Venous News issue 10 – June 2019

June

Issue

19 10 Dominik Heim: The 20th European Venous Forum (EVF)

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Raghu Kolluri: Role of elevated central venous pressure

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“Urgent action” is required to improve referral for venous ulcer patients Despite the recent emergence of Level 1 evidence supporting the early intervention of venous ulceration, Alun Davies (London, UK) warned at the Charing Cross Symposium (15–18 April, London UK) that the guidelines and recommendations are consistently being ignored, and highlighted that “urgent action is required for venous ulcer patients, to improve referral pathways between primary and secondary care”.

Alun Davies

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enous ulcers on the lower leg can be a major source of patient distress and social isolation, Davies noted, substantially impacting the patient’s quality of life. What remains less immediately apparent, however, is the burden of this condition on health services. With an estimated cost of venous ulcers to the UK National Health Service (NHS) exceeding £1 billion each year, Davies pointed to forecasting of this figure to increase, given the UK’s ageing population and growing incidence of obesity. As principal investigator of the EVRA (Early venous

reflux ablation) ulcer trial, Davies presented the first Level 1 evidence supporting early intervention with ablation for venous ulcers in 2018. The EVRA trial, he told the CX audience one year on, was partly stimulated by the lack of translation of the UK National Institute for Health and Care Excellence (NICE) guidelines into clinical practice. In July 2013, it was recommended that patients with a venous leg ulcer should be referred to a vascular specialist within two weeks. However, this recommendation “usually went ignored” by healthcare Continued on page 2

Fedor Lurie:

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VenaSeal maintains safety and efficacy at extended fiveyear follow-up

The first-ever 60-month data on Medtronic’s VenaSeal closure system were presented at the Charing Cross Symposium (CX; 15–18 April, London, UK), indicating that at five years, treatment with the cyanoacrylate adhesive for closure of diseased vein segments was not inferior to the alternative treatment arm of radiofrequency ablation (RFA). Nick Morrison of the Center for Vein Restoration in Mesa, USA, delivered the outcomes during a superficial venous session at CX 2019. THE DATA WERE the result of long-term outcomes from the VeClose study, in a five-year follow-up extension of the trial’s original threeyear follow-up period. Morrison explained that, in order to continue to assess the safety and efficacy of the VenaSeal closure system for the long-term effect of the closure, the investigators “wanted to follow up as many patients as we could gather out to five years”. Of the original trial’s 222 patients, the extended VeClose study was able to enrol 89 patients, of which 47 had been randomised to VenaSeal cyanoacrylate and 33 randomised to RFA with Medtronic’s ClosureFast system; the remaining nine patients were roll-in cyanoacrylate patients. The primary endpoint of the extension study was complete closure, defined as Doppler ultrasound examination showing closure along the entirety of the treated target vein, with no discrete segments of patency exceeding 5cm. Among the randomised patients, this endpoint of closure rates was sustained over a long-term period, with “no new failures reported and noninferiority demonstrated through 60 months”. Morrison reported a 91.4% closure rate in the VenaSeal arm, vs. 85.2% in the RFA arm. Continued on page 2

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“Urgent action” is required to improve referral for venous ulcer patients Continued from page 1

professionals, Davies said, “be it nurses or primary practitioners.” Results of the EVRA trial showed that the time to ulcer healing was shorter with early intervention using endovenous ablation, as the median time to ulcer healing was 56 days with this treatment as opposed to 82 days for the deferred intervention group. In the previous ESCHAR trial results, it was reported that surgical correction of superficial venous reflux in addition to compression bandaging did not improve ulcer healing, but reduced recurrence at four years and resulted in a greater proportion of ulcer-free time for the patient. Management of venous ulcers in the UK, based on these findings, therefore typically involves applying compression therapy to heal the ulcer, followed by surgical intervention to treat underlying venous reflux and, thereby, reduce the risk of leg ulcer recurrence. However, as the EVRA investigators argue in the New England Journal of Medicine publication of the study, “Although compression therapy improves venous ulcer healing, it does not treat the underlying

We need our vascular colleagues to champion the fact that these patients need urgent intervention.” causes of venous hypertension. Treatment of superficial venous reflux has been shown to reduce the rate of ulcer recurrence, but the effect of early endovenous ablation of superficial venous reflux on healing remains unclear”, they comment on the background for the trial. The EVRA trial has received funding from the UK National Institute for Health Research (NIHR) to follow up the 450 patients up to three years. Although Davies acknowledged that the EVRA findings support the need for early intervention, he asked the CX audience that even this trial’s definition of an early intervention may not have been early enough. Referring to the fact that the mean time between the patients’ onset of a leg ulcer to time of intervention was just over three months, Davies postulated: “If we treated these patients as if they had cancer, and referred them early, we could have had an even better response.” An explanation for the lack of uptake of the

Editors-in-chief: Stephen Black, Alun Davies, Ian Franklin Scientific Advisors: Lowell Kabnick, Raghu Kolluri, Armando Mansilha, Kasuo Miyake, Erin Murphy, Ramesh Tripathi Publisher: Stephen Greenhalgh Head of Publishing: Sadaf Kazi Editor: Zoë Öhman

guidelines may lie with certain barriers preventing the optimal implementation of this intervention, including a lack of education, system failure, inadequate facilities and the perception of cost. Interestingly, Davies said that these barriers have led the UK Venous Forum to issue a guidance information leaflet, that has so far been distributed to healthcare funding bodies and parliament, detailing a strategy of early referral, and the early assessment of patients with a venous leg ulcer. Placing this early intervention into the context of a global pathway, Davies stated: “I see no reason why the diagnosis should not be made in the community. The compression should be started immediately provided [the physician] is happy that the arterial supply is adequate. Then there should be an urgent vascular assessment with a venous intervention in a standard patient. There should be no reason why this cannot be done at the same day as the diagnostic ultrasound. “From diagnosis to treatment, we should be able to do it within two weeks. We can certainly do it with cancer and other diseases, so why should we not be able to do this with leg ulceration?” Offering a direction in which to target this intervention, Davies emphasised: “We really need to get the message out to patients, who are often elderly, to let them know that there are good forms of treatment. So when they see their doctor, they can say that they need to be referred to a specialist.” Moreover, he highlighted the importance that politicians and payers buy into the process. “We need to spend a significant amount of time convincing our politicians that it is a benefit to treat these patients early,” Davies said, referring to the health economics of venous ulceration. “But what is also important,” he added, “is the need to educate public health doctors and nurses. We need our vascular colleagues to champion the fact that these patients need urgent intervention.”

VenaSeal maintains safety and efficacy at extended five-year follow-up Continued from page 1

The study further monitored changes in Venous Clinical Severity Score (VCSS), Aberdeen Varicose Vein Questionnaire (AVVQ), Quality of Life survey (EQ-5D) and clinical, aetiology, assessment and pathophysiology (CEAP) scores compared to baseline. Additional secondary endpoints included satisfaction with treatment, adverse events related to target great saphenous vein, and details of adjunctive procedures performed on the study limb. Both arms, Morrison noted, demonstrated “sustained improvement in disease-specific, generic quality of life and functional outcomes. […] No serious adverse events, pulmonary embolism, deep vein thrombosis or treatment limb related adverse events were reported between 36- and 60-month visits.”

Reducing the need for compression and anaesthesia

“VenaSeal uses an advanced medical adhesive to safely and effectively close the diseased vein segment,” Morrison said, outlining benefits of a treatment that is non-thermal, non-tumescent and non-sclerosant. One “main advantage” highlighted by Morrison is the rapid recovery period for patients, and importantly for patients living in warmer climates, a reduced need for compression stocking therapy post-procedure is key for patients “who just cannot tolerate compression hosiery. [With VenaSeal] there is no need for compression hosiery, which is very nice in a hot climate”. When choosing between the use of RFA versus cyanoacrylate glue, Morrison tells Venous News that, beyond this key benefit, the choice “comes down to practicality. Because we do not have to use a tumescent or anaesthesia, that is an advantage to patients—even if they may not be aware of it, if they have not had a procedure in the past— the lack of tumescent is certainly an advantage”. The rapid recovery period is a factor that initially led Kathleen Gibson (Bellevue, USA) to consider VenaSeal an “ideal option” for a younger, less diseased patient population who values the ability to return to physical activity as soon as possible and is less inclined to wear stockings. However, Gibson adds that the cyanoacrylate therapy is further suited for the elderly with medical comorbidities, advanced venous disease and reduced mobility, who may not be able to apply their compression stockings.

