Venous News 9 – January 2019 US Edition

Jan

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19 09

New ATTRACT data show greater benefits of catheter-based therapy for iliofemoral DVT patients

A new study, recently published online in the journal Circulation, reports on outcomes from a subgroup of 391 patients with acute iliofemoral deep venous thrombosis (DVT) in whom pharmacomechanical catheter-directed thrombolysis (PCDT) was evaluated within the ATTRACT trial.

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he authors, Anthony Comerota and colleagues, reveal that in patients with acute iliofemoral DVT, “PCDT does not influence the occurrence of the post-thrombotic syndrome (PTS) or recurrent venous thromboembolism (VTE) through 24 months.”

However, as the authors write: “In patients with acute iliofemoral DVT, PCDT does appear to provide greater reduction in acute leg pain and swelling through 30 days follow-up, as well as reduced PTS severity, reduced moderate-or-severe PTS, and greater improvement in venous disease specific quality of life through 24 months.”

Outlining the clinical implications of their findings, the authors suggest these findings support the early use of PCDT in patients with acute iliofemoral DVT who have “severe symptoms, low bleeding risk, and who attach greater importance to a reduction in early and late symptoms than to the risks, costs, and inconvenience of PCDT.” Suresh Vedantham, Mallinckrodt Institute of Radiology, Washington University in St. Louis, USA, and national principal investigator of ATTRACT told Venous News: “At all evaluated time points during the 24 months of follow-up, the symptoms and signs of venous disease were reduced in the patients with acute iliofemoral DVT who received early thrombus removal with PCDT. Given the absence of a PTS-prevention effect and the known risks of thrombolytic therapy, the first-line use of PCDT for iliofemoral DVT may be best considered on an individual basis for patients with low bleeding risk and severe leg symptoms causing functional limitations. When this is done, thanks to the ATTRACT investigators, it will constitute evidencebased therapy for the first time in the 25 years since catheter-directed DVT therapy was introduced. Further studies will help us better understand the magnitude and clinical importance of the long-term treatment effects.”

As previously reported in Venous News, the ATTRACT trial outcomes in recent years indicated that PCDT did not prevent the post-thrombotic syndrome (PTS) in patients with acute proximal DVT. As iliofemoral DVT patients are described as “phenotypically distinct” from patients with calf or femoral-popliteal DVT based on the former having

Thom Rooke:

Avoiding sclerotherapy complications

Page 12

Johann Chris Ragg:

Profile

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NICE aortic guidelines debate prompts scrutiny of venous guidelines and evidence gaps more frequent and severe PTS as well as more frequent recurrent thromboembolic events, the Comerota et al set out to distinguish the outcomes in this group from the total 692 patients who participated in ATTRACT. Expanding on the purpose of studying this subgroup among the ATTRACT patients, the authors state: “Contemporary clinical practice guidelines (including a Scientific Statement from the American Heart Association) recommend that studies of DVT therapy report outcomes separately for patients with iliofemoral versus less extensive DVT.” They go on to add that “These and other guidelines … also identify thrombus extent as a key factor to consider when deciding which patients should receive endovascular thrombus removal, which accounts for why some randomised trials have evaluated endovascular DVT therapies exclusively in patients with iliofemoral DVT.” Comerota and colleagues outline the methods used: “Within a large multicentre, randomised trial, 391 patients with acute DVT involving the iliac and/or common femoral veins were randomised to PCDT with anticoagulation vs. anticoagulation alone (No-PCDT) and were followed for 24 months to compare short-term and long-term outcomes.”

The researchers note that between 6 and 24 months, Continued on page 2

At the 2018 Vascular Societies’ Annual Scientific Meeting (VSASM; 27–29 November, Glasgow, UK), Bruce Campbell from Exeter Medical in Exeter, UK, who previously chaired National Institute for Health and Care Excellence (NICE) advisory committees for interventional procedures and medical technologies, discussed what the venous field can learn from the debate in the vascular community over the NICE guidelines for abdominal aortic aneurysm treatment. Campbell suggested that one area which currently requires further evidence is the use of ultrasound-guided thrombolysis for deep vein thrombosis.

THE RECENT DRAFT NICE aortic guidelines caused controversy in 2018, as they concluded based on current available Level 1 evidence from UK-based randomised controlled trials that vascular surgeons are not rec-ommended to offer endovascular aneurysm repair (EVAR) if surgical repair is possible—or if the patient is unfit for surgery. “There is uproar in the vascular community”, Campbell said, “about the fact that there is disagreement with these guidelines.” The Continued on page 4

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Patient selection is the greatest challenge for venous specialists in 2019 Manj Gohel Comment & Analysis Manj Gohel, one of the Editors-in-Chief for Venous News, discusses the patient selection issue facing the venous world in 2019.

THE LAST DECADE has seen the ongoing transformation of venous disease into an increasingly complex subspecialty dominated by innovative technology and pioneering medical devices. These advances have been driven by a desire to optimise our management of superficial venous reflux and acute deep vein thrombosis (DVT), but also by the growing appreciation of thrombotic and non-thrombotic venous outflow obstruction, pelvic venous disease and other vein disorders. Treatment advances are undoubtedly welcome. However, the high prevalence of venous disease on imaging and the relatively poor correlation between anatomical disease and clinical severity creates a real challenge for clinicians to identify those patients most

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Editor’s comment

likely to benefit from intervention.

Perhaps the least controversial area is superficial venous reflux, where multiple high-quality randomised studies including the recent EVRA trial, have demonstrated unequivocal clinical and health economic benefits after endovenous ablation for the majority of patients, particularly those with advanced venous disease and ulceration. Recent advances in non-thermal endovenous modalities complement established thermal ablation techniques to allow specialists to provide individualised care using a combination of modalities if necessary. Unfortunately, there is no such clarity in the management of deep venous disease.

Rather than providing clarity over the role of early thrombus removal for acute

DVT, the ATTRACT trial results have increased the confusion. The trial did not demonstrate a difference in rates of post-thrombotic syndrome (PTS) between groups randomised to early thrombus removal or anticoagulation alone at 24 months, although recently published data do suggest that there may be greater benefits for patients with iliofemoral DVT (see page 1). Advocates of early thrombus removal strategies highlight the number of patients screened for the study and the fact that modern pharmacomechanical thrombolysis and thrombectomy devices may offer superior technical success. However, clinicians favouring anticoagulation alone after acute DVT will point out the >50% of patients who did not develop PTS and the lack of health economic evidence for early thrombus removal. The inconvenient truth is that both positions have considerable merit.

Post-thrombotic and non-thrombotic venous outflow obstruction has seen an explosion of interest in recent years and a number of excellent stenting options are now available. A recent randomised trial of 51 patients with chronic venous outflow obstruction demonstrated impressive quality of life and clinical improvements in patients treated with stenting. There is little doubt that a large proportion of the population with clinically significant deep venous obstruction remain undiagnosed.

