanithy outlines the benefits of intravascular ultrasound (IVUS) during haemodialysis access intervention.

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horacic central veins include intra-thoracic segments of the internal jugular, subclavian, brachiocephalic veins and superior vena cava. These veins are located central to the superior thoracic aperture (C7–T1 intervertebral disc level), central to the lateral margin of the first rib, and superior to the diaphragmatic caval opening.1 Patients with haemodialysis access are prone to developing thoracic central vein obstruction (TCVO) due to their underlying renal failure, altered haemodynamics of the arteriovenous circuit, and previous central vein catheter, pacemaker or defibrillator placement. The incidence of TCVO in this patient cohort is thought to be rising and is currently estimated to be 20–40%.2

TCVO may be partial (that is, stenosis) or complete (that is, occlusion).

Patients with TCVO can present with arm/neck/face/breast swelling, pain, access dysfunction and respiratory distress. Visible chest wall collaterals may also be unsightly for the patient.

Most of the haemodialysis circuit can be readily imaged with standard ultrasound, as the circuit is very superficial. However, TCVO can be virtually impossible to image with ultrasound. Computed tomographic (CT) or magnetic resonance (MR) venography can provide excellent depiction of central venous anatomy. However, CTV carries an additional radiation burden and MRV usually requires administration of gadolinium, which may be complex

IN.PACT AV DCB shows “consistent effectiveness performance” in subgroup analysis Medtronic recently shared a sixmonth subgroup analysis from the IN. PACT AV Access trial, which evaluated how the IN.PACT arteriovenous (AV) drug-coated balloon (DCB) performed in different target lesion types, arteriovenous fistula (AVF) types, and target lesion locations in the arm, with the goal of determining where the DCB may demonstrate the most clinical benefit to patients receiving haemodialysis.

THIS ANALYSIS, A follow-up to the full sixmonth clinical outcomes from the IN.PACT AV Access trial, presented at the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) meeting in September, was outlined by Robert Lookstein (Mount Sinai Hospital, New York, USA) at the Vascular Interventional Advances (VIVA) meeting in Las Vegas, USA (4–7 November). At the time of the November presentation, the IN.PACT AV DCB was an investigational device. The device has since received US Food and Drug Administration (FDA) approval.

in this cohort of patients with end stage renal failure or approaching it. Hence the mainstay of CVS assessment is currently digital subtraction angiography (DSA).

IVUS is an invasive modality that provides cross-sectional imaging of the veins but without the need for ionizing radiation or contrast administration. In addition to being a diagnostic tool that is easy and repeatable, it aids treatment decision-making.

The VIDIO trial has demonstrated that DSA can underestimate the degree and morphology of iliofemoral vein stenosis when compared to IVUS. There is paucity of published literature evaluating IVUS for TCVO assessment in haemodialysis patients.3 De Graaf et al performed DSA and IVUS on 12 patients with suspected TCVO. IVUS showed significant stenosis in 12/12 vs. 8/12 with DSA. After angioplasty, significant residual stenosis was demonstrated in 10/12 vs. 3/12 with DSA. The authors concluded that IVUS was more sensitive in diagnosing significant TCVO and aided the decision-making process in deciding treatment strategy.4 This is in line with what we have learned from the iliofemoral venous treatment literature that IVUS aids precise device dimension selection (diameter and length of stenosis), appropriate landing zones and adequacy of treatment (for example, wall apposition of stent).

These are fundamentally important steps that contribute to optimised outcomes.5 Clearly, high quality large data studies are required to demonstrate the benefit of IVUS in haemodialysis access.

Currently, no consensus exists on the optimum treatment of TCVO. The mainstay of treatment is high-pressure

The IN.PACT AV Access study is a randomised controlled trial, which has enrolled 330 subjects at 29 sites in the USA, Japan, and New Zealand. The primary effectiveness endpoint was defined as freedom from clinically-driven target lesion revascularisation (CDTLR) or access circuit thrombosis measured through six months post-procedure, and the primary safety endpoint was defined as the serious adverse event rate involving the AV access circuit through 30 days postprocedure.

Additional endpoints include but are not limited to: access circuit primary patency, cumulative target lesion revascularisations, and number of interventions required to maintain target lesion patency.

The study enrolled a challenging patient population who had been undergoing dialysis for an average of 4.3 years. Overall, the IN.PACT AV DCB group demonstrated clinical benefit compared to the PTA control group.

Target lesion types

The analysis assessed the six-month target lesion primary patency (TLPP) in participants with de novo (30.3% [100/330]) and restenotic lesions (69.7% [230/330]) in a comparison between the treatment of IN.PACT AV DCB and standard PTA control: nD e novo lesions: At six months, participants in the IN.PACT AV DCB group demonstrated a 90.7% TLPP rate compared to a 75.6% TLPP rate in the Standard PTA control group (difference of 15.1%). n Restenotic lesions: At six months, participants in the IN.PACT AV DCB group demonstrated a 78.9% TLPP rate compared to a 52.4% TLPP rate in the standard PTA control group (difference of 26.5%).

balloon angioplasty, but the outcomes are generally poor with reported patency at six and 12 months 29–60% and 25%, respectively. The use of bare metal stents has similarly poor outcomes with one-year patency 33–56%. The reported outcomes even with stent grafts are as low as 40% patency at 12 months. The patency rates with drug coated balloon angioplasty are better.6 Reliance on DSA alone to determine adequate treatment may have contributed to these relatively poor outcomes.

In conclusion, reliance on DSA alone for TCVO can underestimate the extent and severity of these lesions. This can be overcome with use of IVUS. IVUS use during treatment aids appropriate device selection and adequacy of treatment.

References 1. Dolmatch BL, Gurley JC, Baskin KM et al. Central Vein Work Group and the Technology Assessment Committee. Society of Interventional Radiology Reporting Standards for Thoracic Central Vein Obstruction: J Vasc Access. 2019 Mar; 20(2): 114–122.

2. McFall RG, Lu T. Application of intravascular ultrasound in end-stage renal patients with central venous occlusive disease. Methodist Debakey Cardiovasc J. 2018 Jul-Sep; 14(3): 196–199.

3. Gagne PJ, Tahara RW, Fastabend CP et al.

Venography versus intravascular ultrasound for diagnosing and treating iliofemoral vein obstruction.

J Vasc Surg Venous Lymphat Disord. 2017 Sep; 5(5): 678–687.

4. de Graaf R, van Laanen J, Peppelenbosch N et al.

The value of intravascular ultrasound in the treatment of central venous obstructions in hemodialysis patients. J Vasc Access. 2016 Mar;17 Suppl 1:S12–5.

5. Murphy E. Use of IVUS to optimise outcomes in venous stenting. Venous News 6th April 2018.

6. Kitrou PM, Papadimatos P, Spiliopoulos S et al.

Paclitaxel-coated balloons for the treatment of symptomatic central venous stenosis in dialysis access: Results from a randomized controlled trial. J Vasc Interv Radiol. 2017 Jun;28(6):811–817.

Narayan Karunanithy is a consultant interventional radiologist at Guy’s and St Thomas’s Hospital (London, UK) and honorary senior lecturer at King’s College London (London, UK).

AVF types and target lesion locations

The analysis also evaluated the effectiveness of IN. PACT AV DCB compared to standard PTA in participants with different AVF types and target lesion locations. In all cases, IN.PACT AV DCB was favoured compared to standard PTA control: n Participants with target lesions in different AV fistula types treated with IN.PACT AV DCB, including radiocephalic, brachiocephalic, and brachiobasilic, had TLPP rates of 81.7%, 80.8%, and 84.6%, respectively. n Participants with target lesions located in the anastomosis, cephalic arch, and swing point treated with DCB had TLPP rates of 84.6%, 84.0% and 83.3%, respectively.

In conclusion, the consistent effectiveness

The study enrolled a challenging patient population who had been undergoing dialysis for an average of 4.3 years.” performance was observed in all analysed subgroups— superior target lesion primary patency was achieved with IN.PACT AV DCB in both de novo and restenotic lesions, and all studied types of AV access. Superior target lesion primary patency was also achieved at all studied anatomic locations, especially the anastomosis and cephalic arch.

January 2020 | Issue 85

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Patient-centred guidelines: The vascular access life plan Nick Inston Rob Jones Comment & Analysis Nick Inston and Rob Jones discuss the new kidney disease outcomes quality initiative (KDOQI) guidelines and the vascular access Life plan.

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ecent updates to a number of dialysis access guidelines have been published. A change of approach in some of these guidelines has been adopted. The European Renal Best Practice (ERBP) guidelines, and in particular the KDOQI guidelines, have developed a less prescriptive and more patient-orientated guideline principally based on the lack of quality evidence in studies of vascular access.

As a consequence, a shift particularly in the new KDOQI guidelines is towards patient-directed care linked with renal replacement management and the overall life plan of the patient.

The overarching goal identified in the guidance is to “achieve reliable, functioning, complication-free dialysisaccess to provide prescribed dialysis while preserving future dialysis access site options as required by the individual patient’s end-stage kidney disease (ESKD) life plan”. This is delivered through a Patient Life-plan first, followed by their corresponding Access Needs (P-L-A-N). Rather than a one size fits all (fistula first, distal first) policy, this approach is centered on the patient life-plan based on timelines with respect to overall renal care. The second aspect is the access needs.

The use of targets has largely been avoided. The only target is for interventions on arteriovenous fistulas and grafts (AVF/AVG) where a 1-2-3 intervention goal is applied.

For each (one) access creation, there should be two or fewer interventions to facilitate its use and three or fewer interventions per year to maintain it. The only target for central venous catheters is <1.5 catheter-related blood stream infections per 1,000 catheter days.

In defining the life plan it is essential to include the patient as well as members of the vascular access team. All aspects of renal replacement and vascular access must be considered alongside the patients’ abilities, interests, preferences, and goals. These preferences may change over time and the ESKD life plan for each patient will require regular review.

It is suggested this should be annual with a quarterly review of access for

functionality, complication risks and potential future dialysis access options.

These require consideration, discussion, and formal documentation, and it is suggested that this is done with the patient and healthcare team together.

This is a significant move from the traditional guidelines where a one size fits all approach has been applied. This ‘one size fits all’ approach has previously led initiatives in vascular access based on a quantitative approach (e.g. Fistula First initiative/Best practice tariff) which in most cases has not been proven to be effective, and in some instances has resulted in opposite effects to those planned.

A major difference in the new KDOQI guidelines is the interpretation and application of available evidence. Whilst a native arteriovenous fistula is still recommended as the access of choice the guidelines do state that “there is insufficient evidence” for the choice of access in both incident and prevalent patients based on the risk of mortality and all-cause hospitalisations. This is in stark contrast to other guidelines that state that “AVFs have lower mortality and less hospitalisation frequency and costs”.

A reason for such a discrepancy is in the interpretation of results and the addition of new data, which highlights that the risks of access types on mortality are largely due to selection bias.