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June

High-intensity focused ultrasound system provides noninvasive treatment of venous insufficiency in feasibility study A new treatment modality is aiming to take the idea of minimally-invasive procedures to the next level for treatment of varicose veins and venous insufficiency. Alfred M Obermayer of the Institute of Functional Phlebosurgery, Karl Landsteiner Society in Vienna, Austria, presented the technique and preliminary results of using high-intensity focused ultrasound (HIFU) for treatment of varicose veins—a method which he states requires “no knife, no needle, no catheter and no anaesthesia”. The technology was presented at the Charing Cross Symposium (CX; 15–18 April, London, UK) for the CX Innovation Showcase.

“I

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Venous innovation

am proud to present to you this new kid on the block, for treating insufficient veins in a completely noninvasive manner,” Obermayer said at CX, presenting the results of an Austrian feasibility study with “the first-time use worldwide”. “The whole procedure is an automatic procedure,” said Obermayer, “and the heart of the system is in the visualisation and treatment unit.” The HIFU system (SONOVEIN, Theraclion) received CE mark during the week of CX. The device design includes a HIFU transducer at 3MHz producing a focal heat deposition of 85°C, as well as an embedded ultrasound at 7.5MHz for visualisation of the target vein, and a single-use membrane and liquid for cooling and coupling which is designed to protect the skin against burns. “The use of HIFU is already well-established in two common pathologies: in breast fibroadenoma, and in thyroid nodules. Especially in thyroid nodules, there is a need for very precise treatment because of the big vessels and nerves in this area. The patients also appreciate the excellent cosmetic results—of course, no surgery means no scar,” Obermayer said, adding that HIFU induces a

shrinking process of the lesions within two years of up to 95%, and the technique has proven clinical results with 21 peer-reviewed articles since 2014. Obermayer explained the procedural method using the system: “The first step is the positioning of the SONOVEIN unit and compressing

The procedure can be performed without any sedation or even anaesthesia.” the vein. The second step is the treatment planning— everything happens on a touch screen. The treatment start and the treatment control are visualised in real time.” A feasibility study was set in motion, with the aims “to assess the reaction of the vein, the reaction of the patient and, of course, the reaction of the doctor; is this a tool which I can use?”, said Obermayer. Following ethical approval for the study in Austria,

The vascular community should “be more critical” about accepting new technologies into clinical practice

Obermayer and his colleagues treated 50 legs (62% [31/50] recurrent; 74% [33/50] C4–C6), following patients for three months. On the patients included in this study, he notes that those with “difficult and challenging situations” were chosen, in order to “get the benefit of this completely extracorporeal system”. Treated structures included recurrences, neovascularisations at the stumps, perforators, great saphenous veins and anterior accessory saphenous veins. No adjunctive methods (such as sclerotherapy, phlebectomy and ligation) were allowed in this feasibility study, and were not performed either at the moment of intervention or during the three-month follow-up period. For all patients enrolled in the study, Obermayer reported that the procedure was feasible, with 34% of cases treated without any anaesthesia. No sedation or other medication was used in the study, and no significant side effects (such as skin changes or skin burns) were observed. “Very mild and transient dysaesthesia was reported at early follow-up in four cases,” noted Obermayer, adding there was no occurrence of thrombosis or pulmonary embolism in the study, despite the lack of anticoagulation medication. Presenting some cases, Obermayer demonstrated “important aesthetic improvement at day three”, which improved further at three months, as well as an elimination of pain and healing of ulcers associated with venous insufficiency. “In summary,” he told the audience at CX, “this is a completely new method, with many benefits. You can treat over skin with severe atrophic disorders such as ulcers, it is extremely precise with its heat deposition, no sterile field is needed, the procedure can be performed without any sedation or even anaesthesia, it can treat very tortuous structures, and it is a safe procedure with a high level of patient satisfaction.” In terms of main limitations, Obermayer points out that as the feasibility study was the first in the world, no long-term results are currently available. He further added that structures within 5mm distance from the skin “may need subcutaneous infiltration”.

Isaac Nyamekye (Worcester, UK) has reported that, compared with Venefit (VNUS closure) and radiofrequency-induced thermotherapy (RFITT) systems, endovascular radiofrequency (EVRF) ablation provided inferior truncal ablation at six months. He added this result indicated that operators should be more cautious about adopting “new, unproven, endovascular techniques into clinical practice”.

system had the shortest ablation time, with the EVRF system having the longest ablation time (p<0.0001). Although this did not translate into a significant difference in the rate of successful early truncal ablation (two weeks) between the groups, the rate of successful truncal ablation (full ablation) at six months was significantly lower with the EVRF system at six months: 79.3% vs. 98.3% for RFITT vs.100% for Venefit (p<0.00001). However, there were no significant differences in quality of life scores between groups—all patients saw an improvement in their baseline EQ5D pain/discomfort scores and saw reductions in their baseline Aberdeen Varicose Vein Questionnaire scores. Furthermore, Nyamekye noted there were no reports of deep vein thrombosis,

SPEAKING AT THE Charing Cross Symposium (CX; 15–18 April, London, UK), Nyamekye presented the results of the 3RF study, which compared three radiofrequency ablation systems (Venefit, RFITT, and EVRF). The rationale for the study, he said, was that “not all devices are the same”. The Venefit device, for example, has a heat coil (70mm) applicator tip whereas the RFITT system has a bipolar tip (15mm) and the EVRF system a monopolar (5mm) tip. Additionally, the RFITT and EVRF systems are activated by foot, but the Venefit system is activated by hand.

Isaac Nyamekye

In the study, 182 patients with great saphenous varicose veins were randomised to receive treatment with the Venefit system (58), the RFITT system (64), or the EVRF system (60). The primary endpoint was successful ablation at six and 12 months. Secondary endpoints included complications, treatment time, seven-day pain scores and table counts, and health-related quality of life. There were no significant differences between treatment groups in terms of age, great saphenous vein diameter or length, and gender. According to Nyamekye, the RFITT

pulmonary embolism events, or thermal injury events. The majority of patients, Nyamekye noted, scored zero for both pain and tablet count scores after their procedures. Of those who did have a pain/tablet score, they scored low—the median total pain scores were 3, 2.5, and 5 for Venefit, RFITT, and EVRF respectively. Nyamekye concluded his presentation by saying EVRF provided “inferior” ablation compared with the other systems. However, he added that the real message of the study was that the vascular community should “be more critical before accepting new unproven endovenous technologies into clinical practice, if we do not want to repeat some of the controversies seen in other areas of vascular medicine”.

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Venous leg ulcers

Diagnostic biomarkers and fluorescence imaging may have the potential to advance venous wound care

ular ess nges

“A lot more bacteria than anticipated” have been discovered on wounds in a patient cohort consisting of 89% venous leg ulcers, and using fluorescence imaging proved superior for detecting infection in wounds. This was the conclusion of Tomas Serena (Warren, USA), the president of the Association for the Advancement of Wound Care, presenting the results in the iWounds programme at the Charing Cross Symposium (CX; 15–18 April, 2019). The recent discovery follows years of clinical assessment, fluorescence imaging and research, Serena noted.

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erena opened his presentation with a case, as he told the CX audience about a patient with a venous leg ulcer who was placed into a clinical trial. Although the wound did not look infected, the patient was subsequently treated, as he tested positive for generic staph aureus. Serena described this experience: “When the person who controls your budget for the next 10 years is in your clinic and you get the diagnosis of infection incorrect […] you begin a journey into how to do a better job, and that is what we have been on for 14–15 years.” He argued that symptoms can vary widely between patients and many may even be asymptomatic. This idea stimulated Serena and colleagues to initially conduct a pilot study to evaluate the diagnostic accuracy when fluorescence imaging was used adjunctively to the clinical severity score (CSS) assessment, to identify wounds with moderate to heavy bacterial loads. Adult wound care patients were

recruited for a prospective, single-blind, single-site clinical trial. With 89% of the cohort having venous leg ulcers, the average wound area was 10.81cm2, and the majority had been living with their wound for over 12 months. “It was a three-step process. First, the investigator carried out a CSS assessment, then we took a picture, to see if the fluorescent image demonstrated infection. Then finally, we did a quantitative tissue biopsy and histology to confirm [infection],” Serena explained. A positive fluorescent image, Serena said, has a 100% accuracy rate of detecting infection. Of note, he said that the low number of true negatives in this population prevented the calculation or statistical analysis of specificity and negative predictive value. According to Serena, the results of the clinical questionnaire highlighted the fact that fluorescence images guided at least one aspect of wound care in 90% of study patients. He reported that

clinician confidence was seen to increase by 21%, while such images enabled the identification of true positive wounds missed by CSS alone (in 47% of wound treatment plans). Outlining next steps in this field, Serena noted an additional project his team has been working on: “We are now developing biomarkers for infection, to be used in clinical trials”. Although he said that these are currently available in Europe, they are not presently approved for use in the USA. Thus, Serena et al set out to develop an assay to detect bacterial proteases from commonly known wound pathogens. Of the 366 patients studied, Serena stated the most interesting finding was the 133 patients who were not clinically diagnosed with infection, but tested positive for bacterial protease activity (BPA). This indicated that the initial stages of pathogenicity do not necessarily result in observable clinical signs of infection. According to Serena, the US Food and