Paradoxically, there is a growing concern that there is over-treatment of clinically insignificant non-thrombotic disease.

Similar challenges exist for the diagnosis and treatment of pelvic congestion and ‘nutcracker’ syndromes. The presence

of left common iliac vein compression, pelvic vein incompetence and renal vein compression in a significant proportion of asymptomatic subjects highlights the importance of careful clinical evaluation before deciding that such an anatomical finding is clinically relevant.

The reality is that in all controversial areas of venous practice, there is widespread acceptance that some patients do benefit from intervention, whether it be early thrombus removal for acute DVT, stenting of chronic venous outflow obstruction, embolisation of pelvic vein reflux or intervention for nutcracker syndrome. Identifying the optimal target population remains the true challenge.

Both sceptics and advocates should work together to design and publish high quality trials to evaluate which patients benefit most. In an era where value-based healthcare and cost-effectiveness are important parameters evaluated by policy makers, we cannot be complacent and need to keep producing evidence. These are heterogeneous patient populations where randomised trials may be difficult to design and deliver. However, nonrandomised prospective studies and other study designs can help us to get the answers we need. Only then can we truly realise the potential benefits of the extraordinary venous treatment options we now have available.

Manj Gohel is Editor-in-Chief for Venous News, as well as a consultant Vascular and Endovascular Surgeon at the Cambridge University Hospitals NHS Trust in Cambridge, UK.

New ATTRACT data show greater benefits of catheter-based therapy for iliofemoral DVT patients Continued from page 1

there was no difference in the occurrence of PTS (Villalta scale >5 or ulcer: 49% PCDT vs. 51% NoPCDT; p=0.59). Furthermore, PCDT led to reduced PTS severity as shown by: lower mean Villalta and Venous Clinical Severity Scores [VCSS] (p<0.01 for comparisons at 6, 12, 18, and 24 months; and fewer patients with moderate-or-severe PTS (Villalta scale>10 or ulcer: 18% vs. 28%; 0.021) or severe PTS (Villalta scale >15 or ulcer: 8.7% vs. 15%, p=0.048; and VCSS

>8: 6.6% vs. 14%; p=0.013).

From baseline, PCDT led to greater reduction in leg pain and swelling (p<0.01 for comparisons at 10 and 30 days) and greater improvement in venous disease specific QoL (VEINES-QoL unit difference 5.6 through 24 months, p=0.029), but no difference in generic QoL (p>0.2 for comparisons of SF-36 mental and physical component summary scores through 24-months). In patients having PCDT vs. no-PCDT, major bleeding

within 10 days occurred in 1.5% vs. 0.5% (p=0.32), and recurrent venous thromboembolism over 24 months was observed in 13% vs. 9.2% (p=0.21).

Comerota et al further note that, while they chose the Villalta scale as the primary outcome measure based on current recommendations, they conclude that additional studies to compare the performance characteristics of the Villalta scale and the VCSS threshold score “would be worthwhile”.

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Jan

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19 09

Conference coverage

NICE aortic guidelines debate prompts scrutiny of venous guidelines and evidence gaps Continued from page 1

continues at the time of publication, as publication of the final guidelines has been postponed.

Speaking to Venous News, Ian Franklin (Imperial College London, UK) who chaired the session commented that the purpose of the session at the VSASM was to prompt discussion around avoiding a situation wherein a guidelines committee examines a venous therapy and finds “the evidence and data simply is not there”.

“For all the treatments for venous disease, including lysis and stenting, we need to consider what we can do to avoid a similar situation to that of EVAR,” Campbell said. Examining the abdominal aortic aneurysm controversy more in-depth, Campbell outlined the points by which the Vascular Society argued the NICE draft document were limited. The Vascular Society argued that NICE “gave undue emphasis to just one randomised controlled trial, focused on long-term outcomes only, failed to take account of patient preferences, focused largely on cost-effectiveness, ignored implementation and training issues, and finally, used outdated evidence”, explained Campbell. “In terms of the production

of the evidence… NICE uses what they consider to be the best evidence, and focused on the main aim of abdominal aortic aneurysm patients, namely to prolong life by preventing aneurysm rupture.”

However, Campbell underlined the important differences between aneurysms and venous disease. “Untreated aortic aneurysms” Campbell pointed out, “does absolutely nothing to quality of life.

Venous disease does affect quality of life: varicose veins do, ulcers definitely do, and then there is deep vein thrombosis and post-thrombotic syndrome—so they are quite different in that respect.” Secondly, venous treatments are in general less costly in comparison to endovascular aortic treatments—“miniscule compared to the cost of fixing an aneurysm”, Campbell emphasised. Therefore, costmodelling may prove less of a threat to venous treatment guidelines than it has for EVAR. In addition to these concerns, current recommendations such as the NICE CG168 guidelines on varicose veins have experienced poor implementation rates, leading to worries about uptake in future

deep venous treatment guidelines. “We know that treating varicose veins and venous ulcers is very cost-effective,” Campbell explained, “the problem however lies with affordability, as varicose veins are so common that it would cost the UK National Health Service (NHS) too much to treat them all. That is different to acute deep vein thrombosis. That is a problem which does not affect millions.”

In fact, upon review of current data, Franklin commented to Venous News that although there is a “very strong body of evidence” in the superficial venous field, “there are some clear gaps we need to fill for acute deep venous and venous stenting.” Identifying these gaps methodically is important, Franklin suggests, “as the venous world hopes to avoid a similar situation to the aortic guidelines, five years from now.”

“What evidence does NICE need?”, Campbell asked, answering, “quite simply, well-designed, high quality trials.”

Such studies should include the correct population of patients and indications, as well as appropriate comparators and relevant clinical outcomes along with quality-of-life measures. In fact, Campbell

Bruce Campbell

pointed to a document published by NICE in 2012 which recommends further research to examine thrombolysis for proximal deep vein thrombosis, as the current evidence was identified to be weak. In this Individual Research Recommendation, the specific outcomes required are clearly defined by NICE as mortality, major bleeding, venous thromboembolic event recurrence at three and 12 months, post-thrombotic syndrome at two years including incidence rate and severity, as well as quality of life.

SeCure trial finds laser safe and effective in treating perforator veins, leads to 400µm optical fibre FDA approval The SeCure trial of VenaCure EndoVenous Laser Treatment (EVLT) 400µm fibre kit (Angiodynamics) to treat incompetent perforator veins in patients with CEAP classification 4b, 5 and 6 has surpassed the study’s performance goal, with a 95.2% initial technical success rate.

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he study data were delivered in two presentations at VEITHsymposium (13–17 November, New York, USA) by Mark Adelman (NYU Langone Hosptial, New York, USA) and Kathleen Gibson (Lake Washington Vascular Surgeons, Bellevue, USA).