It is a somewhat sobering thought that the aggressive approach to vascular access that has been advocated may have been based on inappropriately interpreted data.

Applying generic data to patient subsets is also flawed. For example, the relative risks and benefits of vascular access in patients with limited life spans, the elderly, and pre-dialysis patients are poorly understood. Iatrogenic morbidity is high in dialysis patients, with vascular access being a major cause. Attempts at assisted maturation, rescue, and further surgery add to the clinical and economic burden. Even with increased efforts to create access before initiation of dialysis 80% of US patients start on a central venous catheter (CVC).

The introduction of qualitative outcome measures may help address these issues with the main goal to provide a goal of “reliable,” “complication-free access that delivers the prescribed dialysis” on an individualised basis.

Access creation, contingency, and succession are highlighted as key areas. Rather than a distal first, fistula first approach, the recommendations for creation are based on anticipated duration of access need and also on operator discretion and best clinical judgement. Technical aspects of access creation are likewise based on surgeon preference, as there is insufficient evidence to recommend one technique over another.

The controversial practice of surveillance is addressed. Monitoring using regular clinical examination is recommended whilst there is insufficient

Ultimately, it is patients themselves who decide if we are successful.” evidence to recommend surveillance.

This includes methods using access blood flow, pressure, and imaging as surveillance modalities. This may appear surprising as this is against recommendations from other guidelines and the practise is widespread. An underlying concept of surveillance is the diagnosis of non-clinically relevant findings. The pre-emptive treatment of asymptomatic stenosis, (not associated with clinical indicators) is not recommended in either AVF or AVG. When clinical monitoring indicates a problem, a full clinical evaluation and imaging is recommended. A confirmed clinically-relevant stenosis should be treated with the choice based on the patients ESKD life plan, the operators best clinical judgment and expertise and the involvement of the team managing the patient.

Balloon angioplasty is recommended as is a stent-graft in specific situations such as graft vein stenosis and in stent re-stenosis. Bare metal stents are no longer recommended.

The role of surgery in failing access is considered particularly when endovascular attempts have been unsuccessful, lesions are not amenable to endovascular approaches, and where surgical outcomes are deemed better.

This also takes into consideration the operators’ experience and expertise.

These guidelines are likely to provoke much debate as they present a nonprescriptive approach to many of the common scenarios that occur in dialysis access. In parts, they are at odds with other previous and recent guidelines particularly with regards to interpretation of evidence.

The emphasis on clinical expertise and team approach may be a major issue in their usability. Access care delivery is far from uniform and in many cases is not a principal area of practice for many operators. The level of training, expertise and specialisation in vascular access is highly variable.

Healthcare policies and remuneration are still based on previous guidelines and data interpretation. If the use of qualitative percentage-based targets for access remains, it will be challenging to employ a better, more patient-oriented practice.

Whilst this may present a challenge, this should not be a reason to reject them. The involvement of the patient in their care and ongoing ESKD life plan appears to be a missing link in previous guidelines and is importantly at the centre of these new guidelines. Access is major source of concern for dialysis patients and patients’ perspectives of access vary widely from clinicians’ views.

Vascular access may be dealt with in isolation by clinicians but for the patients, access preference is important. The effect of access type and interventions on “Quality of Life” and “achievement of life goals” should not be underestimated.

Concerns may be raised that ascertaining the outcome of such vague recommendations will be difficult and performance indicators will be forfeited.

This does not have to be the case. Rather than a loss of traditional endpoints, we should look to the potential gains of incorporating wider application of patient-related outcome measures both in clinical practice and in research.

ESKD is a chronic illness with major impact on quantity and quality of life.

In vascular access care we are aiming to provide “the right access, in the right patient, at the right time for the right reasons”. Ultimately, it is patients who decide if we are successful.

References for this article can be found online at vascularnews.com Nick Inston is a consultant renal transplant vascular surgeon at University Hospital Birmingham NHS Foundation Trust, Birmingham, UK. Rob Jones is a consultant interventional radiologist is University Hospital Birmingham NHS Foundation Trust, Birmingham, UK.

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January 2020 | Issue 85

Limb salvage

Vascular limb salvage (VaLS) clinic helps to meet the VSGBI time-to-treatment targets and improve outcomes for CLTI patients Described as “deliberately challenging”, the new time-to-treatment targets published by the Vascular Society of Great Britain and Ireland (VSGBI), as part of the Peripheral Arterial Disease Quality Improvement Framework, have prompted a number of different measures in the UK for the treatment of patients with chronic limb-threatening ischaemia (CLTI).

At the 2019 Vascular Societies’ Annual Scientific Meeting (VSASM; 27–29 November, Manchester, UK), Andrew Nickinson (University of Leicester, Leicester, UK) spoke about the potential benefits offered by a specialist vascular limb salvage (VaLS) clinic, as well as missed opportunities for the timely recognition of CLTI within primary care.

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ddressing VSASM delegates, Nickinson said: “I think we are increasingly recognising that delayed diagnosis and management of CLTI are detrimental to outcomes, and there is a growing effort to try and reduce time-to-treatment after patients have been referred to us as vascular surgeons.”

Benefits of a limb salvage clinic

Focusing on the work done in Leicester for patients with CLTI, Nickinson discussed how “a nurse-led, open access, outpatient limb salvage clinic” has attempted to provide a one-stop assessment. According to the speaker, patients referred into the clinic receive a detailed vascular assessment—including duplex arterial ultrasound—within the same day, before a decision regarding next steps is made “there and then” by a vascular consultant.

Moreover, it was said that these patients have access to dedicated outpatient angiography slots, “with the aim of this project being to treat patients in 10 days or less of initial referral”. In order to establish whether or not this limb salvage service can help to meet time-to-treatment targets, Nickinson explained that an investigation evaluating one-year amputation outcomes was conducted.

“To do this, we interrogated our prospectively maintained clinic database and included all patients who were managed with chronic limb threatening ischaemia or diabetic foot ulceration over a one-year period from the inception of the clinic (February 2018 to February 2019),” commented the speaker.

As part of the study, two comparative cohorts were formed; patients assessed prior to the start of the clinic (from May 2017 to February 2018), and also patients who were managed through alternative pathways, while the clinic was functioning. In terms of the latter group, Nickinson added: “This included for example, the people who still made it through to the elective outpatient setting.” Primary outcomes for the investigation were the rate of major amputation and amputation-free survival at 12 months.

“In total, we assessed 294 patients in the first year of the clinic, of which 222 had chronic limb threatening ischaemia or neuropathic diabetic foot ulceration.

From the patients diagnosed with CLTI, approximately 75% went on to have a revascularisation procedure,” Nickinson revealed.

Regarding times to treatment, as Nickinson highlighted, the clinic was able to assess patients, on average, within two days of initial referral, and move them onwards to revascularisation within six days of assessment. “If you drill into those numbers further,” Nickinson continued, “this actually equates to five working days, given that the clinic does not work, at the moment, on weekends”.

“Looking at our primary outcome, which was major amputation at 12 months, those patients in the VaLS

clinic had half the rate of major amputations compared to the other comparative cohorts, and this result was found to be statistically significant. The trend continued for amputation-free survival also and, in absolute terms, there was a 15% improvement, which was again statistically significant.”

Nickinson did note both the strengths and limitations of the data, as while this was “one of the few studies which actually provides comparative institutional data to compare our findings”, there is a possibility of selection performance bias in this cohort, as well as some crossover between these groups. Returning to the original question, Nickinson said of the clinic’s ability to improve time to treatment, “I think our early results indicate that yes, it can. What is more, this service

L to R: Robert Davies, Jivka Dimitrova, Andrew Nickinson, Svetlana Dubkova

This service potentially provides a blueprint for other trusts to meet these challenging targets.” potentially provides a blueprint for other trusts to meet these challenging targets. We have also shown that the clinic can improve amputation-related outcomes for patients”.

Missed opportunities for timely recognition of CLTI in primary care

Following his presentation on the success of a specialist limb salvage clinic, Nickinson turned his attention to what may be happening before patients reach the clinic and, specifically, whether or not a timely diagnosis of

CLTI is being made in primary care. “The aim of this work was to investigate potential missed opportunities for timely recognition of CLTI in primary care,” the speaker told attendees at VSGBI. To answer the question, Nickinson et al conducted a population-based cohort study utilising Clinical Practice Research Datalink, which includes approximately 11 million patients managed in 694 general practices across the UK. It was explained that Nickinson and colleagues “identified all patients who underwent a major amputation, for either chronic limb-threatening ischaemia or diabetic foot ulceration in England, over a 16-year period (using hospital episode statistics (HES) data), and linked that to the Clinical Practice Research Datalink in order to look at primary care consultations which occurred in the year prior to the patient having an amputation”.

Within each of the consultations identified, investigators also evaluated whether or not the patient underwent some form of cardiovascular assessment.

Moreover, the primary outcomes of the study were the timings of a last primary care consultation and cardiovascular assessment prior to the patient undergoing an amputation.

Providing an overview of the findings, Nickinson outlined: “In total, we studied a predominantly male cohort of 3,260 patients with a median age of 72; as you would expect with a cohort like this, the one-year mortality rate was very poor (34%).”

He continued: “What is interesting is that patients on average will seek a consultation with a healthcare professional in primary care 19 times in the year preceding their amputation, while over 30% of people will see someone over 25 times. Despite this, the prescription rates of best medical therapy continue to be poor, which is in keeping with the current literature.”

“When looking for missed opportunities, we identified that 67% of patients will consult a professional in primary care within that 30-day period prior to their amputation, but only 13% undergo any form of cardiovascular assessment during this time. Indeed, a quarter of patients will not undergo any kind of cardiovascular assessment in the primary care setting during the year prior to their amputation.”

According to the speaker, the data highlights that although patients are consulting the general practitioners and healthcare professionals within their community, it is possible that they are not undergoing the appropriate assessment.

A closer analysis of the results involved the stratification of patients depending on whether or not they had undergone a recent cardiovascular assessment (90 days before their amputation, or greater than 90 days). In the late cohort (greater than 90 days), it was identified that there was a higher proportion of patients from more deprived areas of the country, as well as significant, albeit small, difference in age, with the late cohort younger on average.

Concluding his presentation, Nickinson posed the question “do missed opportunities exist?”. In response, he affirmed that “this is a complex problem, and one solution potentially could be greater education, not just for our patients so that they recognise the symptoms and present, but also for those healthcare professionals who do not specialise in vascular surgery, to help improve recognition of CLTI”.

“That is a difficult task, as we know that up to 50% of patients presenting with CLTI have no history of PAD [peripheral arterial disease] symptoms, but I do feel that we need to focus on those patients who may not fit that at-risk stereotype, including those of a younger age and from more deprived areas. This is important because, as we have established, major amputation carries a significant risk of mortality, and there is an opportunity to improve outcomes.”

“The research team would like to thank the George Davies Charitable Trust, who generously fund the VaLS clinic and ongoing research,” said Nickinson in closing.