Measuring success in venous ulcer healing: “Ambiguous and difficult to define” Defining success in wound healing remains a nebulous concept, with no consensus on what constitutes a successful outcome. Dave Bosanquet (Bristol, UK) outlined the difficulties at the Charing Cross Symposium (CX; 15–18 April, London, UK), arguing that a “core outcomes set” was needed to help characterise success. SYSTEMATIC REVIEWS OF wound healing literature have found that “over 100 different outcomes are being reported in the RCTs [randomised controlled trials]”, said Bosanquet, asking: “How do you pick the outcomes that are meaningful, clinically relevant and important to patients? In order to address such variation, the key thing that is needed is a core outcomes set—a core outcomes set is where you decide what outcomes are so important that they should be reported in all trials involving wound care.” The Food and Drug Administration (FDA) definition of wound healing has been widely accepted as the industry gold standard, defined as 100% reepithelialisation of a wound surface, without exudate, drainage or dressing, that is confirmed, once healed, two weeks later. “RCTs and cohort studies are good at reporting the first two aspects,” Bosanquet pointed out. “What we are not good at doing is checking that those wounds do not reoccur after a couple of weeks.” Surrogate outcomes are also used to define endpoints: “Wound healing is a complex process comprising a number of stages. It is not just complete closure—you have a lot of studies that report an outcome of a 50% reduction in wound size after four weeks […] we are talking about surrogate outcomes.

Rather than the end outcome of actual wound healing, you are evaluating a half-way outcome. And we know that wounds do not necessarily heal in a linear fashion, and that the percentage change can be exaggerated when we look at small wounds compared to large wounds. We have also got to recognise that some wounds are never going to heal.” Measures can be based on efficacy, efficiency or effectiveness, broadly referring to healing (and recurrence), the speed at which that happens (the number of visits, time to heal, and number of dressing changes), and the cost, both financial and to the patient. They can also be grouped into symptoms, such as exudate, oedema, odour and pain, quality of life measures, patient preference and acceptability, resource usage (in terms of staff time, number of visits, cost), and the tissue type: granulation or necrosis. “When we have all these varying outcomes, how on earth do we synthesise the data? How do we perform meaningful meta-analysis?” he asked. He highlighted comments from the European Wound Management Association that: “If the only gold standard was total wound closure, no therapy would ever be considered efficacious,” and: “Conversely, if a nonspecific endpoint is chosen, any positive findings may

Drug Administration (FDA) responded to this finding by implying that there remains no proof that bacteria are bad for wounds. Acknowledging the truth in this, Serena and colleagues initiated a large trial aimed to prove that BPA has prognostic power in predicting the time for wounds to heal. What they found was that positive tests for BPA indicated a high likelihood that wound healing would be impaired. “It actually is a really good surrogate endpoint,” noted Serena, as he put forward that BPA should be viewed as a point-of-care immediate predictor of healing, which has been derived prospectively in a randomised controlled trial. “We have been in contact with the FDA, and are hopeful we can get this approved in the USA,” Serena said. “I think we can conclude that, from both of these diagnostics, what we have found is a lot more bacteria than we anticipated, and bacteria locations—we did not anticipate this. The question is now: What do we do about it?”

not translate into a clear clinical benefit at the bedside.” Development of a core outcome set involves an exhaustive systematic review to summarise outcomes currently being reported, then gathering together a large group of key individuals comprising patients, healthcare professionals and industry, “and through a Delphi process achieve consensus on what are the actual outcomes that are important to report for patients undergoing clinical trials”. Bosanquet concluded: “Healing itself, as defined by the FDA, is generally well done in the literature, with the exception of checking that your wound has not recurred after a couple of weeks. Surrogate outcomes, such as a 50% area of reduction after a few weeks, are done quite frequently, but have inherent problems, as all surrogate outcomes do. There are a number of other outcomes, inconsistently reported, which make comparison difficult. We await the results of the core outcome set to help decide how we should define success in wound healing.”

How do you pick the outcomes that are meaningful, clinically relevant and important to patients? [...] the key thing that is needed is a core outcomes set, where you decide what outcomes are so important they should be reported in all trials.”

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European Venous Forum

Twenty years of the European Venous Forum: How it all began Dominik Heim Comment & Analysis In this article for Venous News, Dominik Heim speaks to Michel Perrin and Bo Eklöf about the founding of the European Venous Forum (EVF; 27–29 June, Zürich, Switzerland), an international symposium for venous specialists that this year will celebrate its 20th annual meeting. Heim, as the 2019–2020 president of the Forum, asks the question: who is behind the EVF?

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ürich hosts—in collaboration with the Swiss Society for Phlebology (SGP)—the 20th annual meeting of the European Venous Forum (EVF) this year in June. The 2019 EVF meeting takes place at the University of Zürich, in the most prestigious university building more than 100 years old. It will be another exciting get-together of more than 500 phlebologists, angiologists, surgeons, dermatologists and interventional radiologists from all over Europe, with further guests from the USA and Japan, to discuss the latest aspects of phlebology. As a migrating event, the list of towns that EVF has paid tribute to is long—in fact, it is twenty city names long. It all began in Lyon, France in 2000, with Michel Perrin as the first congress President and Andrew Nicolaides as Chairman. Michel Perrin recounts the conception of this meeting: “In the Sydney airport lounge,

professor Andrew Nicolaides, who was in transit on his way to Japan, approached me and said, ‘Michel, do you think it is time to create a European Venous Forum?’ I answered, ‘Give me five minutes to think about this proposal and get back to you.’ Five or perhaps 10 minutes later, my answer was positive. That was a genuine democratic process—but does a scientific society need it?”, he smiles. Following the recent annual meetings in Paris, France (2014), St Petersburg, Russia (2015), London, UK (2016), Porto, Portugal (2017) and Athens, Greece (2018) it is now the turn for Zürich, situated in the centre of Europe. But, who is behind the EVF? “A bunch of old men,” someone commented lately. Is it really so? EVF was founded to follow the example of the American Venous Forum (AVF), Bo Eklöf, a former president of AVF tells me at our personal interview meeting in

Bo Eklöf at his home in Helsingborg, Sweden, during the interview in March 2019

Andrew Nicolaides, Founder of EVF and Chairman of the EVF Board

Michel Perrin, Founder of the EVF

Helsingborg, Sweden last March. Perrin confirms this, stating that AVF “was the stimulus for the creation of EVF”. Perrin adds—laughing now, as he looks back at that first Lyon congress—“I did not care about an article published in a French vascular journal some months later, which stated that ‘Michel Perrin is a traitor, because he organised an English-speaking convention in Lyon: the Gaul capital.’” From the very beginning, EVF imposed strict rules for itself: “Congress language is English. EVF provides a platform for discussion of all new advances and aspects of phlebology, with emphasis on education and discussion”. Out of all submitted abstracts, the best 30 are selected and presented at the annual meeting. The speaking time is strictly 10 minutes, followed by another 10 minutes set aside for the paper’s discussion. The ample discussion time may be a source of stress for the presenters, but “that is where the truth comes out” says Eklöf. For, that is its mission: “Education, scientific knowledge, research and clinical expertise of the highest quality and establish standards in the field of venous disease”. Its annual meeting, including this year’s congress in Zürich, is one of the formats EVF works towards. But, there are now many other additional EVF events. In 2010, Bo Eklöf and Peter Neglén started the EVF HOW courses with its unique structure, designed as expert-led events focusing on practical venous education. No more than 100 participants per event can attend from all over Europe, with a faculty of well-known specialists (the proportion of participants to faculty should be three to one), 24 working stations with a representant from the industry and a faculty member. There is also the possibility to review all the activities of the course during one year on an interactive website. Based on the success of these annual EVF HOW courses, smaller courses and workshops have been developed and are taking place in different European cities since 2015: the so-

called EVF HOW Plus courses. At these events, a very limited number of people is taught by specialists in their field on a particular topic, such as venous stenting, sclerotherapy and other treatments. What makes these courses and workshops so special? According to Eklöf, it comes down to “the very open atmosphere, where

EVF provides a platform for discussion of all new advances and aspects of phlebology, with emphasis on education and discussion.” nobody is afraid of asking silly questions (that do not exist anyway). These events are unique, because they are very well-structured”. There is something else that is special about EVF, namely, its guidelines. Since 2009, several internationally approved guidelines on different venous topics have been produced and published with work from the EVF. These guidelines have been developed in collaboration with other phlebological organisations and societies, in accordance with the mission of EVF to “establish standards in the field of venous disease”. In conclusion, is EVF simply “a bunch of old men”? No, but perhaps rather “the wild bunch”, as seen in the classic 1969 Western movie by Sam Peckinpah. The EVF celebrates its 20th annual reunion in Zürich, on 27–29 June, 2019. Happy birthday, EVF! Dominik Heim is a general surgeon and venous specialist at the Venenzentrum in Thun, Switzerland, and the president of the EVF in 2019–2020.