They explained that incompetent perforator veins are associated with the development of venous ulcers.

While endovascular ablation has demonstrated good technical success and a low complication rate, most studies have focused on successful ablation of the vein rather than venous ulcer healing, and very few studies have investigated the effectiveness of perforator vein ablation in patients with venous ulcers.

The purpose of the SeCure study was to see if the laser device would act equally or better than radiofrequency devices recorded in the literature.

The study is a single arm, prospective, multicentre, non-blinded trial with an intent-to-treat population of 83 patients (125 perforator veins). It enrolled patients with CEAP class 4b, 5 and 6 attributable to the incompetent perforator vein, as long as the saphenous trunks were either normal or previously treated.

Multiple incompetent perforator veins in one limb could be treated, but only one limb of each patient was permitted study treatment.

The primary objective was ablation of incompetent perforator veins with a performance goal of 75%.

Secondary endpoints were procedural technical success rate (successful access and entry into the incompetent perforator veins to be ablated and the ability to deliver the intended laser energy); one, three, nine and 12-month primary ablation closure rates; and changes in Venous Clinical Severity Score (VCSS), CEAP symptoms, quality of life from baseline and procedurerelated adverse events.

Pathologic incompetent perforating veins are defined as those with outward flow of >500msec, a diameter of >3.5mm, and located beneath a healed or open venous ulceration.

Adelman explained that approximately two-thirds of limbs with skin changes have incompetent perforator veins as well as superficial or deep venous reflux, and that 63% of recurrent varicose veins are associated with incompetent perforator veins. Further, the Society for Vascular Surgery (SVS) and American Venous Forum (AVF) recommend the treatment of perforator veins with reflux >500ms and a vein diameter >3.5mm.

Describing the procedure, Gibson tells Venous News, “The treatment is performed with a 400 micron laser fibre that can be placed either through a micropuncture needle or catheter. Local anaesthetic is administered around the laser fibre tip prior to activation.”

Results

The initial technical success performance goal, in other words the ability to deliver the laser energy to the perforator vein, was set at 75% for the trial, but the study result was in fact 95.2% (p<0.001), Adelman reported. Further, the 10-day ultrasound data for the closure rate surpassed the performance goal (based on radiofrequency ablation literature) of 70% and was 76.8% in the study.

As for the reintervention rate, Adelman explained that there were very few reinterventions in the first six months and only one attempted reintervention that failed. However, at the nine and 12 month intervals, four out of five reinterventions, and five out of eight were retreated successfully, respectively. Methods of retreatment were direct ligation, foam sclerotherapy and laser retreatment.

Adverse events at three months were measured in 83

patients: deep vein thrombosis (2), vein thrombosis (1), superficial thrombophlebitis (1), skin ulcer (4), entry site wound (1), procedural pain (1).

Following the presentation of results by Adelman, Kathleen Gibson took to the podium to discuss the changes in VCSS, quality of life and ulcer healing.

Gibson reported that there was a statistically significant improvement in VCSS from a mean of 12.4 at baseline to 8.7 at 12-month follow-up. Similarly, at each follow-up time point, the VEINES and VAS scores improved from baseline (VEINES = mean 45.2 at baseline to 51 at 12-month follow-up; VAS = mean 23.4 at baseline to 14.7 at 12-month follow-up).

In terms of ulcer healing, Gibson showed that 23% of the patients had ulcers on entry into the study, which declined to as low as 8.5% at six months follow-up and was recorded at 12.8% at the 12-month follow-up.

Further, wound healing also saw an improvement from baseline with a median 3.8cm2 recorded at screening to 2.6cm2 at 12 months follow-up.

Adelman concluded that while this is a somewhat challenging procedure, in his experience, the use of laser is easier than radiofrequency because the access is smaller and it is therefore easier to get into the perforator veins. “The SVS and AVF are already recommending treatment for C5 and C6 disease, and this trial includes C4b as well. It found that 400µm optical fibre with the 1470nm laser had a superior closure rate to radiofrequency and led to the FDA clearance of 400µm optical fibre for the treatment of incompetent perforator veins,” Adelman added.

Gibson concluded, “the SeCure trial showed that the laser could be used as a safe and effective treatment for treating incompetent perforator veins, and there was significant improvement in patient quality of life, with increased ulcer healing and decreased wound size.”

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Fluoroscopy time “should not be used” to estimate the effective radiation dose A study that examined the radiation exposure to patients during endovenous recanalisation, recently published in the Journal of Vascular Surgery: Venous and Lymphatic Disorders, has found that fluoroscopy time was not an indicator of estimated effective dose. Mohammad Barbati, from RWTH University Hospital Aachen, Aachen, Germany, presented the data at the Cardiovascular and Interventional Radiological Society of Europe annual meeting (CIRSE; 22–25 September, Lisbon, Portugal), and further concluded that the effective radiation dose of an endovenous recanalisation was less than endovascular aortic repair.

ACCORDING TO BARBATI, postthrombotic obstruction can be effectively treated by percutaneous transluminal angioplasty and stenting. However, the patients are exposed to significant amounts of radiation during both preoperative planning and the intervention itself. Barbati and colleagues therefore aimed to measure the amount of radiation exposure to patients during venous recanalisation, while also recording factors affecting the amount.

Patients with post-thrombotic syndrome and non-thrombotic MayThurner syndrome, who were undergoing endovenous recanalisation from June 2015 to May 2016 were included in the study. The investigators performed the intervention in an operating theatre with a mobile C-Arm (Philips), while recording and calculating the amount of radiation.

The indirect parameters of radiation that were measured included: fluoroscopy time, cumulative air kerma (the energy extracted from an X-ray beam per unit mass of air) and dose area product (the absorbed dose multiplied by the area irradiated). The direct parameter of

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Venous interventions

radiation included effective dose—the sum of the equivalent whole body dose— measured via two electronic dosimetry devices placed in the pelvic and neck area.

In total, 78 cases were included in the study (mean age: 44.04±14.62 years; average body mass index [BMI]: 27.13±5.13). The mean fluoroscopy time for all patients was 63.4 minutes; much longer in those with bilateral post-thrombotic syndrome (98 minutes) compared to those with non-thrombotic May-Thurner (14.1 minutes). Regarding the whole patient cohort, skin entrance dose at the pelvic area was “almost 18 times more” than the amount observed at the neck. Barbati explained that this finding is due to the intervention focusing on the pelvic and abdominal area.

Furthermore, the measured effective dose for all patients was 25.16mSv. Barbati attributed the difference observed between the effective dose in patients with bilateral post-thrombotic syndrome (mean effective dose: 37.51mSv) and those with non-thrombotic May-Thurner (mean effective dose: 8.74mSv) to two specific factors. Barbati explained that

Mohammad Barbati

both BMI (as higher BMIs require a higher dose) and the extension of the disease was likely to influence the dose— as patients with bilateral post-thombotic syndrome need more radiation.