Issue 85 | January 2020

Market Insights

First sirolimus device for peripheral arterial disease enters European market Concept Medical has received the CE mark for its MagicTouch sirolimus-coated percutaneous transluminal angioplasty (PTA) catheter, making it the first company to have a commercially available sirolimus device for peripheral arterial disease. The MagicTouch catheter has also been approved for treating erectile dysfunction (MagicTouch ED) and for managing arteriovenous fistula complications (MagicTouch AVF).

A PRESS RELEASE reports that the company will “now intensify its efforts to market and promote its products in Europe and other relevant markets that accept the CE certification for marketing authorisation”. Concept Medical is also on the path to receive US market approval of the MagicTouch range of catheters; in August 2019, the US Food and Drug Administration (FDA) granted Breakthrough Device Designation to both the MagicTouch PTA catheter and the MagicTouch AVF catheter.

Another press release—reporting the FDA Device Designation for MagicTouch PTA—states that the MagicTouch range uses “nanolute technology” to deliver sirolimus. It adds that this technology has “a proven commercial history in coronary applications in more than 30,000 patients worldwide”. Furthermore, according to this press release, an ongoing pilot study (XTOSI) is investigating the safety and efficacy of MagicTouch PTA for managing severe critical limb ischaemia (belowthe-knee lesions and femoropopliteal lesions). This study has already shown that both device success and technical success with the catheter are 100%. At six months, freedom from clinically driven target lesion revascularisation was 91% and the rate of primary patency was 82%. Principal investigator Edward Choke (Sengkang General Hospital, Singapore) is quoted in the press release as saying “I am very encouraged by the excellent results so far in these challenging cohort of patients… more than 90% had the most severe Rutherford scores of five or six.” He adds that he did not “encounter any distal embolisation or ‘slow flow phenomenon’ after the application of a sirolimus-coated balloon in below-the-knee vessels”.

Speaking about the FDA Breakthrough Device Designation for MagicTouch PTA, Sahil Parikh (Columbia University College of Physicians and Surgeons, New York, USA) comments: “The breakthrough designation demonstrates how important it is for us to have new technologies for below-the-knee

interventions. Patients with critical limb ischaemia 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.”

Other sirolimus devices

Concept Medical is one of several companies who have developed sirolimus devices for the management of peripheral arterial disease. These include: Orchestra BioMed, in collaboration with Terumo, which has the Virtue sirolimus-eluting balloon; MedAlliance, which has the Selution sustained limus release (SLR) device; and Surmodics with the Sundance sirolimus-coated balloon (SCB). Like MagicTouch, all of these devices were granted FDA Breakthrough Device Designation status for peripheral indications (including below-the-knee lesions) this year.

An Orchestra BioMed press release describes the Virtue SEB as a “novel first-in-class drug/device combination product that delivers sustainedrelease bioabsorbable encapsulated sirolimus, a proven drug for preventing restenosis, directly to the artery without the need for a coating”. The SABRE trial (first-in-human), published in JACC: Cardiovascular Interventions in 2017, indicated that the balloon was associated with 100% procedural

success for the management of in-stent coronary restenosis. At six months, in the 36-patient, perprotocol analysis, late lumen loss rate was 0.12±0.33mm. The study also showed that, at one year, the balloon was associated with a target lesion failure rate of 2.8% and a major adverse clinical events (MACE) rate of 2.8% (per-protocol analysis).

The Selution SLR device, a MedAlliance press release reports, “involves unique microreservoirs made from biodegradable polymer” intermixed with sirolimus. It adds that these microreservoirs “provide controlled and sustained release of sirolimus”. Two-year data (presented at VIVA 2019; 4–7 November, Las

Vegas, USA) from a first-in-human study of patients (50 overall) with superficial femoral artery and popliteal artery lesions show that 87.5% of patients were free from target lesion revascularisation at two years. No primary target lesion revascularisation event was observed after month 11.

About the Sundance SCB, the Surmodics president and CEO, Gary Maharaj, comments: “The Sundance SCB is intended to address the unmet clinical need in patients with critical limb ischaemia and infrapopliteal arterial disease by providing a revascularisation option with a proprietary sirolimus coating. This second platform adds to our stable of drug-coated balloon devices and furthers our effort to provide treatment solutions for the entire peripheral anatomy. The Sundance SCB has the potential for improved outcomes in critical limb ischaemia patients over other available treatment options, and its availability is in the best interest of patients.”

BIBA Briefings

41

Need for alternatives to paclitaxel

2019 has seen much debate over the safety and efficacy of paclitaxel after the Katsanos meta-analysis (published in December 2018 in the Journal of the American Heart Association) indicated that paclitaxel-coated balloons (and paclitaxel-eluting stents) were associated with an increased mortality risk at two years compared with control treatments. Therefore, finding alternatives to paclitaxel in the peripheral space has become a hot topic. For example, a BIBA MedTech survey, conducted just after the Katsanos paper was published (January 2019), found that 80% of respondents (101 overall) believed that looking for alternative drugs to paclitaxel was a priority.

The SABRE investigators Stefan Verheye (Antwerp Cardiovascular Centre, Antwerp, Belgium) and others report that paclitaxel (in the context of coronary artery disease) is “widely considered to be less effective and more toxic than other antirestenotic drugs (i.e. the limus family of sirolimus and its analogues)”. However, they note that previous attempts to deliver sirolimus on a balloon when using the same methodology as that for paclitaxel balloons proved unsuccessful “due to insufficient tissue uptake and shorter tissue retention of limus drugs compared with paclitaxel”.

These past difficulties are why Concept Medical, Orchestra BioMed, MedAlliance, and Surmodics have all sought to develop novel approaches to delivering sirolimus.

The most recent FDA statement (released 7 August 2019) on the safety of paclitaxel advises that “for many patients, alternative [commercially available] treatment options to paclitaxel-coated balloons and paclitaxel-eluting stents provide a more favourable benefit-risk profile based on currently available information”.

However, it also says that the benefits of a paclitaxel-coated device may outweigh the risk of late mortality in individual patients who have a “particularly high risk for restenosis and repeat femoropopliteal interventions”.

Of note, in October 2019, Eva Freisinger (University Hospital Muenster, Muenster, Germany) reported in the European Heart Journal that, in a real-world safety analysis, they did not find an association between mortality and paclitaxelbased drug-coated balloons at 11 years.

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

45

Issue 85 | January 2020

CAVA: Catheter-directed thrombolysis does not change post-thrombotic risk for iliofemoral deep vein thrombosis patients Additional ultrasound-accelerated catheter-directed thrombolysis (CDT) does not change the risk of post-thrombotic syndrome in patients with acute iliofemoral deep-vein thrombosis (DVT) at one-year follow up, compared with standard therapy alone, according to findings of the CAVA trial published in November 2019 in Lancet Haematology. However, preliminary results of a post-hoc subgroup analysis suggest that if recanalisation is successful, post-thrombotic syndrome is less severe and quality of life scores are higher one year after an acute iliofemoral DVT.

E

xamined in presentations by both Pascale Notten and Cees Wittens (Maastricht, The Netherlands)—winners of the best abstract session at the International Union of Phlebology chapter meeting (UIP; 25–27 August, Krakow, Poland)—results of the CAVA trial also showed a high rate of thrombotic events, mostly due to in-stent thrombosis.

Notten et al write: “Between May 2010, and September 2017, 184 patients were randomly assigned to either additional ultrasound-accelerated CDT (n=91) or standard treatment alone (n=93). Exclusion because of screening failure or early withdrawal of informed consent resulted in 77 patients in the intervention group and 75 in the standard treatment group starting allocated treatment.

“Median follow-up was 12 months (IQR 6–12).

Twelve-month post-thrombotic syndrome occurred in 22 (29%) patients allocated to additional treatment versus 26 (35%) patients receiving standard treatment alone (odds ratio 0.75 [95% CI 0.38–1.50]; p=0.42).

Major bleeding occurred in four (5%) patients in the intervention group, with associated neuropraxia or the peroneal nerve in one patient, and no events in the standard treatment group. No serious adverse events occurred. None of the four deaths (one [1%] in the intervention group vs. three [4%] in the standard treatment group) were treatment related.”

Moreover, as reported in Lancet Haematology, a total of 24 thrombotic events occurred in 20 patients.

Eighteen per cent (n=14) of patients from the intervention group developed 17 events versus seven events in 8% (n=6) of patients from the control group (p=0.06). Of the 17 thrombotic events which were seen in the intervention group, more than 70% (12 out of 17) were due to in-stent thrombosis.

Speaking to Venous News about the findings of the CAVA trial, Notten says: “When comparing our results to the two previous large trials (CaVenT and ATTRACT), our outcomes regarding the development of post-thrombotic syndrome are similar to the ATTRACT trial and show no statistically significant difference between treatment groups as opposed to the CaVenT trial.

“With the CAVA trial, discussion regarding the role of additional catheter-directed thrombolysis in the

Pascale Notten (left) and Cees Wittens (right)

Further research, including optimising patient selection, interventional techniques, and peri-interventional treatment regimens, is essential.” treatment of acute iliofemoral deep-vein thrombosis persists. Further research, including optimising patient selection, interventional techniques, and periinterventional treatment regimens is essential.”

Can successful thrombolysis prevent post-thrombotic syndrome?

A subgroup analysis of the results, presented by Wittens at UIP, aimed to assess the success rate of additional ultrasound-accelerated CDT in restoring patency (to 90% or more), and its relation to the development of post-thrombotic syndrome at one year.

Wittens explained: “As the degree of residual vein occlusion correlates with the risk of post-thrombotic syndrome, it has been said that the preventative impact of ultrasound-accelerated CDT might depend on its Continued on page 46

Raghu Kolluri:

Profile

Page 50

Dan Carradice:

The silent crisis of venous leg ulcers

Page 54

Study establishes association between reflux of lateral subdermic plexus and restless leg syndrome Reflux of the lateral subdermic plexus could be closely related to the symptoms of restless leg syndrome and nighttime cramping, according to a review conducted on prospective symptom tracking and patient outcomes at The Vein Institute in Rochester, New York, USA. Patients suffering from conditions such as restless leg syndrome frequently present with symptoms of chronic venous insufficiency, but no specific pattern or association has been identified until now.

SPEAKING AT THE 2019 Vascular Interventional Advances conference (VIVA; 4–7 November, Las Vegas, USA), Swar Shah (Rochester General Hospital and The Vein Institute, New York, USA) explained the paradigm of restless leg syndrome to those in attendance: “Many of these patients will present with more than the classic truncal symptoms, but the restless legs will typically present with a chronic inability to find comfortable positions when sleeping at night, and night-time cramping comes with this.”

As Shah reported during his presentation, prospective symptom tracking on the standardised patient intake form began at The Vein Institute in January 2015, under the supervision of Raj Pyne (Rochester General Hospital and The Vein Institute, New York, USA). Pyne noticed that many of the patients with symptoms of these conditions demonstrated a similar distribution of varicosities or spider vein clusters (or both) with a common pattern along the lateral lower thigh, knee and calf emerging.