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Boston Scientific follows BD with a venous stent on US market

IN MAY 2019, Boston Scientific became the second company to have a venous stent on the US market after it received US Food and Drug Administration (FDA) approval for its Vici venous stent. Just two months’ prior, BD received FDA approval for its Venovo stent—making it the first device to be approved for iliofemoral venous occlusive disease. Vici is a self-expanding nitinol stent that, according to Boston Scientific, has been “designed to be uniformly strong and crush resistant, capable of restoring blood flow by creating a cylindrical, patent vessel”. The Venovo stent is also a nitinol stent or rather, in the words of BD, it is a “flexible nitinol stent”. According to BD, Venovo is designed with “a balance of radial strength, compression resistance and flexibility needed for the treatment of symptomatic post-thrombotic and non-thrombotic iliofemoral lesions”. Approval for the Vici stent was based on data from the VIRTUS study, which was a prospective, multicentre, single-arm study of 170 patients. Study investigator Mahmood Razavi (Heart and Vascular Center, St. Joseph Hospital, Orange, USA) and colleagues report in the Journal of Vascular Surgery: Venous and Lymphatic Disorders that: “The Vici venous sent is safe and feasible for treatment of symptomatic iliofemoral venous obstruction, with excellent 12-month patency rates and significant improvement seen in clinical symptoms and quality of life indices.” The results of the VERNACULAR trial led to the

BIBA Insights

approval of Venovo. As reported in Venous News last year, this trial showed that, at 12 months, the Venovo was associated with a primary patency rate of 88.3%, and a low reintervention rate of 7.4%; it was not associated with any core-lab-assessed stent fractures. After the Venovo stent received FDA approval, VERNACULAR trial investigator Michael Dake (Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, Stanford, USA) commented: “The unique attributes of the Venovo stent make it particularly well-suited to treat iliofemoral occlusive disease. Most importantly, it is purpose-built for application in veins, and engineered to address the special challenges of venous lesions that are very different than those posed by arterial narrowing.” Both stents are already approved for use in Europe and, according to their respective companies, developed with physicians in mind. Jeff Mirviss, senior vice president and president, Peripheral Interventions, Boston Scientific, comments: “The FDA approval of the Vici venous stent system is the latest example of our

BIBA Briefings

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commitment to building the most comprehensive portfolio of technologies specifically developed to meet the needs of physicians treating both chronic and acute venous disease.” Similarly, Steve Williamson, worldwide president of Peripheral Intervention at BD, states: “The FDA premarket approval of the Venovo venous stent represents a significant advance for interventionalists treating iliofemoral venous occlusive disease, an underrecognised condition. We designed the Venovo venous stent in collaboration with clinicians to enable them to treat both post-thrombotic and nonthrombotic lesions. Clinicians will now have access to the broadest range of stent sizes in the USA for these difficult-to-treat lesions.”

Above: Venovo venous stent (BD) Left: Vici venous stent (Boston Scientific)

BIBA Briefings provide in-depth analysis of the latest market intelligence from BIBA MedTech Insights, which provides consulting and market analysis services to medical professionals and organisations in the medical device industry in Europe and North America. The platform also reviews data and news. For more information about BIBA Briefings or BIBA MedTech Insights, please contact Merveille Anderson: merveille@bibamedical.com

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Interview

Profile

Fedor Lurie

Fedor Lurie started his medical career in Ekaterinburg, Russia, on the east side of the Ural mountain chain. Now a long-time prominent figure in some of the largest venous and vascular societies in the USA, Lurie speaks to Venous News about the path that led him here—a career filled with mysteries, mentors, and memorable cases.

How did you decide to become a medical doctor, and what led you to the venous specialist field? I grew up fascinated by mysteries. I dreamed of travelling the world, finding the Loch Ness monster, discovering lost tribes of the Amazon jungle, solving the secret of the Bermuda triangle, and flying to other worlds in search of extra-terrestrial intelligent life. Reading mostly science fiction during my teens, my interest in science and math grew. I was ready to chose a career in science when I came across an article in a popular science magazine written by a physician. It described solving challenging clinical cases. This was a turning point; I decided to go to medical school. At first, I was overwhelmed by how much one needs to learn to be able to practice. But the very first clinical rotation confirmed exactly what led me to choose a medical career—every single patient is a mystery that is challenging to solve. Seeing pain and suffering strengthened my desire to solve those mysteries for as many patients as I can. My interest in math and physics was a factor in choosing cardiovascular surgery as my specialty, but getting into the venous field was accidental. My department chair assigned me a task of developing a venous surgery division; I was disappointed. As a junior faculty member who just completed a series of complex aortic reconstructions, I was looking forward to continue on the aortic track. It did not take long, however, to find another mystery: venous valves. Kistner, Raju, and Sottiurai described different techniques of deep vein valve repair, but indications to this surgery, and functional assessment of results remained unclear. This mystery set me off on a journey that is still far from completion.

Who were your mentors, and how have they shaped your career?

I was fortunate to have great mentors thoughout my career. My surgical training was in the department of Professor Lidsky, who started using heparin for treatment of deep vein thrombosis (DVT) in the 1940s, and wrote the first textbook on chronic venous disease. I had the privilege to learn the importance of knowledge promulgation and consensus building from the great master Bo Eklöf. Robert L Kistner (he prefers “Bob”) became more than a mentor: he and his wife Adelaide made my wife Galina and me a part of their family. Years of working with Bob gave me an opportunity to observe his highly individualised patient approach, unmatched clinical skills, and most importantly, continuous quest for new treatment options based on in-depth patient observation.

You were president of the American Venous Forum (AVF) in 2014–2015. As someone with a long-term involvement in the AVF, what were you most proud of during your time as president, and how has your work with the AVF continued?

Prior to my presidency, the Board established a priority for strategic planning. In 2014, we developed a strategic plan with several objectives. Our scientific objective was to identify and address the major gaps in knowledge related to venous and lymphatic disorders. In 2015 we developed a Day of Science and Innovation—a one-day

meeting with participation from the US Food & Drug Administration (FDA), National Institute of Health (NIH) and industry and clinical researchers, which drove identification of research priorities. The administrative objective was to increase the diversity of the AVF membership. Today, the AVF is a truly multispecialty society. The strategic objective was to develop the health policy strategy. In 2014–15 we engaged in discussions with the Centers for Medicare and Medicaid Services (CMS) leading to our participation in the Medicare Evidence Development & Coverage Advisory Committee (MEDCAC), developed relationships with private payers influencing their policies, and started building a process for more robust and credible guidelines.

You are the principal author of a recently published guidelines document on compression therapy following venous interventions. Which were the collaborating societies, and what were the key recommendations of these guidelines? We had asked several societies to participate in the development of these guidelines before the work began. The Society for Vascular Surgery, the American College of Phlebology, the Society for Vascular Medicine, and the International Union of Phlebology nominated their representatives and participated in the entire process of evidence collection, analysis, grading, and making recommendations. The key recommendations are specific to the treatment modality, and the disease stage. Although the level of evidence deserves major improvements, it is clear that compression therapy remains to be a key component of comprehensive venous care, especially in advanced stages of chronic venous disease.

Remember that the only reason for your existence as a specialist is your ability to provide the best care for your patients.” What are some of your other current research interests?

My main research interest still relates to haemodynamics, but it is more focused now on biological effects of abnormal blood flow. Together with my previous research fellow Maxim Shaydakov, we have looked at the molecular mechanisms in endothelial cells around the normal human deep vein valve. This has not been done before, and somewhat surprising findings are the base for the current investigation of the mechanisms involved in the DVT initiation. On the arterial side, we also found an interesting relationship between the shear rate of the blood flow in the carotid arteries and the risk of stroke. Our Vascular Surgery fellow Nizar Hariri recently published these

results in the Journal of Vascular Surgery. Another fascinating area is defining the appropriate dose of compression therapy. Recently developed technology allows interface pressure measurements in routine clinical practice. I believe that looking at clinical outcomes with an objectively measured dose of compression will change our clinical practice. Together with my current research fellow Junjie Ning, we are exploring this intriguing subject.