Moreover, longer fluoroscopy times correlated with length of pathologic veins (p<0.01) and longer operative time (p<0.01), while a higher effective dose correlated with longer fluoroscopy times (p<0.01).

Additional findings included that the duration of the intervention took 215.71±153.40 minutes on average; longer for patients with post-thrombotic syndrome (mean: 280.50±46.65 minutes for bilateral) compared to those with non-thrombotic May-Thurner (mean: 60.60±16.86 minutes). Furthermore, the mean number of stents used per patient was two (range: 1–8), while the mean length of the stented area was 198.57±175.64mm.

Comparing the current findings with aortic data in this area, Barbati noted that although the fluoroscopy time is longer in venous interventions due to the characteristics of the radiation used

in these interventions, the effective dose is not necessarily as high as the aortic operation.

In relation to radiation effects, Barbati reported that the threshold for deterministic injuries, such as skin erythema or skin nekrosis, was not reached. Nonetheless, Barbati stated that stochastic effects (the long-term effects of radiation, such as cancer) should also be taken into consideration, and efforts should be made to reduce the amount of radiation each patient is subject to.

Barbati maintained that reduction of radiation exposures can be achieved by first choosing safe diagnostic tools that do not produce radiation, such as MR phlebography or duplex ultrasound. Furthermore, “proper use of the fluoroscopy machine”, as well as minimising the object-to-image receptor distance; using pulsed fluoroscopy instead of continuous fluoroscopy, implementing an AP view (putting the source under the table) as opposed to a lateral view, while also using lead shielding for the neck and pelvic area are all factors that can contribute to the reduction of radiation exposure.

In terms of what to tell patients when they have concerns about the additional risk of death from cancer, Barbati suggested telling them that the risk is low, although he emphasised that physicians should take into consideration patients with non-lifethreatening conditions, as the solution for these patients may lie in conservative management.

Concluding the findings, Barbati emphasised that fluoroscopy time cannot be used to estimate the effective dose, while, interestingly, the effective radiation dose of an endovenous recanalisation was less than endovascular aortic repair.

Immediate compression after deep vein thrombosis has potential to reduce post-thrombotic syndrome Elham E Amin (Department of Biochemistry, Cardiovascular Research Institute Maastricht) Maastricht University, Maastricht, the Netherlands and others write in Blood that the use of immediate compression therapy after deep vein thrombosis was associated with a significant reduction in the risk of residual vein obstruction. As patients without residual vein obstruction had a significantly lower incidence of post-thrombotic syndrome (PTS), immediate compression has the potential to be used as an approach to reduce PTS risk.

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min et al report that post-thrombotic syndrome affects 10% to 20% of patients who have had a deep vein thrombosis. They add that the syndrome is both costly (to healthcare providers) and associated with a decrease in quality of life. “At this time, there is no cure for the condition; therefore, acute treatment of deep vein thrombosis should include prompt prevention of post-thrombotic syndrome,” the authors comment.

One approach to reducing the risk of post-thrombotic syndrome would be to address the modifiable risk factors for the condition. For example, venous hypertension is thought to be a cause of the syndrome and it is thought to be caused by a combination of vein-wall remodelling, residual obstruction and valvular reflux. However, according to Amin et al, “the role of residual vein obstruction as an independent risk factor for the onset of post-thrombotic syndrome remains controversial”.

Therefore, given the use of compression therapy for the prevention of residual vein obstruction was also unclear, the authors aimed to review the effect of

compression therapy on the presence of residual vein obstruction and to assess the association of residual vein obstruction with the incidence of PTS. Using data from IDEA (Individualised duration of elastic compression therapy against long-term duration of therapy for prevention of post-thrombotic syndrome), Amin et al identified 592 patients (mean age 57 years). Of these, 72 (12.2%) received no compression, 369 (62.3%) received multilayer compression banding, and 151 (25.5%) received compression hosiery. They comment: “Of the patients in the non-compression group, 66.7% had residual vein obstruction compared with 46.3% of the patients who were receiving compression therapy (47.4% for compression bandaging; 43.7% hosiery). This corresponds to an absolute reduction of 20.4% (p=0.05) of residual vein obstruction when compression therapy is applied in the acute phase.”

Significantly more patients with residual vein obstruction developed post-thrombotic syndrome than those without the condition both at six months and at 24 months: 55.7% vs. 44.3% (p=0.029) and 46% vs. 54% (p=0.013), respectively. “This suggests that residual vein

obstruction does contribute to the development of postthrombotic syndrome, and that compression therapy may prevent post-thrombotic syndrome [because it appears to prevent residual vein obstruction] from the very early start of thrombosis treatment,” the authors observe.

However, they add: “How precisely immediate compression therapy affects the recovery of venous patency cannot be answered by the current study. We may only hypothesise that mechanical compression reduces the vein diameter, and thereby increases the venous return, and as a result, promotes thrombus resolution. Better venous return reduces oedema and improves calf muscle function.”

Concluding, Amin et al recommend that immediate compression therapy—either with multilayer bandaging or with compression hosiery—“should be implemented in daily clinical practice” in addition to adequate anticoagulation therapy in patients with deep vein thrombosis. “Furthermore, identification of patients at increased risk for post-thrombotic syndrome should be performed in the acute phase to be able to provide these patients with adjunctive treatments,” they add.

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How to avoid complications with sclerotherapy Thom Rooke Comment & Analysis Writing for Venous News, Thom Rooke provides an overview of the benefits and potential drawbacks to the use of sclerotherapy in venous treatment. From indications to technology, techniques and strategy, Rooke outlines some important basic steps which may help minimise risks and complications.

SCLEROTHERAPY INVOLVES THE improbable prospect of injecting caustic agents into veins for the purpose of destroying them. Although the potential risks to those who perform this procedure are not insignificant (my own list of ailments includes back pain, eye strain, and repetitive stress injury), the risks to the patient are, surprisingly, minimal— and can be reduced even further if attention is paid to a few specific factors that contribute to complications. To keep things simple, let us consider three broad areas of concern: Indications (for performing sclerotherapy), drugs and equipment, and sclerotherapy technique.

Indications

Indications for sclerotherapy fall into four distinct categories based firstly upon venous function and secondly on venous signs and/or symptoms. Venous function is divided into two groups: veins that function normally (i.e., peripheral veins which return blood to central veins), and those that do not function normally (i.e., veins which

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Superficial venous treatment

are more akin to swamps than rivers).