“This corresponds to the lateral subdermic plexus, which is a small grouping of tributary veins that drain into the Vein of Albanese and then to the deep venous system,” Shah said, highlighting the association. “Many patients who started to undergo Continued on page 46

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January 2020 | Issue 85

CAVA: Catheter-directed thrombolysis does not change post-thrombotic risk for iliofemoral deep vein thrombosis patients Continued from page 45

ability to achieve successful recanalisation.”

According to the preliminary analysis, recanalisation was considered successful in 53% of patients (41 out of 77) who received additional ultrasound-accelerated catheter-directed thrombolysis, while a total of 75 patients in the CAVA trial received standard treatment only. Overall, post-thrombotic syndrome developed in 22% of patients (n=9) from the successful thrombolysis subgroup, and 35% (n=26) of the patients from the control group (p=0.15).

Comparing the successful thrombolysis subgroup to those who underwent unsuccessful thrombolysis— post-thrombotic syndrome developed in 13 out of 36 patients (37%)—no significant difference in proportion of post-thrombotic syndrome was seen (p=0.17).

However, the severity was significantly lower in those successfully treated. Generic and disease-specific quality of life questionnaires also differed significantly between groups, favouring those who were successfully treated.

Based on the findings of the subgroup analysis, said Wittens, successful thrombolysis does result in benefits such as a lower severity of symptoms and improved quality of life for patients when considering multiple aspects. Commenting on these results, Wittens added: “The subgroup analysis shows that proper quality control of an intervention is essential to evaluate an intended treatment. Unfortunately, this trial shows that only 53% of the patients received a successful intervention.”

He concluded: “Since the preliminary subgroup analysis showed a significant improvement in clinical scores and quality of life in those successfully recanalised, the overall conclusion of the various trials should not be that early thrombus removal is not effective in achieving better clinical outcomes and that this treatment should be abandoned; it tells us that early thrombus removal actually has the capacity to limit long-term postthrombotic morbidity, if only we are able to improve the process of patient selection and develop better interventional treatments.”

Read commentary on CAVA from editors-inchief of Venous News on page 47.

Study establishes association between reflux of lateral subdermic plexus and restless leg syndrome Continued from page 45

treatment of these veins—mainly in association with other typical varicose veins or coincidentally for cosmetic spider veins—experienced a significant improvement in their restless leg syndrome and nighttime cramping symptoms,” he revealed.

A proposed aetiology for restless legs was also presented by the speaker, who discussed a hypothesis for why these symptoms occur. The normal thigh component of the lateral subdermic plexus drains inferiorly toward the knee to the deep veins, while the calf component drains superiorly towards the knee. Without the aid of gravity— when patients are laying supine—Shah explained that there is impaired flow from the lateral subdermic plexus to the Swar Shah deep veins which, along with reflux, can lead to venous stasis.

“Our theory is that it is this venous stasis which causes the restless leg syndrome to develop, and we think that it may be related to iliotibial band irritation, although this theory is not borne out in the literature,” Shah commented.

In order to explore this theory further, prospective symptom tracking and patient outcomes were evaluated; this focused on patient-reported symptoms of restless legs, patient-reported symptoms of nighttime cramping and venous reflux with augmentation in the lateral subdermic plexus on venous ultrasound lasting more than 500 milliseconds.

“The spectral Doppler ultrasound findings would show a dilated lateral system (4mm with four seconds of reflux is pretty typical) and, by comparison, we would often see patients with either large varicose veins or no large varicose veins in the more standard vessels we evaluate, such as the great saphenous vein,” said Shah, who added that “in more than one patient, the great saphenous vein was non-dilated and nonrefluxing, yet there were still symptoms of restless leg syndrome”.

As a result, patients who underwent treatment with ultrasound-guided foam sclerotherapy (USGFS) were also tracked, including clinical success (defined as technical success, short-term symptom relief by 90 days, and long-term symptoms relief at one year) and any major or minor complications.

In total, 510 patients were identified between

January 2015 and December 2017; 322 of these persons (63.1%) had an abnormal lateral system based on the investigators’ criteria, while the remaining 188 patients (36.9%) had either a normal lateral system, or the system was not identified.

Focusing on the results, Shah said: “As we go to correlate the ultrasound findings with their symptoms, we start to see some patterns emerge. In patients with restless leg syndrome, 83% will have a positive ultrasound, and with patients suffering from night-time cramping symptoms, 89% will have a positive ultrasound. When you combine these results together, as restless leg syndrome and the cramping symptoms, a positive ultrasound will be present in

Our theory is that it is this venous stasis which causes the restless leg syndrome to develop, and we think that it may be related to iliotibial band irritation.”

91% of patients with symptoms, while 98% of patients without will have a negative ultrasound.”

The technical success rate was 94%. For patients who underwent USGFS, 93% (224 out of 241) reported symptom resolution at 90-day follow-up, indicating clinical success. At one year, this number was virtually unchanged at 92%, underlining that this can be “a very durable and likely permanent treatment option”.

Based on the findings of this study, Shah concluded: “We view our study as a starting point, and we would like to see a standardised, multicentre evaluation take place in the future. If this does prove to be a cause of restless leg syndrome, as we think it might be, then it would open up a new avenue for potential treatment options. Not only would it be safe and effective, but it would also be cost-effective.”

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Issue 85 | January 2020

Section Name

Where does the CAVA trial leave early thrombus removal for iliofemoral DVT? Manj Gohel Stephen Black Comment & Analysis Results from the Dutch CAVA trial were published recently in Lancet Haematology and, at first glance, this is another trial that failed to demonstrate any meaningful benefit for early thrombus removal in patients with acute iliofemoral deep vein thrombosis (DVT).

IN CAVA, 184 participants with iliofemoral DVT were randomised to ultrasound-accelerated catheter-directed thrombolysis (CDT) or standard care alone. One-year rates of post-thrombotic syndrome (PTS) were 29% and 35% in the intervention and standard care groups respectively, a non-significant difference.

The researchers should be commended for their efforts in trying to answer a question of enormous clinical relevance and for their perseverance in completing a trial that took over seven years to recruit. However, there are important methodological flaws to raise. Twentytwo participants (12%) withdrew consent within two days of randomisation, 30% of thrombolysis interventions were stopped early, and only 45% (35/77)

of participants starting thrombolysis underwent venous stenting, with only half of patients considered to have had successfully delivered therapy. Follow-up was limited to one year and the sample size was relatively small, meaning that CAVA was underpowered to detect anything other than a large difference.

The generalisability of CAVA will be questioned, as with ATTRACT and CaVenT. Patients enrolled into these studies only constitute a small minority of the overall population presenting with iliofemoral DVT, illustrated by the fact that less than 2.5% of the screened population in ATTRACT were randomised. Inevitably, many patients with severe symptoms will not have been included due to the lack of clinician (and/

or patient) equipoise. Perhaps the bigger question relates to the technical success.

In all three randomised controlled trials (RCTs), rates of technical success and venous stenting were relatively low, which could explain poor outcomes in the intervention arms of these trials.

Conversely, the technical outcomes in these multicentre studies could be seen as more reflective of practice, rather than selected centres of excellence.

The relationship between technical success of early thrombus removal (and durable deep venous patency) and clinical outcomes does warrant further investigation, and debate on the open vein hypothesis continues as a result.

Even with the reduced rate of postthrombotic syndrome after CDT in the CaVenT trial, and the reduced rate of moderate-severe PTS in the iliofemoral DVT subgroup in the ATTRACT trial, these benefits were underwhelming and did not match the advantages perceived by the many enthusiastic advocates of these interventions. The results of the CAVA trial compound this situation.

The apparent discord between published evidence and the experience of large swathes of the clinical community creates significant challenges, particularly as the next iterations of international guidelines are likely to reflect results from published randomised trials, and are therefore unlikely to recommend widespread early thrombus removal, which is common practice in many centres.

Despite another large RCT hoping to clarify the issue, the role of early thrombus removal in the management of acute iliofemoral DVT remains as controversial as ever. Worryingly, there seem to be increasingly partisan views

Compression achieves short-term reduction in pain scores following venous intervention Results of a randomised controlled trial conducted at Imperial College, London, UK, have shown that the application of compression stockings is associated with a significant reduction in pain during the first few days following intervention. In addition, it was found that patients undergoing endothermal ablation and phlebectomies benefited more from compression in the postoperative course.

T

he findings of the “Compression following endothermal ablation” (COMETA) investigation were reviewed by Roshan Bootun (Imperial College, London, UK) at the annual meeting of the American Vein and Lymphatic Society (AVLS; 7–10 November 2019, Phoenix, USA). He began: “As we know from interventional treatment, most patients end up with bandaging for a variable period of time, followed by compression stockings, which are often worn for a very long period of time as well.”

Based on National Institute of Health and Care Excellence (NICE) guidelines in the UK, for the treatment of varicose veins in the legs, it is recommended that compression bandaging or hosiery should only be used following interventional treatment for a maximum of seven days. In response to this, the COMETA study was launched, with the aim of testing compression after thermal ablation by establishing pain scores over the first 10 postoperative days.

According to Bootun, patients with reflux of the

great saphenous vein (GSV) or small saphenous vein (SSV) were randomised to one of two groups, receiving compression stockings for seven days or no stockings at all. Stockings used in the study were Class II (18– 24mmHg), and all patients wore them for the first 24 hours post-intervention.

Overall, 206 symptomatic patients with venous reflux

As we know from interventional treatment, most patients end up with bandaging for a variable period of time, followed by compression stockings.”

47

for and against intervention. In reality, both perspectives have merit.

Unwavering advocates of aggressive early thrombus removal should recognise that many patients with iliofemoral DVT treated with anticoagulation alone do not develop PTS (around 50% or more in CaVenT, ATTRACT and CAVA).

Likewise, those sceptical of early thrombus removal strategies should accept that many patients with severe symptoms (most likely to benefit from thrombolysis) were not included, and superior technical and clinical outcomes from thrombus removal—than those reported in CaVenT, ATTRACT and CAVA—are feasible. Both sides can also probably agree that the outcome measures in RCTs remain suboptimal.

There are exciting technological advances for thrombus removal, with a range of pharmacomechanical thrombolysis and thrombectomy options widely available. Whether these advances can deliver better technical success and superior clinical outcomes remains to be seen. As with many areas of venous disease, the biggest challenge remains case selection. More work is needed to define specific subgroups of patients that may benefit most from aggressive thrombus removal. Until we make progress with better patient selection and clearly good technical results though, this controversy is likely to persist.

Manj Gohel is a consultant vascular and endovascular surgeon at Cambridge University Hospitals, Cambridge, UK. Stephen Black is a consultant vascular surgeon at Guy’s and St Thomas’ NHS Foundation Trust, London, UK.

of more than 0.5 seconds were randomised into either the compression cohort (100 patients) or no compression group (104 patients). At the two-week follow up, a pain score from the first 10 days was recorded as a primary outcome, as well as other secondary outcomes such as ecchymosis score, time to resume activities, and the venous clinical severity score (VCSS). There was no significant difference in terms of baseline characteristics and veins treated between the two cohorts.