In the last year, which research paper(s) have you found particularly interesting, and why? This is a hard question to answer within a few lines. The field of veins and lymphatics is so broad that it is increasingly challenging to keep up with new information. The most interesting for me are the papers that open a new side of a known subject, or those

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more comprehensive look at the role of inflammation in chronic venous insufficiency than in the majority of recent publications. In addition to measuring inflammatory mediators, they have investigated their interconnectivity showing its significant disruption in the blood obtained from refluxing veins. This paper raises many new questions that are vitally important for our understanding of the biology of venous disease.

What do you think are the main challenges currently facing the field?

The biggest challenge in the venous field is the lack of high-level evidence. It applies to both clinical and basic sciences. Pathogenetic mechanisms of venous disease are under-investigated and poorly understood. This means the foundation of many current treatments and management options is quite shaky. The current clinical evidence is often based on underpowered studies, and studies that failed replication attempts. Today’s regulatory and ethical environment requires a much stronger base for clinical decision-making.

Could you describe a particularly memorable case you have had, and what you learned from it?

A 36-year-old mother of three came with a venous ulcer due to primary chronic venous disease and great saphenous vein reflux. She was previously denied insurance coverage because she was asymptomatic. It turned out that years ago, she quit her standing job because of her symptoms, and started home-based business with her husband, so that she could sit at work. She then became “asymptomatic” until she developed an ulcer. This case not only shows the importance of proper clinical investigation of every patient, but also demonstrates how ignoring true clinical disease definitions leads to tragedies for people.

In your career thus far, what has been your proudest moment?

that spark the drive for further research. Two recent papers fall in these categories. The first is “Risk factors associated with the venous leg ulcer that fails to heal after one year of treatment” by Raffi Melikian et al from Tufts University, Boston, USA. It suggests that deep vein disease, and particularly deep reflux plays a major role in ulcer resistance to treatment. Current obsession with iliac vein obstruction has overshadowed this aspect of the natural history of venous ulcers. I hope that this paper will trigger some interest in researching the role of deep vein reflux. The paper was published in the Journal of Vascular Surgery: Venous and Lymphatic Disorders (JVS-VL). Another interesting paper came from Ulka Sachdev and colleagues at the University of Pittsburgh, USA and was also published in the JVS-VL. The authors of “Suppressed networks of inflammatory mediators characterize chronic venous insufficiency” took a

The proudest moment in my professional carrier has been becoming president of the American Venous Forum. Over the years of working with AVF—the most respected venous society in the world—I developed close friendships with many of the past presidents, but always looked up to them. To have my name listed next to these giants of the venous field is a true professional honour.

What advice would you give to physicians and venous specialists who are at the beginning of their career?

Remember that the only reason for your existence as a specialist is your ability to provide the best care for your patients. Pursuing other goals damages both you and the specialty that you choose.

Outside of work, how do you most like to spend your time?

The most enjoyable time to me is time spent with my family. When children and grandkids are not around, I enjoy playing scrabble with my wife. We also like travelling; learning about different cultures is always fun. My long-time hobby is fishing: not only for the thrill and the sport of it, but being outdoors in the early morning or at sunset is a great way to relax.

Academic appointments (selected)

2016–present Adjunct Research Professor, Division of Vascular Surgery, University of Michigan, Ann Arbor 2012–present Associate Director, Jobst Vascular Institute, ProMedica, Toledo, USA 2000–2012 Clinical Professor, Department of Surgery, John A. Burns School of Medicine, University of Hawaii, Honolulu, USA 1989–1995 Professor of Surgery. Department of Surgery, Ural Medical Academy, Ekaterinburg, Russia

Society appointments (selected)

2016–present Society for Vascular Surgery: Research Committee member 2016–present Society for Vascular Surgery: Program Committee member 2015–present American Venous Forum: Chairman, Science and Innovation Day committee

Past society appointments (selected) 2015–2017 American Venous Forum Foundation: President 2014–2015 American Venous Forum: President 2011–2014 Society for Vascular Surgery: Director, Board of Directors 2006–2011 American Venous Forum Foundation: Director, Board of Directors 2004–2012 Pacific Vascular Symposium: Co-Chairman 1982–1986 Urals Society of Young Scientists: Chairman

Memberships

American Heart association American Venous Forum American Venous and Lymphatic Society Society for Vascular Surgery European Venous Forum (Honorary Member) German Phlebology Society (Corresponding Member)

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Role of elevated central venous pressure in patients presenting with chronic venous insufficiency: A single-centre experience Raghu Kolluri Comment & Analysis Raghu Kolluri gives an overview of elevated central venous pressure—a condition which Kolluri argues is elusive, underdiagnosed and in need of further examination in order to establish its role and relationship to chronic venous insufficiency. IT IS NOT uncommon to encounter patients who are “non-responders” to medical therapies. Venous disease is no exception to this rule. We have all encountered situations wherein even well-planned endovenous therapies do not resolve a patient’s chronic venous insufficiency (CVI) related symptoms. We have learned that obesity and calf pump dysfunction can lead to symptoms consistent with CVI. O ­ ur understanding of lipoedema and venolymphatic physiology has also improved over the

last decade, leading to increased use of the terms phlebolymphoedema and phlebo-lipo-lymphoedema. However, the prevalence and role of elevated central venous pressure and other related systemic causes that may lead to symptoms similar to CVI are unknown. The reasons for this deficit in knowledge may be manifold. Elevated CVP is an elusive diagnosis, and an underdiagnosed condition. While invasive right heart catheterisation is the gold standard, the more commonly

used transthoracic echocardiographic assessment of the right atrial pressure is also quite challenging since most of these patients are obese. A careful history may reveal underlying risk factors for the development of elevated CVP. These include cardiac risk factors such as ischaemic or non-ischaemic cardiomyopathy, congestive heart failure, diastolic dysfunction, rheumatic fever, intravenous drug abuse, and tricuspid regurgitation, as well as pulmonary diseases including chronic obstructive pulmonary disease, asthma and obstructive sleep apnoea (OSA). Lack of optimal response to compression therapy and proximal displacement of oedema into thighs, buttocks, genital areas and pelvis are clues that oedema is either from lymphoedema or due to a systemic cause or due to elevated CVP. Patients may report shortness of breath with compression garment application or after initiation of the sequential compression therapy. Sequential compression can also result in excessive volume displacement proximally, resulting in hospitalisation from acute right heart failure or pulmonary oedema. Physical examination findings include elevated jugular venous distension, positive hepatojugular reflux, a prominent pulmonic component of the second heart sound and a holo/ pan-systolic murmur of the tricuspid regurgitation in the left third or fourth intercostal spaces. Systolic hepatic pulsations may be palpable in severe tricuspid regurgitation. To assess the prevalence of elevated

Study finds significant association between low bilirubin levels and venous thromboembolism

A recent paper published by Hakan Duman (Recep Tayyip Erdoğan University, Rize, Turkey) and colleagues in the Journal of Vascular Surgery: Venous and Lymphatic Disorders has concluded that lower levels of bilirubin were significantly associated with venous thromboembolism (VTE), in a study of 103 VTE patients and a control group of 50.