Venous signs/symptoms also split nicely into two categories: veins that produce signs/symptoms (such as pain, swelling, or significant cosmetic problems), and those that do not. Using this scheme, indications for sclerotherapy can be broken into the following four categories: 1. Veins that function normally and do not produce symptoms. These go by another name: “Normal veins.”

Some patients may not like the way they look (think of, for example, the prominent veins that develop on the back of the hands with aging), but they work properly. Although patients may complain bitterly about them, destroying these veins with sclerotherapy runs a risk of creating unnecessary problems. These patients should be gently persuaded to avoid treatment.

2. Veins that function normally but produce symptoms. Examples include the collaterals that form around occluded veins (for example,

the network that forms over the shoulder and upper chest wall when the axillary vein is obstructed.)

Although patients may dislike the appearance of collaterals, or complain of discomfort in the affected areas, these veins are often crucial for returning blood from the affected limb. Injecting them is an invitation for unnecessary complications.

3. Veins that function abnormally but do not produce symptoms. Nobody should look for malfunctioning veins in asymptomatic individuals, but in my practice I occasionally see someone who went to a venous screening event and was told “You have bad varicose veins and you should really let us take care of them.” They come to me for a second opinion. I never have complications with these veins—because I do not treat them.

4. Veins that function abnormally and do produce symptoms. Sclerotherapy for these veins is appropriate and has a low risk of complications. Have at it.

Drugs and equipment

The proper needles, syringes, and sclerosing drugs are obviously important. My own complication rate dropped dramatically when I stopped using hypertonic saline early in my career—it was cheap and avoided the risk of allergic reaction, but was too toxic and unpredictable to use safely.

I get fewer complications when I use less concentrated agents. I may need to reinject some veins during the treatment session, but that is okay—you cannot un-cook burned lasagna, and you cannot un-sclerose skin that has been treated too aggressively.

Technique

There are several considerations one can employ to avoid complications. n Clearly visualise the target vein; for me, this means wearing Grandma’s magnifying glasses. For others it is ultrasound, special vein lights, or

US FDA plan shakeup of its 510(k) clearance programme The US FDA has announced plans to modernise its 510(k) clearance programme for approving medical devices for the US market. Data show that about 20% of current 510(k) devices are approved on trials that compare novel devices to predicate devices that are more than 10 years old. With its revised programme, the agency wants to ensure medical devices coming to market account for advances in technology or demonstrate that they meet more modern safety and performance. The announced changes follow a report from the International Consortium of Investigative Journalists (ICIJ) that heavily criticises how medical devices are approved for use.

UNDER THE EXISTING 510(k) clearance programme, a medical device can be approved for market if (according to a study) it shows comparable safety and efficacy to a similar device that is already on the market. However, a limitation of this programme is that a substantial amount of devices (20%) are compared with devices (or predicates) that are more than 10 years old. In a statement, Scott Gottlieb (FDA commissioner) and Jeff Shuren (director of the Center for Devices and Radiological Health) comment: “Older predicates might not closely reflect modern technology

embedded in new devices, or our more current understanding of device benefits and risks”. They stress that they are not suggesting these older devices, or the devices that are compared to them, are unsafe but note “we believe encouraging product developers to use more modern predicates would give patients and their doctors a choice among older and newer versions of the same type of device, promote greater competition to adopt modern features that improve safety and performance, and help make sure that newer devices reflect more modern technology and standards that can

Destroying normal veins with sclerotherapy may create unnecessary problems. certain tricks to ensure that the needle enters the lumen of the vein. You need to hit the vein. n Avoid injecting larger varicosities (especially perforators) near the point where they connect with the deep system; clot may form within the superficial vein and extend into the deep system. n If thrombus or coagulum becomes trapped in the injected vein, do not be afraid to puncture the vessel and release it. This problem might be minimised by using elastic compression after the procedure, but there is no consensus on this. n Did I mention you should hit the vein? Do not inject into the skin. n Never, ever inject into an artery.

This may result in complications of biblical proportions. If I have not mentioned it already, you need to hit the vein …

If the points I have just made seem obvious—that is because they are. Yet, amazingly, practitioners still make these mistakes. Do not be one of them.

Thom Rooke is the Krehbiel Professor of Vascular Medicine at the Mayo College of Medicine and founder of the Mayo Clinic Wound Care Center in Rochester, USA. References 1. This article specifically addresses the use of needleinjection sclerotherapy to treat small veins, spider veins, and telangiectases, although the risks associated with catheter-directed sclerotherapy of larger veins are similar in nature.

2. Yiannakopoulou, E. Safety concerns for sclerotherapy of telangiectases, reticular and varicose veins.

Pharmacology 2016; 98: 62–69 3. Lurie, Fedor, et al. Journal of Vascular Surgery. In press.

improve patient care and outcomes”.

Therefore, the FDA is proposing to list devices on its website that have demonstrated substantial equivalence to older predicate devices, with predicates that are more than 10 years old as a starting point. However, before going ahead with this plan, Gottleib and Shuren state that the agency is seeking public feedback on “whether we should make public those devices or those manufacturers who make technology that rely on predicates that are more than 10 years old, whether other criteria should inform our point of reference, and whether there are other actions we should take to promote the use of more modern predicates”.

Additionally, early next year, the FDA intends to finalise guidance establishing an alternative 510(k) pathway that will allow manufacturers of certain wellunderstood device types to rely on objective safety and performance criteria to demonstrate substantial equivalence as a way to make the pathway more efficient and to adopt modern criteria as the basis for the predicates that are used to support new products.

Gottleib and Shuren conclude their statement by saying “We are proud of the work CDRH staff are doing to make sure that the devices we regulate are safe.”

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19 09

Interview

Profile

Johann Chris Ragg

Johann Chris Ragg speaks to Venous News about the innovations he pioneered and the work that inspired his projects, as well as the challenges and benefits of running a private vascular clinic specialising in endovenous treatments. Ragg recounts his most memorable cases, gives advice to young specialists at the start of their career and discusses what could be the next big thing in venous research and innovation.

What led you to become a medical doctor, and why did you choose a career in the venous field?

I grew up in a German medical clinic—the building belonged to my grandparents. As a result, all kinds of diseases scared me a lot. During my time as a student, I escaped to solid natural science, in particular physics, but biophysics brought me back to the human body and medicine. I was selected for an interdisciplinary vascular project in Berlin, Germany, responsible for arterial recanalisation lasers.

One morning in 1996 a resident came in and said “do you know some American started to close vessels with lasers?”, before adding, “actually, just veins”. From that very moment, my attention switched from arteries to veins.

What mentors have helped to shape your career, and what lessons have you learned from them?

My first boss at Charité University Clinic Berlin was Professor Giancarlo Biamino, a well-known cardiologist and angiologist. We shared six years in the cath lab and healthcare centre. His dedicated care for patients and his enthusiasm for vascular innovations definitely shaped my career—as well as his habit to skip lunch and see another patient instead.