Bootun underlined that of those randomised to compression, they had follow-up data for 63%, compared to 66% in the non-compression group. “If we look at the pain score using a visual analogue scale (VAS), we found that the results were significantly better in the compression group on days two, three and four,” the presenter revealed, before adding that “a subgroup analysis of patients who underwent interventional treatment with phlebectomy showed that the pain score was much better with compression stockings on days one to three, five and seven”.

Further analysis of the follow-up data showed no significant difference between the groups at two weeks with regard to VCSS, generic quality of life, and disease-specific quality of life. The time to return to normal activities between both cohorts was also similar.

Six-month follow-up data demonstrated very little difference in terms of complete occlusion rates (87.5% in the compression group vs. 92% in the noncompression group) and the incidence of deep vein thrombosis (with just one case recorded), while a similar improvement in clinical and quality of life scores was discovered at six months. Summarising the findings, Bootun concluded that “the effect of compression on endothermal ablation alone is still unclear”.

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January 2020 | Issue 85

Lower polidocanol-to-air ratio for reticular vein treatment demonstrates “similar” efficacy and safety In the treatment of reticular veins of the lower extremities using polidocanol foam, it has been found that both a 1:2 ratio and 1:4 ratio of polidocanol to air demonstrate similar levels of efficacy and safety. According to Elika Hoss (Mayo Clinic, Scottsdale, USA), the effectiveness of both ratios was determined by patient and physician evaluation.

“AS YOU KNOW, sclerotherapy is the gold standard treatment for lower extremity reticular veins and telangiectasias,” said Hoss, who was speaking at the annual meeting of the American Vein and Lymphatic Society (AVLS; 7–10 November 2019, Phoenix, USA).

Explaining how this procedure works, Hoss continued: “With the injection of a sclerosant, we have control of inflammation and fibrous cord formation. Also, foam sclerotherapy involves the off-label addition of a gas to the liquid sclerosing agent to create a foam.”

Highlighting some of the advantages of foam sclerotherapy, Hoss underlined that foam displaces blood, allowing for greater contact time with the vessel wall and greater endothelial cell injury. In addition to this, the vasospastic response caused by the foam increases the likelihood of vein closure.

“The effect of different ratios of foam stability and efficacy has been controversial,” commented Hoss, who highlighted that the European consensus recommends a sclerosant to air ratio of 1:4. In order to determine whether a 1:2 ratio would be more efficacious, a prospective, randomised, split-body study of 30 patients (between the age of 25 and 70 years) was established.

Hoss and her colleagues’ study, which was also patient- and evaluator-blinded, included patients with Fitzpatrick skin type I-IV, as well as C1 bilateral and symmetric lower extremity reticular veins

and telangiectasias under the CEAP classification. Alternatively, patients with visible varicosities, skin changes of venous stasis, deep vein incompetence, and a history of deep vein thrombosis (DVT) were excluded.

Outlining the experimental design, Hoss said: “All patients received sclerotherapy to the bilateral legs on two consecutive days. Reticular veins were randomised to treatment with polidocanol 0.5% foam in either a 1:2 or 1:4 ratio, while telangiectasias were treated with glycerin. Elika Hoss

The effect of different ratios of foam stability and efficacy has been controversial.”

In addition, all patients received thigh-high 30–40mmHg graduated compression stockings, which were worn for seven days.”

Investigator evaluations, as part of the study, included a blinded assessment of adverse events (such

as erythema, pigmentation or swelling) postprocedure on day zero and day one. Adverse events were also evaluated at both 21 days and 90 days, in addition to blinded evaluation of improvement that was ranked from 1–4. In terms of subject evaluation, there was a blinded assessment of adverse events (including pain during or after injection) on day zero and one, as well as a blinded evaluation of improvement, again after 21 days and 90 days. Patients were also asked to keep an outcome diary, highlighting adverse events up to week 12.

Safety results from the 30 patients enrolled in the study (all female; mean age of 54 years) showed that there was “no statistically significant difference” in investigator-assessed adverse events at baseline, 21 days or 90 days. Moreover, no statistically significant difference was found in subject-assessed adverse events between groups, including the patient diary which noted similar levels of pain, swelling, bruising and itchiness between groups at any time point.

Looking at the study’s efficacy findings, Hoss stated that a “0–50% improvement was seen at day 21 by investigators, and a 26–75% improvement at day 90; there was no statistically significant difference though between legs”. She added that “subjects found similar rates of improvement (0–50% at day 21; 26–75% at day 90)”, again showing no statistically significant difference.

Concluding her presentation, Hoss closed: “The two different polidocanol to air ratios were similar in efficacy and safety for the treatment of reticular veins of the lower extremities. Limitations of the study include the use a quartile scale for improvement, and one may consider using a 1:4 ratio, given that it allows for a lower concentration of polidocanol to be used. Further studies may be considered for high polidocanol to air ratios.”

Retrospective study demonstrates efficacy of radiofrequency ablation and open surgery for varicose vein treatment Long-term evaluation of superficial venous reflux below the knee, in patients who received invasive treatment for varicose veins, has found that both radiofrequency ablation (RFA) and open surgery achieve “acceptable and comparable results”. The retrospective cohort study was presented at the annual meeting of the American Vein and Lymphatic Society (AVLS; 7–10 November 2019, Phoenix, USA).

“V

aricose veins are a widespread problem,” said Beatrix Cucuruz (Goethe University Hospital, Frankfurt, Germany; Center for Vascular Disease, Nuremberg, Germany), who discussed the findings of the investigation. The speaker underlined that up to 30% of the population have varicose veins which should be treated, and added that “paraesthesia is reported in 4–20% of patients after stripping of the great saphenous vein (GSV)”.

Regarding the treatment options available, Cucuruz explained that “in our institute, we mainly use RFA or open varicose vein surgeries,” though other ablation techniques, such as endovenous laser ablation (EVLA), mechanochemical ablation (MOCA) and chemical ablation, as well as foam sclerotherapy, can be utilised.

The aim of the study was to examine whether or not postoperative paraesthesia can be reduced with RFA, and if there is a durable occlusion of the veins following this procedure. Moreover, the

study sought to determine the incidence of recurrent varicose veins and whether there are any changes of the remaining GSV at the thigh after RFA. “We looked for patients who were treated for varicose veins between January 2007 and December 2008,” said the speaker who, outlining the study methods, commented that “all of these persons presented with incompetence of the GSV down to the ankle”. RFA was conducted using the ClosureFast catheter from Medtronic, and all patients wore compression stocking for six weeks following their treatment.

The data collected showed that 60 patients were treated during this period with RFA, while 352 underwent open surgery. Twenty-four of those 352 patients were treated with stripping of the GSV above the knee, instead of the entire vein. In terms of the demographics analysed in each of the two groups (RFA and open surgery), there was no significant difference in terms of age or previous heart disease. However,

Cucuruz also highlighted that the number of patients in the RFA group who had a history of deep vein thrombosis (DVT) was higher Beatrix Cucuruz compared to the open surgery cohort (12/60 vs. 4/352, p=0.001).

With a technical success rate of 100%, results of the study showed that following RFA, just one patient out of 60 (2%) experienced paraesthesia during the postoperative course. Out of those who underwent open surgery with stripping of the entire GSV, 8% developed postoperative paraesthesia (27 out of 328), while none of the 24 in whom the GSV was stripped only above the knee experienced this.

Turning her attention to the long-term follow-up data, Cucuruz revealed that the recanalisation rate after RFA was 12% (7/60); the recurrence rate was

15% (9/60) following this procedure. By comparison, the recurrence rate following open surgery on the entire GSV was 12% (40/328), higher than the 8.3% recurrence rate (2/24) for patients who underwent stripping above the knee.

“Looking at the follow-up for patients with remaining GSV at the calf (60 patients who had undergone RFA, plus 24 patients who underwent stripping above the knee), 98% did not show any reflux (82/84)” explained Cucuruz. “Also, only 2 out of 82 (2%) patients show progression of GSV incompetence with indication for reintervention”.

Summarising her findings, Cucuruz concluded: “In almost all patients, reflux of the GSV below the knee was abolished. In addition, there was a higher rate of postoperative paraesthesia in patients with stripping of the entire GSV. The number of patients lost to follow-up was a limitation of the study though, as this was a lot more common in the group who underwent open surgery for varicose veins.”

50

January 2020 | Issue 85

Profile

Raghu Kolluri

Following his recent appointment as president of the Society for Vascular Medicine (SVM), Raghu Kolluri (Columbus, USA) speaks to Venous News about how the venous field is being affected by the results of recent trials, his involvement with The VEINS at VIVA, and key areas of innovation to watch out for in 2020.

When did you decide to enter the field of vascular medicine?

I decided to enter the field of vascular medicine towards the end of my first year of an internal medicine residency at Riverside Methodist Hospital (Columbus, USA). I saw a patient with bilateral brachial artery fibromuscular dysplasia, which I reported along with my mentor (now my colleague and partner at work) Gary Ansel (Columbus, USA). I was fascinated by the field of vascular medicine and was able to do a month of “awayrotation” at The Cleveland Clinic’s Vascular Medicine section during my second year of residency training.

I fell in love with vascular medicine during that time.

Following residency training, I went to The Cleveland Clinic for advanced fellowship training in vascular medicine. We were trained to manage all aspects of vascular disorders and thrombosis, and I was exposed to the first iteration of radiofrequency ablation technology and other superficial venous therapies. Although I enjoy practicing all aspects of vascular medicine, I was particularly attracted to venous disease since it was a highly neglected field at that time. My interest in venous disease only became stronger later on in clinical practice, as I cared for many patients suffering from debilitating venous disease.

During your training, were there any vascular or venous specialists who particularly inspired you?

Of course, I have several role models and mentors. Ansel and Mitchell Silver (Columbus, USA), now my practice partners, encouraged me to get into the field of vascular medicine while in training. Spending time with Ansel on the hospital floors and in the cath lab was truly inspiring.

The one individual who influenced my professional life the most is John Bartholomew (Cleveland, USA).

He trained several doctors in vascular medicine and genuinely cares for his patients. His thoroughness in every aspect of patient care left a significant impact on my career, and his passion for thrombosis and venous disease has rubbed off on me.

How has the venous field changed, and do you agree that future trials must focus on “technical success”?

Venous care is still a relatively neglected field, especially when compared to peripheral arterial disease (PAD) or coronary artery disease (CAD). Nevertheless, we have come a long way, with tremendous growth in the venous space in the last couple of decades. I recall a time when deep venous interventions were offered only for palliative care, and therapies for long-term sequelae of post-thrombotic syndrome were available only in a few select centres in the USA. I hope venous patients will ultimately benefit from evolving technologies in the superficial and deep venous space, and for pulmonary embolism (PE). I agree that we must focus on technical success in deep venous interventional trials, but appropriate assessment of technical success is equally important. Also, patient-reported outcomes are as important as anatomic success; ultimately, the patient needs to feel better.