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Research

he endogenous anti-inflammatory marker bilirubin is associated with atherothrombosis, as a possible antithrombotic agent that inhibits platelet activation and potentially organ infarction, the authors note. However, no studies known to Duman et al had previously investigated the role of bilirubin in VTE. This single-centre, case-control crosssectional study found that bilirubin concentration “is independently associated with the presence of VTE”. “Human life is in a state of equilibrium”, Duman tells Venous News. “The pathological process in the metabolism begins because of the negative side of this balance. Serum bilirubin levels, as an antioxidant, are also part of this balance. In our study, we showed that it may be associated with venous thrombosis. I think future studies will also reveal the unknown benefits.” The study’s VTE arm included 34 patients with distal deep vein thrombosis (DVT), 30 patients with proximal DVT, and 39 patients with pulmonary embolism. In addition lower bilirubin levels in the VTE arm (0±2.6µmol/L vs. 7.3±3µmol/L; p=0.001), VTE patients also had higher levels of high-sensitivity C-reactive protein (hs-CRP) concentration (0.8 [0.3–2]

mg/L vs. 1.1 [0.2–3] mg/L; p=0.008) and a higher white blood cell count (7.4±1.5 ×109/L vs. 8.2±2.7 ×109/L; p=0.02). Patients in the VTE subgroup of pulmonary embolism were found to have the lowest bilirubin and highest hs-CRP values, with significantly higher Hakan Duman levels of bilirubin in the control arm as compared to the pulmonary embolism patients. Meanwhile, hsCRP value showed a significant difference between all subgroups versus the control arm, and although white blood cell count was higher in the VTE arm, this difference was not significant. The authors summarise previous literature, stating: Atherothrombosis is considered a chronic inflammatory disease VTE may cause inflammatory marker levels to rise

Patient with elevated central venous pressure and peau d’orange skin changes due to proximal displacement of oedema with compression therapy.

central venous pressure in chronic venous insufficient patients, we conducted a prospective descriptive study in our centre. We enrolled 264 consecutive patients referred to the vascular lab with a diagnosis of CVI, between September 2015, and August 2016. All of these patients underwent venous reflux duplex study and a limited echocardiogram to assess elevated CVP. Demographics and other potential risk factors for oedema and CVI-like symptoms were collected. A validated obstructive sleep apnoea risk screening tool called the STOP-BANG score was administered in patients without a history of OSA. We noted a high prevalence of OSA, patients at risk for OSA, and elevated CVP. Raghu Kolluri is an angiologist in Columbus, USA, and chairman of the VEINS at the annual Vascular InterVentional Advances (VIVA) meeting.

Because endothelial injury is a common mechanism in both arterial and venous thrombosis, inflammation may be a common risk factor Previous reports suggested that antioxidant capacity increases in mild unconjugated hyperbilirubinemic individuals, and slightly elevated bilirubin may have a protective role in cardiovascular disease Bilirubin is a possible antithrombotic agent that inhibits platelet activation and, potentially, organ infarction, which could contribute to the reduced mortality rate in mildly hyperbilirubinemic individuals Duman et al suggest in discussion of their findings, “Inflammation may be part of the event at various

Human life is in a state of equilibrium. Serum bilirubin levels, as an antioxidant, are part of this balance [and] we showed that it may be associated with venous thrombosis.” stages of haemostasis through the activation of coagulation or by the inhibition of the fibrinolysis and anticoagulant pathways. C-reactive protein levels are independently associated with cardiovascular disease and may play a role in the identification and stratification of individuals at risk of cardiovascular diseases.”

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Deep vein thrombosis

The optimal pathway for acute deep vein thrombosis treatment involves identification, management and surveillance Prakash Saha (London, UK), speaking during the Venous and Lymphatic Challenges programme at the Charing Cross Symposiym (CX; 15–18 April, London, UK), outlined his three “key steps” to optimising treatment of acute deep vein thrombosis: identification, management, and surveillance. He added that the last step, surveillance, had not received “a lot of focus”.

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ccording to Saha, one in 1,000 patients in the UK are diagnosed with deep vein thrombosis and, of these, 30% will go on to develop post-thrombotic syndrome. However, the proportion of patients who develop post-thrombotic syndrome rises to more than 90% if there is iliofemoral involvement—which is the case for an

estimated 10–15% of patients. Overall, he noted, deep vein thrombosis costs the UK National Health Service (NHS) approximately £1 billion per year. In terms of managing deep vein thrombosis, Saha reported that the focus has been on managing patients in an ambulatory setting, ensuring ultrasound is available at all times for identifying

patients, providing early anticoagulation treatment, and “increasingly” identifying patients who need early triage and transfer for interventional treatments. The optimal pathway for managing deep vein thrombosis, he argues, needs to emphasise surveillance as well as identification and management. Saha noted that, generally, “there has been

less concern about long-term outcomes”, and this meant that the third part of the pathway, surveillance, has received less focus. Furthermore, he stated that a multidisciplinary team—including primary care physicians, specialist nurses, interventional radiologists, and vascular specialists among others— should oversee the pathway. The first step—identification— involves accurate diagnosis, safety and timely treatment, and avoiding pulmonary embolism. Although ultrasound is the “cornerstone” of this part of the pathway, Saha said, it has limitations, such as a lack of availability of equipment or ultrasound imagers. “Innovations (for example, portable ultrasonography or specialist nurse-led procedures) may cover these issues,” he observed. Another important part of identification is having access to crosssectional imaging modalities such as computed tomography venogram. Management—the second step in the pathway—involves good patient information, conservative measures (where appropriate), anticoagulation, and interventional treatments. Saha commented that the “BLAST tool” could be used to help determine which patients would benefit from catheter-directed thrombectomy, with BLAST standing for “bleeding risk, life expectancy, the anatomy of the deep vein thrombosis, the severity of the deep vein thrombosis, and timing”. An important factor in managing patients with deep vein thrombosis, Saha observed, was to recognise that these patients are “different from aneurysm patients”, because they are “young”, with an average age of 39 years and “tech savy”. Therefore, medical mobile apps had a potential role in their management. Ultimately, Saha explained, the “key to good outcomes” was choosing the right patient, choosing the safest technique, proper planning (which “prevents poor technique”), and—to quote Gerard O’Sullivan (Galway, Republic of Ireland)— “making sure the first cases go okay. Maybe not perfect, but not disastrous.” Surveillance was an important step in the pathway, Saha said, because deep vein thrombosis can lead to “chronic problems”. He added that the “St Thomas’ postinterventional protocol” (that is, the protocol of Guy’s and St Thomas’ NHS Foundation Trust) included full therapeutic low-molecular weight heparin (LMWH) ultrasound on the day after the procedure, and spilt dose LMWH for two weeks and ultrasound. Other steps in the protocol include ultrasound surveillance at six weeks, three months, six months, and yearly after the procedure. He added that there was also a need to assess Villalta scores and quality of life measures.

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Varicose veins

The evolution of varicose vein treatment: From 19th century ligation to noninvasive therapy Mark S Whiteley Comment & Analysis The last two decades have seen a major revolution in the treatment of varicose veins and venous reflux disease—and we may be on the brink of the next big shift. This is what Mark S Whiteley writes for Venous News, in an overview of the developments that have taken place in this field since the emergence of endovenous interventions introduced in the last 20 years, and the preceding techniques that made these possible. IN THE 1890s, Friedrich Trendelenburg introduced the idea that visible varicose veins were caused by underlying truncal valve dysfunction—and to cure that, he introduced the Trendelenburg ligation. Previous to this, treatments had been aimed at the visible varices alone. The following century showed little advance in varicose veins treatment, apart from studies showing that stripping the great saphenous vein was superior to ligation alone and that the treatment of incompetent perforators helped healing venous leg ulcers. In contrast, the last 20 years or so have seen a massive increase in the advancement of treatments for varicose veins and venous reflux disease. Although most people point to the introduction of endovenous surgery as being the major turning point, all of the new advances actually stem from the development of venous duplex ultrasonography in the mid 1980s and early 1990s. It was only because this noninvasive imaging modality that allowed us to see venous fuction in real time became widely available that our understanding of venous disease leapt forward. The ability to identify venous reflux, different reflux patterns, the differences between passive (diastolic) reflux that everyone understands and active (systolic) reflux that many doctors struggle with, and the size of target veins, has shaped many of the new approaches to varicose veins treatment. Moreover, the identification of venous reflux in leg varicose veins arising from pelvic veins has revolutionised the concept that varicose veins can be thought of as a problem isolated to the lower limb. However, to think that everyone has reached the same conclusions from the advent of venous duplex ultrasound would be wrong. Whereas some have used the technique to improve understanding and

hence results, most doctors just use it to identify which truncal vein they are going to treat, ignoring complex patterns, perforators or pelvic venous reflux. It is not surprising that randomised trials of different treatment modalities are not conclusive, if they only concentrate on treating incompetent truncal veins and ignore the other causes of varicose veins. The introduction of venous duplex

techniques. As such, the haemodynamic approach may begin to gain some traction.