What have been the biggest developments in the field during your time as a venous specialist?

I jumped on the venous train at a time when endovenous ablation was very exotic, founding my first vascular clinic in the year 2000.

The conversion from vein surgery to endovenous was concluded in our facility until 2005 which was our first year of 100% non-surgical vein repair—in unselected patients of all stages, including recurrences.

Meanwhile we did more than 50,000 cases.

Is there a particular study or paper in the last year that you believe had been particularly impactful for your practice?

I am a front-line pioneer linked with and talking to hundreds of authors world-wide via our website, venartis.org. Some papers are entertaining, some studies are scientifically brilliant, but the impact on daily practice is low, compared to our own discoveries. Our structures allow me to practice ultrasound for four to six hours a day while treating or checking patients and training assistants, and every new machine shows more real-time details of valve behaviour. That is inspiring!

I feel sorry for all those who do not have the pleasure to du ultrasound of vein valves themselves.

The best source of input were those precious moments of intimate knowledge exchange with friends while enjoying a glass of wine, in a conference night or during a private visit, or best of all: while treating patients together. To give some examples of what and who has inspired my projects, these include: effects of blood proteins on sclerosants (Parsi/Connor, for novel foam), water compression (Gianesini, Obermeyer, for the film bandage), insights in haemodynamics (Lurie, Lattimer), valve anatomy (van Rij, Maleti) aesthetics

(Miyake), and many others.

You set out early as an independent founder of a private interventional vein clinic. What did this experience teach you?

At the start of my career, I was a trained university researcher in the arterial field for six years. When I changed my focus to veins, I started fresh and kind of refined, with a clear analysis and strategy. This was based on several important questions, including: Which is the most frequent venous disease? Which are the most frequent practical problems at present? Which is the fastest way to improve patients’ fates? Which is the fastest way to obtain reliable and essential study results?

My private facilities, which incorporate clinic, outpatient services, research and training activities, offer the advantage of simple structures, fast decisions and fast corrections—thus creating shorter learning curves. Another plus is the ability to have a very close relationship with the patients, with unfiltered communication of their satisfaction. As for any disadvantage and potential limitations of running an independent private clinic, there is the economic aspect. To stay independent by our standards, we never accepted money from any company for product studies.

However, limited finances mean limited scientific outcome. We could have done much better and produced more work with more staff.

In the last decade, you have pioneered treatments such as percutaneous valvuloplasty and invented the transparent film bandage. How were your innovations conceived, and what impact have they had on practice?

It is the compression film bandage which makes foam sclerotherapy of varices become a true alternative to phlebectomy—but faster, less invasive and painless. Seventy per cent of our patients receive it.

Unfortunately, the manufacturer would like to have a single worldwide product, including countries with warm and humid climates. More studies have to be done, wasting time to general marketing. Hyaluronan valvuloplasty is still experimental although we use it every day, searching for optimal products, tools and procedures. For example, monophasic gels of lower viscosity allow precise small-lumen injection and easy spatial distribution, but biphasic gels with larger particles provide better long-term residence. One option is amazing: multifocal vein lumen reduction to normalise a vein’s volume load. It is much more specific than a compression stocking. To clarify haemodynamic relations, you use a fast-resorbable but solid hyaluronan. If successful, you replace it with long-term products. Some cases seem to heal in spite of hyaluronan degradation. It is a new world.

What are your current research or innovation interests?

As vein killing is still daily business, we work on improvements of vein gluing (ScleroGlue project) and a novel viscous sclerofoam, using an

approved chemistry (Biomatrix sclerofoam) for one-step treatment of extended tortuous targets and malformations. However, we consider endoluminal treatment as a transitional phase of one, two or three decades to be replaced by specific prevention or minimal early stage repair.

My current number one focus is on congenital vein valve lesions. In an ongoing study, we found 55.6% of children and adolescents with at least one malformed leg vein cusp. About 85% of these lesions cannot be detected except when using high resolution ultrasound (16–32MHz). Secondary focus for me is the detection of motion-resistant aggregates, different to sludge or thrombus, adhering to vein valves. They seem to summarise and indicate long-term effects of stasis, leading to at least six consecutive stages of vein valve destruction from impaired sinus function to the final

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Interview

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lots of money. Within 10 years, it should be possible to provide data on the medical and financial benefit of early stage treatments.

Maybe physicians will have to adjust their performance and learn how to make money differently while insurances will fight to reduce their expenses.

What advice would you give to young vascular surgeons starting out in their careers?

In general—to look for the best forward-looking and limitbreaking teachers, and the shortest ways to international knowledge exchange. In particular—to become an ambidextrous sonographer and watch as many vein valves and blood motion patterns as possible, as ultrasound is likely to be the basic tool for phlebology for at least another one or two decades.

Can you tell us about your most memorable case?

There are so many! The first 50mm great saphenous vein to be nicely closed with a laser.

The fashion model performing a lingerie show three days after extended spider vein treatment.

The first 18-year-old with successful hyaluronan correction of a congenital vein valve leakage.

The first “incurable” varix recurrency solved in a single session with viscous biomatrix sclerofoam. And a negative one: The first deep venous thrombosis which occured after 11,500 endovenous cases done without anticoagulants.

What have been the proudest moments of your career so far?

loss of cusps. It is my favourite study tool to examine long-term effects of compression garment and certain medication, like Flavonoids.

In your opinion, what are the biggest challenges faced by interventional vein specialists today?

Phlebology is very traditional, too traditional.

The challenge for both surgical and interventional specialists is to overcome the barriers of prejudice. Our opinion on venous insufficiency is from an era where there were no tools to determine a morphological and functional status of single valves, and thus no specific therapy. Today, we can do that—years and decades prior to symptoms. It is our ethical duty to invent and establish reasonable solutions for effective early stage treatments that save not just patients’ health, but also

My first public speech, my first poster prize, my first scientific award… these were precious steps but no matter of pride. I am not satisfied with anything I have done so far, so there is a good chance the proudest moment is still to come. In my imagination, it will be the day that national committees accept that venous insufficiency is not at all chronic, but well treatable and preventable if discovered in early stages.

Outside of medicine, what do you like to spend your time doing?

I am an active tennis player, and I even take part in weekend tournaments in the 55+ category.

Furthermore, my medical activities in Switzerland are a frequent excuse to add a weekend for mountainbiking or skiing, preferably with my wife and the kids. Concerning music, I love a slow blues to balance my hyperactivity and optimism.