What are some of the key areas of innovation that currently interest you?

We are a large Health System in Central Ohio, with 14 hospitals and more than 20 vascular laboratories. We are interested in all aspects of innovation that improve our patients’ lives. I am very excited about some of the advances in duplex imaging. Multi-row array technology allows a lot more elements to be packed into the new ultrasound probe, leading to exceptionally high-resolution images. Visualisation of slow flow and deep structures is fascinating. 3D ultrasound imaging and ultrasound contrast may have some future vascular applications. Point-of-care ultrasound is another area of interest, and I believe this will change the way physicians practice and examine patients. I would also like to see increased utilisation of simultaneous extravascular and intravascular ultrasound in cath labs.

We are also interested in thrombectomy devices for PE and deep vein thrombosis (DVT) management that hopefully will reduce bleeding risks and improve outcomes.

I hope venous patients will ultimately benefit from evolving technologies in superficial and deep venous space, and for pulmonary embolism.”

Before The VEINS, fellow course director John Kaufman described you as “a force of nature”; how successful was the programme this year?

That is very kind of John. He has been a great partner with the management of this highly successful meeting.

We welcomed 400 attendees representing 31 countries, this year. We have a broad range of venous education at The VEINS, and will continue to listen to our attendees and provide patient-centric educational content. Stay tuned for more announcements with regard to The VEINS’ 2020 programme; we have several unique and innovative sessions planned.

You are also part of the American Venous Forum’s Annual Programme Committee; what can attendees look forward to at the AVF meeting in March?

AVF is a highly scientific organisation and I enjoy attending the AVF meeting every year. As always, the latest in basic and clinical science will be featured, in the form of abstracts and presentations. AVF has also formally partnered with C-TRACT to increase the awareness of the trial and the enrolment process. I look forward to hearing an update on this landmark study by Suresh Vedantham (St. Louis, USA).

How excited are you about your appointment as president of the Society for Vascular Medicine?

SVM is my professional home society and it is an honour to lead this society, which consists of incredible

vascular specialists from all training backgrounds.

Although we are not a large organisation, we certainly are mighty. In my opinion, no single specialty can provide comprehensive vascular care. Nationally and internationally, SVM has partnered with like-minded vascular societies at various levels. We routinely participate in writing Appropriateness Use Criteria (AUC) documents and other vascular guidelines. As the USA’s population ages and the prevalence of vascular disease increases, there is going to be a shortage of vascular specialists. We will explore all options to increase training programmes in vascular medicine in the next few years.

If you had to give one piece of advice to new doctors entering the venous specialty, what would you say?

Understand the disease process and the pathophysiology of venous disease. This is more important than focusing on techniques and technologies. It is also important to remember that manifestations of venous disease

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Issue 85 | January 2020

Fact File

Qualifications

1997 MB, Armed Forces Medical

College, Pune, India 1997 BS/MD, Armed Forces Medical

College, Pune, India 2001 MS, Pennsylvania State University,

University Park, USA 2004–2005 Fellowship in Vascular Medicine, Section of Vascular Medicine, Division of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, USA

Academic Appointments (selected)

2005–2013 Principal investigator, Prairie Educational Research Co-operative, Springfield, USA 2005–2013 Clinical assistant professor, Southern Illinois University School of Medicine, Springfield, USA

Professional Appointments (selected)

result from complex venolymphatic and cardiovascular interactions. Unless you think outside of the vascular box, you will not be able to help all patients. With a laundry list of venous therapies now available, it is quite easy to miss underlying systemic causes that may mimic symptoms consistent with venous disease. It is not uncommon for me to see patients seeking a second opinion, with persistent symptoms even though their deep veins have been stented and their superficial veins ablated. Above all, stay humble and collaborate.

During your time as a venous specialist, are there any cases which stand out?

I saw a 99-year-old lady with an extremely painful atrophy blanche venous ulcer. She was dealing with this severe pain for at least 15 years. She said: “I am going to turn 100 in six weeks. I want to blow out my birthday candles without any pain. I have been to many doctors, and they all told me that I am too old.” We had

a lengthy discussion about the potential complications with superficial venous therapies. However, with thermal ablation of the great saphenous vein (GSV) and careful sub-ulcer sclerotherapy, we were able to heal the ulcer before she reached her birthday. That was very rewarding.

What are some of your hobbies and interests outside the world of medicine?

I like to exercise my right brain as much as possible.

Photography is a serious hobby: I enjoy taking pictures and post-processing and printing them. What initially started as portrait photography of my three sons then blossomed into landscape and cityscape photography.

I love listening to rock n’ roll and heavy metal music; I even used to play guitar, and hope to pick it up again soon. In my spare time, I try to recreate my mother’s South Indian recipes. Travelling with my family is also something I look forward to every few months.

2005–2013 Director, Vascular medicine,

Prairie Vascular Institute,

Springfield, USA 2011–2013 Medical director of

informatics, Illinois Referral

Division, Hospital Sisters

Health System (St John’s

Hospital, Springfield; St

Francis, Litchfield), Illinois,

USA 2013–Present Medical director, Vascular laboratories, OhioHealth, Ohio, USA 2013–Present System medical director, Vascular medicine, OhioHealth Heart and Vascular Service, Ohio, USA

Offices (selected)

2009–2011 Chair, American Board of Phlebology 2019–Present President, Society of Vascular Medicine Present Board member, VIVA Physicians Present Annual Scientific Sessions planning committee, American Venous Forum

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Issue 85 | January 2020

Amniotic membrane wound grafts demonstrate improved healing rates for non-healing venous leg ulcers It has been found that the application of dehydrated human amnion and chorion allografts (dHACA) results in a better venous leg ulcer (VLU) healing rate than the use of standard multilayer compression therapy, following a randomised controlled study comparing the two treatment regimens. Displayed in a poster presentation at the Symposium on Advanced Wound Care Fall meeting (SAWC Fall 2019; 12–14 October, Las Vegas, USA), the trial responds to the “significant clinical, humanistic and economic burden” created

by VLUs.

A

ccording to the research, conducted by principal investigator Thomas Serena (Cambridge, Massachusetts, USA) and colleagues, “millions of Americans are afflicted with painful, open, draining sores on their lower extremities”, many of which have a venous aetiology and are incredibly difficult to heal. Although some patients require weeks or months to recover, a significant number of those suffering with VLUs can take years to heal and may, in some cases, even face amputation as a consequence of their wounds.

In terms of costs, the poster presentation highlighted that “the consequence of long-term disability has been estimated at 4.6 million work days lost per year and a cost to the healthcare system of up to US$2.5 million annually in the USA”. Moreover, current VLU rates are reportedly as low as 30% at 24 weeks, emphasising the need for new, advanced therapies that can achieve better results.

Recent clinical data have shown that dHACA, which feature endogenous growth factors to facilitate wound healing, are more effective than other bioengineered skin substitutes in the treatment of diabetic wounds, prompting a new prospective, multicentre trial to “compare the proportion of ulcers healed completely with the use of dHACA vs. standard of care patients with venous leg ulcers”.

Conducted in eight outpatient wound centres, this was the first study to evaluate the efficacy of dHACA in VLU treatment using weekly and biweekly application regimens against multilayer compression bandaging.

As part of the trial, patients with non-healing VLUs treated with standard of care—consisting of appropriate debridement, a primary absorptive dressing and multilayer compression— after a two-week screening period were randomised to either a standard of care group (20 patients), or a cohort receiving “wound-size specific” dHACA plus multilayer compression applied weekly (20 patients) for up to 12 weeks.The primary endpoint of this trial was the percentage of patients healed at 12 weeks (defined as complete epithelialisation).

At the conclusion of the study, it was discovered that both weekly and

biweekly application of dHACA resulted in a statistically significant improvement in healing rates for VLUs, when compared to standard wound therapy.

For those patients who received standard of care only, 30% (six out of 20 patients) healed in 12 weeks, with a mean percentage wound area reduction of 57.8%. Alternatively, 75% of patients (15 out of 20) who were treated with dHACA weekly and biweekly healed within 12 weeks, with a mean percentage wound area reduction of 80.7% (p=0.012).

The findings of this study underline that the use of dHACA results in a greater percentage of patients healed within 12 weeks than multilayer

compression therapy, improving the healing trajectories of patients and benefitting those who had previously failed to heal sufficiently under standard of care.

Speaking to Venous News about the investigation, Serena commented: “The dedicated investigators and research coordinators in the SerenaGroup Research Foundation make publications such as this possible.

“Our cooperative group of clinical research sites conducts roughly a dozen clinical trials per year, publishing 12–15 manuscripts. We are advancing the science of wound healing. We welcome interested physicians and research sites to join the effort.”

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January 2020 | Issue 85

Addressing the silent crisis of venous leg ulcers and its impact on patients With the level of spending on wound care in the billions of pounds, both the financial and health-related impact of venous leg ulcers cannot be understated. Dan Carradice (Hull York Medical School, Hull, UK) speaks to Venous News about the latest report by the All-Party Parliamentary Group on Vascular and Venous Disease, which articulates the extent of this important issue, and what can be done to improve care in the UK.

How did the report, “Venous Leg Ulcers: A Silent Crisis”, come about, and why are venous ulcers an important issue?

The thing to say first is that vascular disease is an unwitting victim of the widespread misunderstanding and misdirection of healthcare attention, and I think that this is true all the way from strategy and planning, down to individual patient care. It is clear that vascular disease is the most common cause of death in UK adults, the most common cause of limb loss, and results in a significant level of physical, mental and psychological morbidity across the country. Despite this, it has received precious little attention compared to other diseases, such as cancer, and when it is considered it is usually fragmented, with all attention limited to heart disease and stroke.

The predominant interest of those involved in the management of vascular disease is targeted towards arterial disease, and it is against this backdrop Dan Carradice that venous disease sits in near silence.

I think that this report came about because both patients and their carers are clamouring to be heard, while healthcare professionals are battling to improve care quality and outcomes. For this reason, we have been working with organisations such as Legs Matter, Lindsay Leg Club, and now members of parliament in the group to produce this report, raising awareness of such an important condition.

In terms of the second part of the question, I think that this is an important issue because lower limb venous reflux is one of the most common causes of disease in adults, with a prevalence of about 40–50% in adults overall. It is difficult to know how many people have active venous leg ulcers, as they are frequently misdiagnosed, but at least 200,000 people seek help for these ulcers annually. There are another 420,000 leg wounds treated every year which never receive a formal diagnosis, and we also have some detailed epidemiological studies which estimate a prevalence of around 0.7%, which would equate to around 400,000 active ulcers in the UK.

What are some of the key reasons for the development of venous leg ulcers, and how do these wounds impact patients’ lives?