The endovenous revolution

Following on from venous duplex ultrasonography, the biggest revolution in the treatment of varicose veins was the invention of successful endovenous thermal ablation. At the end of the 1990s, catheter-bansed radiofrequency ablation and endovenous laser ablation prove to be successful, causing endovenous surgery to take off. Not only did these endovenous thermal techniques destroy the vein, but the catheters were introduced under ultrasound control into the distal vein and passed proximally, without the need for open surgery in the groin. This minimally invasive approach allowed the development of tumescent anaesthesia. With truncal ablation and phlebectomies being possible under tumescent anaesthesia, true “walk-in, walk-out” ambulatory surgery became possible for the treatment of varicose veins. More than just a new technique of treating veins, this allowed vein centres to be set up outside of hospitals, that could concentrate on ambulatory venous surgery. In fast succession, treatment of incompetent perforators was developed in 2001 using the transluminal occlusion of perforator (TRLOP) technique (“reinvented” in America in 2007 as percutaneous ablation of perforator surgery or PAPS), steam vein sclerosis and several different radiofrequency and laser devices became available for leg veins. All of these thermal ablation devices require tumescence because of the heat generated during treatment. This has led to the investigation and development of nonthermal, and therefore non-tumescence

One of the most exciting new treatments for varicose veins and venous reflux disease is HIFU.” ultrasonography split the venous world into two main factions. Unfortunately, a great many doctors who “do” varicose veins as a job and do not attend conferences or read around the subject are unaware of this huge divide. In the English-speaking world, most doctors practice ablative surgery. Some still ligate and strip, although most now have moved on to some form of thermal ablation. Other nonthermal techniques ablative techniques are becoming more widely used. Nevertheless, a large number of doctors remain unaware of the haemodynamic approach to varicose veins and venous reflux disease, championed by the conservative haemodynamic correction of venous insufficiency method (CHIVA). Often called “saphenous sparing surgery”, advocates of this approach present series where the results have been demonstrated to be comparable with stripping. Whereas those of us who treat all of the reflux pathways would regard such results as suboptimal, the randomised studies that have been performed where surgeons ignore perforator vein reflux and pelvic vein reflux, appear to show stripping as equivalent to the thermal ablation

placed ablation techniques. In 1985, a patent was granted to allow detergent sclerotherapy fluids to be mixed with gas to make foam. This was then taken on by a British company hoping to replace surgery with a chemical ablation technique. Although it has become clear in the last decade that foam sclerotherapy works well in small veins within walls, medium and long-term results have been poor in truncal veins, which are larger and have thicker walls. As such, although foam sclerotherapy is an essential technique to be used by any doctor providing venous treatments, it has been shown to have comparatively poor results when used as a sole treatment modality. To improve sclerotherapy results, the endovenous mechanochemical ablation catheter (MOCA, Clarivein) was developed to traumatise the venous wall mechanically and to allow sclerosant to penetrate deeper. Research has shown that this increases the cell death within the vein wall, improving the long term ablation over foam sclerotherapy alone. Finally in the non-thermal nontumescent area, cyanoacrylate glue is being injected intravenously with good

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results in medium-term studies. This appears to use a different mechanism, as the vein wall is not ablated in the same way as it is with the previously described techniques. However, patient satisfaction is high and clinical results are very good.

Pelvic venous reflux

Over the last decade, pelvic venous reflux and pelvic congestion syndrome have become increasingly recognised as part of the varicose vein disease profile. Although we started investigating and treating this in 2000, it has largely been ignored by the venous community until more recently. Amazingly, many of the lessons learned in the 1990s for leg varicose veins are having to be re-learned in pelvic veins. In the 1990s, doctors realised that examining varicose veins with venography, particularly supine, is suboptimal compared to venous duplex ultrasonography, where the patient was semi-erect or erect. However, many now use CT or MRI to examine pelvic veins in a supine patient! With approximately 20% of female patients with leg varicose veins having a major contribution from pelvic vein reflux, and 3% of males, it is now impossible to offer a full varicose vein service unless pelvic veins are assessed and provision for treatment is made as part of the service.

So what does the future hold for varicose vein treatment?

Undoubtedly, new endovenous devices will appear. Indeed, I have just performed the first endovenous microwave treatment in Europe. This technique has all the advantages of endovenous laser and radiofrequency ablation, but without some of the drawbacks of both. However, it is still an endovenous thermal technique requiring tumescence. One of the most exciting new treatments for varicose veins and venous reflux disease is HIFU: high intensity focused ultrasound (see page 4). This new technique has only recently been presented at meetings, so only the principles and very earliest results are known. However, HIFU has been used in other clinical scenarios for non-invasive tissue ablation and so the probability that it will be successful in veins is high. By externally focusing ultrasound to cause ablation at one specific point targeted internally, HIFU is a truly non-invasive technique, a quantum leap forward from minimally invasive techniques. By being able to externally target specific venous areas, those of us interested in vein research will be able to explore whether ablation of all venous reflux is required, or whether a haemodynamic “CHIVA” approach can be used successfully to target specific areas of venous reflux. By being able to use the same equipment to compare strategies, we should be able to identify the optimal way of treating veins: whether it be ablation, haemodynamic or a combination of both. Mark S Whiteley is a consultant venous surgeon, a visiting professor at the University of Surrey in Guildford, UK, and founder of The Whiteley Clinic, with three centres in the UK.

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Market watch

Product News Thrombolex announces 510(k) clearance of Bashir catheter systems for thromboembolic disorders

Thrombolex has announced that the US Food and Drug Administration (FDA) has cleared the Bashir Endovascular Catheter (BEC) for the controlled and selective infusion of physician-specified fluids, including thrombolytics, into the peripheral vasculature, and the Bashir N-X Endovascular Catheter (BEC N-X) for the controlled and selective infusion of physician-specified fluids into the peripheral and pulmonary artery vasculature. The company has also received FDA clearance to begin an early feasibility study evaluating the Bashir platform for treatment of pulmonary embolism. The BEC is the only pharmacomechanical catheter cleared by the FDA that incorporates a physician controlled distal segment with six expandable miniinfusion catheters to deliver physician specified fluids in precise locations in the patient’s peripheral vasculature. Riyaz Bashir, professor of Medicine and director of Vascular and Endovascular Medicine at Temple University Hospital (Philadelphia, USA) says, “My inspiration for the BEC platform technology was to develop a device that I hoped would provide better treatment outcomes by rapid restoration of blood flow through the thrombus thereby enhancing both endogenous and exogenous fibrinolysis.” Bashir goes on to say, “acute venous thromboembolic (VTE) disease has become a significant public health concern in the USA, with approximately 900,000 patients diagnosed and causing up to 100,000 deaths each year.” Marvin Woodall, chairman, CEO and co-founder of Thrombolex comments, “Our dedicated team is proud to have received FDA clearance for our first two catheter-directed thrombolysis (CDT) products to treat patients suffering from acute VTE disorders”. Michael Cerminaro, president, COO and cofounder of Thrombolex says, “Our first two products feature unique platform technologies which will be included in our significant pipeline of new products

FlowTriever

currently being developed.” Brian Firth, chief scientific officer of Thrombolex, points out, “We recently received FDA clearance to begin an early feasibility study (EFS) to demonstrate the safety and feasibility of the Bashir platform technology in the treatment of acute pulmonary embolism. The protocol requires the use of the BECs expandable mini-infusion catheters to deliver low-doses of r-tPA directly into an acute pulmonary embolism.” Firth further states, “The goal is to minimises the risk of major bleeding complications (including intracranial haemorrhage) associated with systemic lytic administration.” Further clinical data will provide new insights into the advantages of rapid restoration of blood flow. Thrombolex believe that harnessing the endogenous lytics in the patient’s own blood in a synergistic manner with a lower dose of exogenous lytic has the potential to accelerate clot lysis and more effectively reduce the total thrombus burden. This should reduce the incidence of chronic pulmonary thromboembolic disease and post thrombotic syndrome. The BEC and the BEC N-X are currently only available in the USA. Plans for distribution outside the USA are forthcoming, the company states.

Inari Medical announces publication of FLARE IDE study results

Inari Medical has announced the publication of its 106-patient prospective multicentre FlowTriever Mechanical Pulmonary Embolectomy (FLARE) study for the treatment of intermediaterisk pulmonary embolism. The study was published in JACC: Cardiovascular Interventions. FLARE was conducted under the direction of co-principal investigators, Kenneth Rosenfield, section head for Vascular Medicine and Intervention at Massachusetts General Hospital, Boston, USA and Victor Tapson, essociate director, Pulmonary and Critical Care Division at CedarsSinai Medical Center, Los Angeles, USA. The study met both of its primary safety and effectiveness endpoints, showing large and rapid reduction

in right heart strain, with no device related major adverse events in the 106 patients enrolled. Just two patients received thrombolytic drugs. The study also showed patients treated with FlowTriever had much shorter intensive care unit and overall length of stay compared to previously published studies in which thrombolytic drugs were used to treat pulmonary embolism. FlowTriever has been used to treat over 1,000 PE patients to date and is the only thrombectomy device cleared by the US Food and Drug Administration (FDA) for pulmonary embolism. “The results of this trial open the door to an entirely new approach to the treatment of pulmonary embolism. It is exciting to be able to offer this potentially life-saving therapy to our patients,” says Thomas M Tu, director of the Pulmonary Embolism Response Team (PERT) at Baptist Health Louisville. “With FLARE complete and the data now published, we are excited to collect a larger set of real-world data on FlowTriever via the FLASH registry,” adds Catalin Toma, interventional cardiologist, UPMC Presbyterian and principal investigator for FLASH. Intermediate and high-risk pulmonary embolism patients treated with FlowTriever will be enrolled in FLASH and followed over the short and intermediate term. Patient enrolment in FLASH began in December 2018. “Appropriate treatment of PE has been hampered by a paucity of data over the years,” says Bill Hoffman, CEO of Inari. “FLARE and FLASH reflect Inari’s commitment to producing and publishing a robust portfolio of clinical data to help physicians understand which patients benefit most, and in what ways, from interventional treatment for pulmonary embolism”.