Career

2018 Foundation of the new angioclinic Vein Center Zurich at Zurich Lake, Switzerland 2013 100,000th vascular catheter intervention 2011 Foundation of venartis.org, non-profit organisation for innovations in Phlebology 2011 Foundation of angioclinic Vein Center Zurich, Switzerland (interventional phlebology) 2011 Foundation of “Akademie für Interventionelle Phlebologie“ (Academy for interventional phlebology), Berlin, Germany 2007 Foundation of angioclinic Vein Center Munich, Germany (interventional phlebology) 2003 Foundation of a private hospital for interventional vascular medicine, “Klinik am Wittenbergplatz Berlin GmbH“ in Berlin, Germany (chief physician) 2000 Foundation of “Zentrum für Gefäßdiagnostik und Therapie” (Centre for vascular diagnosis and therapy, Berlin, Germany)

Awards and Prizes (selected)

2018 Hiroshi Miyake Award Winner, IMAP International Meeting on Aesthetic Phlebology, Sao Paulo (Presentation on “Hyaluronan in Phlebology”) 2018 EVF Poster Prize (Adjunctive hyaluronan instead of tumescence) 2017 AVF, New Orleans: Servier Travel Award winner (Presentation on high-resolution ultrasound for vein valves 2017 ACP, Austin: Presentation prize (Valve damage in children), poster prize (EHIT) 2016 Charing Cross Symposium London: 2nd place, Innovation Forum, work on “Biomatrix Sclerofoam”; Certificate of Merit for presentation “Percutaneous valvuloplasty—a new way to vein restoration” 2016 German Society for Phlebology, First Poster Prize (Biomatrix sclerofoam) 2015 ACP, Orlando: Platinum Award – Percutaneous Valvuloplasty: MinimalInvasive Restoration of Vein Valve Function Using Cross-Linked Hyaluronan

Memberships (selected)

American College of Phlebology (ACP) Union International de Phlébologie (UIP) European Venous Forum (EVF) International Compression Club (ICC) Royal Society of Medicine (RCM) Cardiovascular and International Radiological Society of Europe (CIRSE)

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19 09

Deep venous devices

Two-year analysis of SENTRY trial confirms safety and effectiveness of the bioconvertible IVC filter A study presented at Vascular InterVentional Advances (VIVA; 5–8 November, Las Vegas, USA) found the BTG Sentry bioconvertible inferior vena cava (IVC) filter to be safe and efficacious at protecting patients from pulmonary embolism (PE) during a transient high-risk period.

The late-breaking results from “the most imaging-intensive IVC filter study completed to date” were presented by Michael Dake from the University of Arizona (Tucson, USA).

THE USE OF IVC filters increased between 2005 and 2010 following the release of retrievable devices.

However, a high incidence of reported complications led to an FDA Advisory and a decline in their use.

Complications were related to device design and there were a broad range of reported retrieval rates— estimated at less than 50% overall. Complication rates generally increase with length of implant time.

The success of device retrieval reduces with implant time and often requires the use of aggressive retrieval techniques, with increasing levels of associated complications.

The incidence of PE in the USA is 400,000–630,000 a year, with 50,000–200,000 fatalities a year. One in 10 hospital deaths is estimated to be PE-related. PE is expensive, costing approximately US$52,000 per event.

According to Dake, “when used correctly, IVC filters save lives and reduce injury and costs related to PE, and survival benefit has been shown in appropriate populations. However, the existing retrievable technology has not effectively met the needs of patients and the medical system”.

Dake described the BTG Sentry bioconvertible IVC filter, which was designed to protect patients during a transient high-risk period from PE and reduce the complications of existing technologies of tilting, migration, fracture, perforation and embolisation. “The filter automatically bioconverts after 60 days to leave an unobstructed IVC lumen. It is composed of a stable frame with filter arms held together by a biosorbable filament,” he continued.

“The BTG Sentry filter is designed to automatically bioconvert after the PE risk period has passed,” explained Dake. “Hydrolysis of the bioabsorbable element allows the filter arms to retract to the IVC wall leaving a patent lumen, reducing the risk of IVC occlusion and removing the requirement for, and risk/ cost of, IVC filter retrieval.”

The objective of the SENTRY IVC filter trial was to evaluate the safety and efficacy of the BTG Sentry

Michael Dake

IVC filter. The study was a prospective, multicentre, single-arm trial, involving 129 subjects at 23 sites, with 63 operators. In the study, patients underwent an intensive imaging protocol, including a 24-month CT venogram. Dake reported that “100% of eligible subjects (n=111/111) were imaged at 12 months and 94% of eligible subjects (n=85/90) were imaged at 24 months.”

With regards to patients’ baseline characteristics, Dake said that “a total of 67.5% of subjects had current PE and/or DVT at the time of enrolment and there was 100% contraindication to anticoagulation for some/all of the protection period.”

Trial results

Dake found the composite primary endpoint at six months showed technical success in the majority

of patients (129/130; 99.2%), with 100% freedom from symptomatic PE during the 60-day protection period. There was 98.2% freedom from IVC filterrelated complications to 6 months (112/114), with two symptomatic caval thromboses (at days 8 and 32), which were treated and did not reoccur. There was no tilting, migration, embolisation, fracture or perforation.

Secondary endpoints at six and 12 months found no new symptomatic PE to 12 months and no devicerelated complications to 12 months.

Secondary endpoints to 24 months found two new symptomatic PEs (at days 581 and 632) in subjects with fully bioconverted filters, however the clinical events committee adjudicated these as non-device related.

There were no device-related complications to 24 months. The bioconversion rate (96.5%) was found to compare favourably to published retrieval rates. No new IVC filters were placed to extend the Sentry protection period, while three new IVC filters were placed for new indications between six and 24 months.

“The primary endpoint at six months was met, with a clinical success of 97.4%. Twelve-month results showed 0% new symptomatic PEs, while 24-month results found 2.4% new symptomatic PEs (non-device related), 0% tilting, migration, perforation, fracture or embolisation, no new symptomatic caval thrombosis between 60 days and 24 months, and a 96.5% bioconversion rate compares favourably to published retrieval rates,” reported Dake.

He concluded his presentation by stating that use of the BTG IVC filter “represents an important paradigm shift in the prevention of PE”.

When asked which patients would be most suitable for treatment with the BTG Sentry bioconvertible IVC filter, Dake replied “it is simpler to think in terms of those patients who are not appropriate—those who will require multiple orthopaedic procedures, if they have chronic thrombophilia or a hypercoagulable state such as cancer patients—otherwise a large patient population could benefit from this treatment.”

VERNACULAR trial 12-month data show successful use of Venovo venous stent in obstructive lesions The 12-month results from the VERNACULAR trial have shown that the Venovo venous stent (BD Interventional) is successful when deployed in obstructive iliac and femoral lesions with a primary patency rate of 88.3%, a low reintervention rate of 7.4%, and no core-lab assessed stent fractures.