Venous leg ulcers are caused by high pressure in the veins (venous hypertension), which initiates an inflammatory condition within the skin and the soft tissues of the leg. This results in the breakdown of the skin. There are a range of causes for this increase in venous pressure, but the most important and common, by far, is reflux in the superficial veins of the legs. This, in turn, is also caused by an inflammatory condition in the vein walls, which results in a loss of valvular function.

Ulcers have a profound impact on patients’ lives; they can be painful, distressing and have been shown to significantly limit health-related quality of life, due to physical limitation, social isolation and psychological strain. One study I was involved with performed a

detailed evaluation of objective health-related quality of life, which found that venous ulcers have a similar impact on patients as that of end-stage heart failure.

Is there enough awareness of the physical, social and psychological problems patients with venous leg ulcers experience?

Sadly, I think we are far from where we need to be.

We know this from our own experience as clinicians, but the parliamentary group has also received testimony from multiple people who have been through this condition and suffered from a lack of awareness.

Patients themselves do not understand the significance of their first ulcer when it does occur, as the underlying venous health issues and their implications are not well known. Usually, they will go to see their GP and, if the GP does not know what the wound is, then the patient will try some antibiotics and perhaps try to dress it with a simple adhesive dressing or dermatological creams. In some cases, these patients spend years having such a dressing placed on the wound by a GP practice nurse and never receive access to a vascular specialist. In fact, 75% of patients with known ulcers never receive an appropriate assessment.

For those who are lucky to be diagnosed with a venous leg ulcer, it is still rare that they make the transition from primary to secondary care. Primary care usually involves the conservative management of wounds with dressings, and the quality of these dressings is often quite poor. When they are referred to hospital, some of the commissioning policies can make it challenging to treat them expeditiously, while the lack of investment in this area means that services fail to develop to the level required.

Venous ulcers have a similar impact on patients [in terms of quality of life] as that of end-stage heart failure.”

As part of the report, you wrote about geographical variation in the provision of venous treatments. Could you explain how this “postcode lottery” affects patients?

Geographical variation results in significant inequality of access to NHS services and a failure to deliver clinicallyand cost-effective treatment recommended by the UK’s National Institute for Health and Care Excellence (NICE). This not only leads to poor healthcare, but also inefficient and inequitable use of NHS funding. Both the Government and NHS England are committed to reducing the level of inequality, and, as such, we need to focus on areas like this where inequality is prevalent.

We performed a study where we assessed the published policies of clinical commissioning groups (CCGs) across England, with regard to whether they allowed or prevented the application of NICE’s evidence-based guidelines for the treatment of this venous reflux. Only a third of CCGs had a policy which did not actively prevent the application of these guidelines and evidence-based treatment, while the others employed a range of restrictive or rationing mechanisms, leading to a wide variation in access to treatment. In total, over 90% of patients presenting with superficial reflux do not receive the recommended, evidence-based treatment.

Geographical variation results in significant inequality of access to NHS services.”

What are the key findings of the report with regard to the current state of venous leg ulcer care in the UK? I think we have found that there is a widespread lack of effective information and knowledge at multiple levels; the patients themselves, among communitybased healthcare professionals and, to a degree, at the level of secondary care. What we have also found is that there is a lack of awareness among commissioners, which has led to a drop in investment for treatment of these conditions and, in turn, a lack of infrastructure in secondary care to be able to deal with them. The All-Party Parliamentary Group actually did a piece of research focusing on the proportion of trusts who had a specific team for delivering this care, and they discovered that only half of the trusts they contacted had a team in place. In addition, significant elements of variation in access and the quality of treatment were found.

Looking ahead, what recommendations do you and your peers offer in the report to improve the quality of venous treatment for patients?

To sum up the most important points from the report, I think that education is a hugely important aspect and this needs to be integral, at both a policy-making level and the community level, as well as at a commissioner and secondary-care level. Moreover, there needs to be a separate arm for patients because they need to know that the longer it takes for these wounds to heal, the harder the task becomes. We have to make sure these patients realise that, by delaying care, they are reducing the ability of healthcare professionals to address this problem, so education is crucial.

The second key element relates to healthcare services; we need to have streamlined and agreed pathways for getting patients from the community into expert assessment, secondary care and, ultimately, expedited treatment. The only way we can do this is by ensuring that we have effective organisation and commissioning in this area of wound care, along with a strong emphasis on education.

We have a solid evidence base upon which we can dramatically improve the outcomes for these patients and enable health services to make considerable financial savings, even in the short-term. We simply need to overcome these practical hurdles and apply our knowledge and skills to transform care in this common and debilitating disease.

Dan Carradice is an academic vascular and endovascular surgeon at Hull York Medical School and Hull University Teaching Hospitals NHS Trust (Hull, UK). He is the clinical lead for vascular surgical services and is actively involved in leading research aiming to improve quality of life, and save life and limb.

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January 2020 | Issue 85

Market watch

Product News

E-nya (CryoLife)

CryoLife receives CE mark for two of its stent grafts

CryoLife has received two CE marks, one for the E-nside thoracoabdominal aortic aneurysm stent graft and one for the E-nya thoracic stent graft system.

Two press releases announcing the CE marks, respectively, report that E-nside is the company’s newest proprietary endovascular stent graft for patients with thoracoabdominal aortic disease and that the E-nya thoracic stent graft system is for the minimally invasive repair of lesions of the descending thoracic aorta (including thoracic aortic aneurysms and dissection).

According to the E-nisde press release, the system’s precannulated inner branches are designed to reduce the overall procedure time and patient exposure to radiation. Furthermore, the E-nside multibranch stent graft system was designed based on Jotec’s (part of Cryolife since 2017) extensive experience over the last seven years with more than 2,000 implants in the thoracoabdominal space. The CE mark for E-nside, the press release states, positions CryoLife well in the EU aortic stent graft market due to Jotec’s E-xtra Design Engineering programme. The programme seeks to provide patientspecific solutions, as well as due to the synergies between E-nside and Jotec’s existing portfolio of thoracic and abdominal stent grafts.

Pat Mackin, chairman, president, and CEO of CryoLife, comments: “We are pleased to have received CE mark for E-nside, the only off-theshelf precannulated thoracoabdominal stent graft with inner branches. This device will help us more rapidly serve physicians by eliminating the waiting period experienced by approximately 70% of patients who would normally require a custom-made stent graft. The device will also benefit some patients by eliminating their need for an open surgical procedure.”

The E-nya press release says that the graft builds upon Jotec’s experience in the thoracic endovascular aortic repair (TEVAR) market and increases the number of options to treat a broader range of patients. It adds that the system offers both bare spring and covered proximal configurations with tip capture technology, enhancing the control and

predictability during deployment while achieving optimal outcomes.

Regarding the CE mark for E-nya, Mackin says: “We are pleased to have received CE mark for the E-nya thoracic stent graft system, our next-generation low profile solution for patients with aortic disease. The E-nya system was designed to give physicians more options and control while treating both simple and challenging anatomies, and will be one of the most versatile grafts on the market. We are excited to bring this product to the European market, further enhancing our position as the leader in the growing EU aortic repair market.”

Insera announces first-inhuman treatment of patient with PE using CLEAR aspiration system

Insera Therapeutics announced recently that the first patient with acute pulmonary embolism has been treated with its flagship cyclical aspiration system, CLEAR. Earlier last month, the first two stroke patients were treated using the same platform. The company received CE mark approval for its flagship product, the CLEAR aspiration system, in March 2019.

“Due to the large clot burden in the lung arteries, the 65-year-old gentleman presented with right-sided heart failure and was in critical condition. Traditional treatments using blood thinning medications such as anticoagulation and thrombolytic medications were contraindicated in this patient. We successfully treated this patient with massive bilateral acute pulmonary embolism using Insera’s CLEAR aspiration system,” said Luka Novosel, interventional radiologist at the Sisters of Charity Hospital, Zagreb, Croatia.

“I am very pleased with the ease of use of cyclical aspiration and its ability to rapidly ingest large amounts of clot. It also provides a safer mechanical means of removing life-threatening blood clots without the bleeding risk associated with blood thinning medications.”

Insera’s first-in-human success in treating pulmonary embolism comes on the heels of the recent announcement of the EXTRACT-PE trial results presented at the Vascular Interventional Advances (VIVA) meeting (4–7 November, Las Vegas, USA). This trial advances treatment options for the industry as it establishes the use of vacuum aspiration in patients with acute pulmonary embolism.

The CLEAR aspiration system has European regulatory approval for the aspiration of blood clots, and is indicated for use for acute ischaemic stroke secondary to large vessel occlusive disease, as well as the aspiration of blood clots from arteries (e.g. peripheral arterial disease, pulmonary embolism, and coronary

artery disease), and for the aspiration of blood clots from veins (e.g. in patients with deep venous thrombosis, cerebral venous sinus thrombosis, or patients with renal failure who have clotted haemodialysis grafts).

“To date, we have successfully used the CLEAR aspiration system in nine stroke patients. I am very pleased with the higher trend of first-pass recanalisation using cyclical aspiration.

For example, in our very first patient, we had a six-minute procedure time from groin to recanalisation with TICI 3 on first-pass (complete vessel reopening on the first operative attempt),” said Vladimir Kalousek, accredited interventional neuroradiologist at the Sisters of Charity Hospital, Zagreb, Croatia who has pioneered the use of cyclical aspiration.

“There is a huge unmet need for innovative devices for the removal of life-threatening blood clots. Our unique and proprietary cyclical aspiration technology has been shown to improve first-pass recanalisation, reduce distal embolisation, and has an improved safety profile at the time of the procedure,” said Vikram Janardhan, chief executive officer of Insera Therapeutics. “In the USA alone, it is estimated that every year there are around 225,000 patients with ischaemic strokes due to large vessel occlusions (LVOs), 300,000 patients with PE, 600,000 patients with DVTs, and 100,000 patients with acute limb ischaemia.”

FDA approval granted to calf stimulation device for patients at high VTE risk Sky Medical Technology has received US Food and Drug Administration (FDA) 510(k) clearance for its “geko” device for stimulation of the calf muscles to prevent venous thrombosis in non-surgical patients at risk for venous thromboembolism (VTE).

This adds to Sky’s established 510k clearance for immediate post-surgical stimulation of calf muscles to prevent VTE, increasing blood circulation and oedema reduction.

According to a statement, this is the first

CLEAR (Insera Therapeutics)

muscle pump activator of its kind to be cleared by the FDA for VTE prevention across all patients including non-surgical patients.

VTE is a deadly risk to hospitalised patients, particularly those who are immobile as a result of recovery, and fewer than 50% of hospital patients receive appropriate preventive treatment according to the CDC (Centers for

Disease Control). Estimates suggest that somewhere between 60,000 and 100,000 Americans die each year as a result of the condition, with 10–30% of patients dying within one month of diagnosis.