Misonix to acquire Solsys Medical for approximately US$97 million

Misonix, Inc., a provider of minimally invasive therapeutic ultrasonic medical devices, has announced that it has entered into a definitive agreement with Solsys Medical, a regenerative medical company and allograft producer, to acquire Solsys in an all-stock transaction valued at approximately US$97 million. Solsys markets an advanced wound care product under the brand name TheraSkin, a cellular and tissue-based product for regenerative wound healing designed to help healthcare professionals treat difficult-to-heal chronic wounds. TheraSkin is a clinically proven, minimally manipulated, living human split-thickness skin allograft that is cryopreserved to retain living cells and growth factors while maintaining a mature native human dermal architecture. The versatility in applications and sizes of TheraSkin reduces product waste and helps drive operational efficiencies to better manage total cost of care and quality outcomes needed to treat difficult to heal and chronic wounds. TheraSkin has been applied to over 100,000 wounds supported by multiple clinical studies.

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The planned acquisition of Solsys substantially broadens Misonix’s addressable market through wound care solutions that are complementary to its existing products. In calendar 2019, Solsys is expected to achieve sales of approximately US$32 million. In fiscal 2020, the pro forma company is expected to generate over US$80 million in sales. The combined company anticipates top line revenue growth in excess of 20% per annum over the next several years. Stavros Vizirgianakis, president and CEO of Misonix, commented, “Solsys and its leading wound treatment application, TheraSkin, is highly complementary to Misonix’s existing wound debridement solution, SonicOne. As a result, the combined entity will be ideally positioned to establish a new standard of care in the growing chronic wound care market through what we view as the best-in-class wound treatment solution. The Misonix-Solsys wound care treatment is supported by extensive clinical data that demonstrates the positive impact to critical aspects of wound healing process that lead to improved patient outcomes, as well as clinical efficacy and a strong economic value proposition for hospitals.” Under the terms of the agreement, Misonix will issue approximately 5.7 million new shares to Solsys unitholders. After the completion of the transaction, it is expected that Misonix shareholders immediately prior to the closing will own 64% of the combined entity, and Solsys unitholders will own 36%. Misonix will also assume Solsys’ outstanding secured debt of approximately US$20 million upon closing. Joe Dwyer, chief financial officer of Misonix, comments, “The acquisition of Solsys marks further progress in advancing Misonix’s goals for continued growth and enhancing shareholder value with TheraSkin sales that are growing at an annual rate in excess of 25%. The acquisition also enhances Misonix’s ability to address the domestic wound biologics market, which is valued at approximately US$700 million annually, and is projected to grow at a compound annual growth rate of 8%. We believe this transaction creates significant mid and long-term growth opportunities for the combined company to grow revenue in excess of 20% per annum over the next several years. The transaction has been approved by the boards of directors of both companies. The completion of the acquisition and the issuance of Misonix shares in connection with the proposed transaction is subject to the approval by Misonix shareholders and the completion of the transaction is subject to approval by 55% of Solsys’ Series E unitholders and a majority of its Common unitholders, Series A unitholders, Series B unitholders, Series C unitholders and Series D unitholders, voting as a single class, as well as the satisfaction of certain customary closing conditions. The transaction is expected to be completed in the third quarter of calendar year 2019.

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June

Clinical News Increased risk of VTE found in critically ill H1N1 patients with acute respiratory distress

A new study has found that intensive care unit patients with swine flu (H1N1) and acute respiratory distress syndrome (ARDS) were 33 times more likely to develop venous thromboembolism (VTE), unless prescribed with an anticoagulant when admitted. The findings were published by Andrea T Obi (University of Michigan, Ann Arbor, USA) and colleagues in the Journal of Vascular Surgery: Venous and Lymphatic Disorders, detailing the results of an observational cohort study of 71 patients at a single centre. “To our knowledge, this is the first study to document VTE incidence in adult intensive care unit patients

with severe acute respiratory distress syndrome due to H1N1 viral pneumonia,” noted Obi in a report of the study by the Society for Vascular Surgery. ‘This high rate of VTE was encountered despite empirical anticoagulation in more than half of our cohort.” she added. The severity of swine flu is manifested by non-pulmonary complications, mainly VTE. In response to a clinical report from the University of Michigan in 2009, The Centers for Disease Control and Prevention issued a warning regarding the “development of a hypercoaguable state and fatal thromboembolic events” for patients with this disease. Obi et al analysed the 71 patients admitted to the surgical intensive care unit (ICU) with severe ARDS with

possible H1N1 viral pneumonia between 2009–2010. In this cohort, the empiric use of anticoagulation involved systemic heparin anticoagulation (n=39, 55%) vs. VTE prophylaxis (n=32, 45%). The overall incidence of thromboembolic events was 37%, much higher than 6% observed in their ICU patients overall. Following evaluation for H1N1 infection, they observed 36 H1N1 positive patients, of which 28% presented with deep venous thrombosis (DVT), 28% with pulmonary embolism (PE), and 44% with VTE. Thirty-five patients tested negative for H1N1, of which 23% had DVT, 9% had PE, and 29% VTE. Independent risk factors for VTE included H1N1 infection (OR, 17.9), bacterial pneumonia (OR, 6.0) and vasopressor requirement (OR, 13.1). Importantly, those with H1N1 who did not receive therapeutic anticoagulation were 33 times more likely to have any VTE event. “Whereas a relationship between H1N1 influenza and propensity toward

thrombotic events has been suggested by clinical reports and animal studies, a relationship between seasonal influenza and thromboembolic complications has previously not been proved. Our data are the first to confirm such a relationship,” she added. Their study did not observe a reduction in overall mortality with empirical system heparin anticoagulation. However, Obi suggested, “other benefits to VTE prevention exist, such as elimination of potential post-thrombotic syndrome and pulmonary hypertension.” She notes that “the small sample size and otherwise non-standardized management of the patients may have contributed to lack of mortality benefit.” Ultimately this follow-up study by a group with significant experience in this area suggests consideration of systemic anticoagulation in critically ill patients with influenza A H1N1 viral pneumonia and severe ARDS, the Society for Vascular Surgery states in a press release.

Calendar of events 5–7 June EWMA: European Wound Management Association Gothenburg, Sweden www.ewma.org

5–7 June I-MEET: Multidisciplinary European Endovascular Therapy Nice, France

26–28 June BSET: British Society of Endovascular Therapy Annual Meeting South Gloucestershire, UK www.bset.co.uk

25–27 August UIP: International Union of Phlebology Chapter Meeting Krakow, Poland www.uip2019.com

27–29 June EVF: European Venous Forum Zurich, Switzerland

2–3 October EVF HOW Plus Course: Venous Stenting and Thrombolysis Training London, UK

www.imeetcongress.com

www.europeanvenousforum.org

www.evfvip.com

12–15 June SVS Vascular Annual Meeting London, UK

10 August American Vein and Lymphatic Society Sclerotherapy Course and Ultrasound Hands-On Course Washington, DC, USA

11–12 October 8th Meeting of the American of Wound Healing and Tissue Repair Chicago, USA

www.vascular.org

17–19 June Royal Society of Medicine Venous Forum London, UK www.rsm.ac.uk/venous-forum

Issue

19 10

Events

www.phlebology.org

www.acwound.org

17–19 October 10th annual EVF HOW Riga, Latvia

2–4 November TheVEINS at VIVA Las Vegas, USA www.vivaphysicians.org

7–10 November AVLS: American Vein and Lymphatic Society Phoenix, USA www.avlscongress.org

19–23 November VEITHsymposium New York, USA www.veithsymposium.org

27–29 November The Vascular Societies’ Annual Scientific Meeting Manchester, UK www.vascularsociety.org.uk

www.evfvip.com

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