The geko device is a non-invasive, easy-to-use, battery-powered, and wearable therapy device which, worn at the knee, gently stimulates the common peroneal nerve, activating the calf and foot muscle pumps and resulting in increased blood flow in the deep veins of the calf. Further, the geko device also operates without external pressure to the leg and allows complete mobility.

A study of the geko device’s ability to prevent VTE in acute stroke patients reported 0% VTEs in patients wearing the geko device alone, compared to VTEs in the various control groups who were prescribed sequential compression devices (SCDs) at 2.4% or pharmacological prophylaxis at 1.1%.

The investigators, led by Indira Natarajan (NHS Royal Stoke University Hospital, Stoke-on-Trent, UK), also determined that 30% of patients are contraindicated or became intolerant to SCDs. It is to this unmet need cohort that the geko device was fitted, reporting a VTE incidence of zero and good patient tolerance. The data are said to have driven rapid adoption across multiple NHS trusts and international markets, as well as gaining expanded FDA clearance.

Commenting on the study result, Natarajan said: “The data have shown a need to use the geko device when other VTE prophylaxis strategies are contraindicated or impractical, and provides an option where previously patients would have had no other intervention available to them. The geko device is now in routine use at the Royal Stoke and has marked significant change to our practice.”

Embracing the innovation, Fred Rincon (Thomas Jefferson University, Philadelphia, USA) added: “The geko device represents an exciting new treatment option for clinicians to manage stroke patients at risk for developing a deep vein thrombosis when clinicians are concerned about bleeding in the early management of the patient.”

Commenting on the FDA clearance, Sky CEO Bernard Ross also commented: “This latest 510(k) builds on our previous FDA indications to address life-threatening blood clots and complications related to swelling after orthopaedic surgery, conditions experienced by more than 1 million US patients with unmet need every year. We are excited to extend our access into the US market.

“Our muscle pump activation technology, OnPulse, embedded in the geko device, completely redefines the way vascular-related conditions are treated. Through our innovative mechanism of neuromuscular electrostimulation, we are the first clinically-proven muscle activation technology to prevent and treat a wide range of acute and chronic circulatory conditions both here in the US and internationally.”

Issue 85 | January 2020

Market watch

Clinical News First CLTI patient enrolled in PROMISE II pivotal study of LimFlow system

LimFlow, a specialist in minimallyinvasive technology for the treatment of chronic limb-threatening ischaemia (CLTI), a severe form of peripheral arterial disease (PAD), has announced that the first patient has been treated in its PROMISE II US pivotal trial of the LimFlow percutaneous deep vein arterialisation (pDVA) system.

The successful first case was performed by Mark Archie (HarborUCLA Medical Center, Los Angeles, USA), principal investigator for the PROMISE II trial, and Nina Bowens (Harbor-UCLA Medical Center, Los Angeles, USA), sub-investigator for the PROMISE II trial.

“We are pleased to be the first centre in the country to treat a patient in this important trial,” said Archie. “The LimFlow system offers a promising new therapy with the potential to restore blood flow to the ischaemic foot, heal wounds, and prevent major amputations in a patient population that today is unable to be treated with any current technology”.

PROMISE II is a multicentre, prospective, single-arm study being conducted in the USA and Japan.

Using an adaptive statistical design, the study plans to enrol 60 to 120 “no option” CLTI patients. Endpoints include amputation-free survival at six months, limb salvage and wound healing, and subjects will be followed up out to three years. The “no option” patients who are candidates for the PROMISE II study are no longer eligible for conventional endovascular or surgical therapy for CLTI, as determined by an independent physician committee.

When all other therapeutic options have been exhausted and a CLTI patient is facing major amputation, the minimally-invasive LimFlow system is designed to bypass blocked arteries in the leg and deliver oxygenated blood back into the foot via the veins.

For many patients, restoring perfusion in the lower limbs resolves chronic pain, improves quality of life, enables wound healing, and prevents major amputation.

“Treating the first patient soon after FDA approval of the trial demonstrates the enthusiasm vascular specialists have for a therapy designed to help patients keep their limbs that would otherwise face amputation,” said LimFlow CEO Dan Rose. “With the increasing prevalence of diabetes, obesity, and cardiovascular disease, CLTI has become a public health crisis, recognised by the FDA in designating the LimFlow system as a breakthrough device. We look forward to undertaking a rigorous study of our technology to offer new hope

to patients who have no other options today.”

CLTI is the most severe form of PAD and often occurs in patients suffering from such conditions as coronary artery disease, diabetes, obesity, high cholesterol, and high blood pressure.

Patients with CLTI often experience profound, chronic pain and develop festering wounds or infections that lead to major limb amputation, an event closely associated with increased

mortality and reduced quality of life.

To relieve the symptoms of CLTI, patients today are treated primarily with angioplasty or open bypass surgery.

In many late-stage patients, however, neither option is feasible due to extensive disease in the target arteries or other anatomical constraints.

LUMBRA, real-world study of luminor DCB in Brazil, commences A real-world study investigating the luminor drug-coated balloon (DCB; iVascular) in Brazil has started, following approval for commercialisation of the device by ANVISA, the Brazilian regulatory

luminor (iVascular)

authority.

LUMBRA (Luminor balloon in a Brazilian registry for real world lesions) aims to corroborate the efficacy and safety results of luminor in Europe demonstrated by the EFFPAC and TINTIN trials.

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January 2020 | Issue 85

Events

Calendar of events 23–25 January CACVS: Controversies and Updates in Vascular Surgery Paris, France www.cacvs.org

28–31 January LINC: Leipzig Interventional Course Leipzig, Germany www.leipzig-interventional-course.com

7–13 March Association of Interventional Vascular Surgeons (AIVS) Whistler, Canada www.aivs2020.com

22–24 March 24th European Vascular Course (EVC) Maastricht, The Netherlands www.vascular-course.com

25–26 March LINC Asia-Pacific Hong Kong

17–18 April XXVIIIth Annual Pennsylvania Hospital Vascular Symposium and Second Annual Pennsylvania Hospital/Navix Non-invasive Vascular Laboratory Symposium Philadelphia, USA www.VascularMeeting.com

27 March SITE: International Symposium of Endovascular Therapeutics Barcelona, Spain www.sitesymposium.com

September

www.cxsymposium.com

www.esvs.org

15–16 May Critical Issues in Aortic Endografting Paris, France

28–30 October Controversies in Dialysis Access (CiDA) 2020 Salt Lake City, USA

29–30 May Program for Advanced Limb Preservation (PALP): The AntiAmputation Meeting New York, USA

www.dialysiscontroversies.org

www.palpnyc.org

www.critical-issues-congress.com

10–12 June i-MEET 2020 Nice, France 17–20 June Society for Vascular Surgery (SVS) Vascular Annual Meeting Toronto, Canada www.vascular.org

25–26 June BSET: British Society of Endovascular Therapy annual meeting Wotton-under-Edge, UK

Limbof Chronic work Management es on the years of collaborative s and r Guidelin surgeon of four of having Global Vascula the product chronic limb- r The goal tion of the year sees the world. for patients with for Vascula The publica Ischaemia this ys s around the Society publication. The Threateningr experts and societie treatment pathwacement from r es’ of Vascula the guidelin by vasculato agree on the optimal ed in an announ fruition in European Journal describ come to the providers ischaemia was (JVS). journals: which has r Surgery societies’ threatening a “quixotic quest”, two of the the Journal of Vascula as Surgery was published in and (EJVES) document scular Surgery and Endova evaluation the definition, focuses on global patient he document ent of a large with mortality, and managem a disease associated particular and life. With population quality of practice, creating n, and impaired amputatio evidence-based as well as research, on guiding emphasis ks for treatment evidence or ed framewor standardis areas of low-levelperception of the insight into the overall providing stages of severity. and changing for spectrum and unmet needs, include a wider Conte from the Society disease to were Michael from the European from Kohl Co-editors Philippe Bradbury Vascular Surgery, Surgery and Andrew Nearly 60 Vascular Societies. ts Society for of Vascular Participan Federation on the project. specialties that the World worked all d authors additional and represente . continents n of spanned six tening ischaemia limb-threa to the publicatio treat chronic Vascular News prior Vascular Guidelines to Speaking “the Global for Vascular , Conte said and the guidelines effort from the Society Vascular Surgery all are a combined Society for who have European Societies, the Surgery, of Vascular the past.” In the effort Federation in the World nt guidelines guidelines, Conte independe ive joint produced that we set of collaborat important project we are to create a most very first and limb ischaemia—which said, “the .” was advanced tening ischaemia undertook chronic limb-threa now calling is in a name? used definition to CLTI: What From CLIterminology from the widely limb(CLI) to chronic of a key shift The shift in ischaemia limb of critical (CLTI) is indication this patient g ischaemia g and treating threatenin around lising, identifyin the terminology in conceptua changed . “We have population

T

2019 | Issue

83

en: Alan Lumsd

Profile

www.vascularsociety.org.uk

www.cirse.org

29 September–2 October ESVS: European Society for Vascular Surgery annual meeting Krakow, Poland

www.bset.co.uk

idelines scular gu g Global va limb-threatenin ic on chron Redefining a ia: ischaem ease critical dis

25–27 November Vascular Societies’ Annual Scientific Meeting Brighton, USA

21–24 April CX Symposium London, UK

www.imeetcongress.com

linc-around-the-world.com

12–16 September CIRSE: Cardiovascular and Interventional Radiological Society of Europe Munich, Germany

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nted” “Unprecede t developmen ic of NICE aort guideline aneurysm

Institute N of the National guideline VERSIO THE DRAFT Care Excellence (NICE) on in and for consultati for Health when released that patients with ndation created a furore, be offered its recomme should only 2018, with d aneurysm able to undergo an unrupture if they were fit and providers open surgery, . Many surgeons, service guideline draft the procedure ers have called the n has been and stakehold and its publicatio “unimplementable” since then.

Board,” deferred the NICE repeatedly of the now sits with UK), president “The guideline (London, and Ireland says Ian Loftus for Great Britain nted. “There Vascular Societycalls this step unprecede re-wording who sides and (VSGBI), ise on both ,” he tells Vascular the must be comprom workable guidance closely with to make this that NICE is working .

News, noting progress the guideline onal Interventi ers to Society of stakehold in discussion the British VSGBI and together been of (BSIR) have cated the concerns of Radiology and communi a letter to members NICE In with g community. has been challengin set the vascular writes: “It is no date VSGBI, Loftus and at present there with NICE, for all concernedWe remain in touch help to find a n. to our for publicatio reiterated our desire Conte interests of Michael about the fact that [...] and have is in the best “to recognise solution that did raise our concerns and tening workable Conte said, “We limb-threa s NICE The He adds: constitute this problem,” s, with both scenarios. patients.” practice, what of the guideline in different it.” in current suggests that to change the wording may be different limb ischaemia were unable ischaemia below which of critical BSIR, but perfusion concept of is okay. value previous threshold which everyoneexpanding there is some and above the is critical, 4 diabetes and on page everyone is that with Continued realised we What

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