V

ERNACULAR is a prospective multicentre single-arm clinical trial designed to assess the performance of the Venovo venous stent, a self-expanding stent for the treatment of iliac and femoral vein occlusive disease. A total of 170 patients were treated at 22 centres in the USA, Europe, and Australia. The 12-month data were presented by Michael Dake (Stanford, USA) at VIVA 2018 (5–8 November, Las Vegas, USA). “There was independent analysis of the outcomes”, Dake noted, adding “there was a clinical events committee that adjudicated serious events, and the data safety monitoring board assessed overall patient safety.”

The primary efficacy measure was 12-month primary patency, defined as freedom from target vessel revascularisation and freedom from thrombotic occlusion and stenosis >50% (duplex ultrasound–derived). Secondary outcomes included the Venous Clinical Severity Score (VCSS) pain assessment and Chronic Venous Insufficiency Quality-of-Life Questionnaire (CIVIQ-20), both hypothesis-tested for improvement at 12 months compared to baseline values. One hundred and fifty-six patients completed 12-month follow-up, including 84 patients with post-thrombotic syndrome (PTS) and 72 patients with non-thrombotic iliac vein lesions.

All stents (219) were deployed success fully to the intended location.

The 12-month primary patency rate was 88.3%, which was significantly better than a performance goal (74%) derived from the venous stent literature (p<0.0001). The VCSS pain score at 12 months improved significantly from baseline, with a mean improvement in the pain score of –1.7 (p<0.0001).

CIVIQ-20 scores also improved significantly at 12 months from baseline, with a mean improvement of –15.7 (p<0.0001). Additional observations included a 12-month freedom from target lesion revascularisation of 92.6% (95% CI, 87.5%, 96.1%). Radiographs were assessed by the Yale core lab

for stent fractures, with no fractures reported at 12-month follow-up.

Dake concluded that one-year results from the VERNACULAR trial demonstrated that the Venovo venous stent could be deployed successfully in obstructive iliac and femoral vein lesions, including acute or chronic deep vein thrombosis, post-thrombotic syndrome, or venous compression syndrome (e.g., May Thurner), with a primary patency rate of 88.3%, a low reintervention rate of 7.4%, and no corelab assessed stent fractures.

While the data presented at VIVA reported the outcomes at 12 months, Dake explained the cohort is being followed up for up to three years.

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Issue

19 09

Oral anticoagulants

Apixaban significantly reduces venous thromboembolism in ambulatory cancer patients

Data from AVERT (Apixaban for the prevention of venous thromboembolism in high-risk ambulatory cancer patients) show that ambulatory cancer patients randomised to receive apixaban (Eliquis, Bristol-Myers Squibb and Pfizer) have a significantly lower rate of venous thromboembolism than those randomised to placebo. However, apixaban patients also had a significantly higher rate of major bleeding.

MARC CARRIER (DEPARTMENT of Medicine, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Canada) and others write in the New England Journal of Medicine that venous thromboembolism in cancer patients who are receiving chemotherapy “has a substantial effect on care, including an increase in healthcare expenditure and a negative effect on quality of life”. They add that as a previous small phase 2 trial suggested that apixaban was a safe and effective approach for reducing the risk of venous thromboembolism in such patients, the aim of AVERT was therefore to “assess the efficacy of apixaban thromboprophylaxis in ambulatory cancer patients with cancer and immediate-to-high risk of venous thromboembolism (Khorana score ≥2)”.

Of 574 patients randomised, 291 were assigned to

apixaban and 283 were assigned to placebo; of these, 288 and 275, respectively, were included in the final analysis. The primary efficacy endpoint was the first objectively documented episode of major venous thromboembolism, and the primary safety endpoint was major bleeding.

Significantly fewer apixaban patients experienced an episode of venous thromboembolism than placebo patients: 4.2% vs. 10.2%, respectively (p<0.001).

Carrier et al report: “The adjusted odds ratio for venous thromboembolism associated with the use of apixaban as compared with placebo was 0.39”. Furthermore, three of 288 (1%) in the apixaban group vs. 20 of 275 (7.35) in the placebo group had a venous thromboembolism event during the treatment period (180 days).

However, in the modified intention-to-treat analysis,

Greater height is an independent risk factor for varicose veins

A prospective study of data for nearly half a million individuals, using methods such as machine learning and genomewide association study, has highlighted several novel clinical and genetic risk factors for varicose veins.

Writing in Circulation, Eri Fukaya (Stanford School of Medicine, Stanford, USA) and others note that the factors influencing varicose vein formation “are not fully understood. [...] Epidemiological studies have established multiple risk factors such as age, female sex, pregnancy, obesity, and prior deep vein thrombosis, but several other putative factors remain unconfirmed.”

Therefore, using various approaches (including machine learning), they sought to find clinical, environmental, and genetic bases of varicose veins of more than 500,000 individuals. The authors identified 10 new predictors, as well as confirming that several known factors (e.g. age) increased the risk of varicose veins. They report: “After adjustment for traditional risk factors in Cox regression, greater height remained independently associated with varicose veins (p<0.0001)”.

Additionally, according to Fukaya et al, several “debated risk factors” like oral contraception were not found to be independently associated with varicose veins in the Cox analysis but others were (including systolic blood pressure).

Furthermore, following a genomewide association study, the authors

identified 30 new genome-wide significant loci and this showed “pathways involved in vascular development and skeletal/limb biology”.

They state: “The strongest association was located on chromosome 1 in the CASZ1 gene, in a known blood pressure locus”.

Fukaya et al conclude: “Our discovery of genetic determinants of disease also sets a path for identification of new targets in the effort to develop therapy for varicose veins.”

Insole could be used to deliver oxygen to treat diabetic foot ulcers

Hongjie Jiang (School of Electrical and Computer Engineering, West Lafayette, USA) report in MRS Communications that they have developed a low-cost alternative to continuous diffusion of oxygen therapy for the management

the rate of major bleeding was significantly higher for apixaban patients: 3.5% vs. 1.8% for placebo patients (p=0.046). During the treatment period, these figures were 2.1% and 1.1%, respectively.

There were no significant differences in the rate of death between groups. “This probably reflects the fact that many of our patients had advanced cancer, which was the most common cause of death. Although prevention of venous thromboembolism would ideally reduce overall mortality, a different trial design and a much larger sample would be required to address this question,” the authors comment.

of diabetic foot ulcers—“a siliconebased insole with selective laser-ablated regions to deliver oxygen to wound regions on the sole of the foot”. They explain: “Although polydimethylsiloxane (PDMS) on its own cannot absorb excess exudate from deep wounds, the insole can be worn over a standard exudate-absorbing dressing, such as a polyurethane-based commercial wound dressing foam, which still allows oxygen permutation (albeit after a time delay).”

In the MRS Communications paper, Jiang et al describe how the insole can be used to selectively deliver oxygen to diabetic foot ulcers on the sole of the foot. “The insole can be customised to match each patient’s wound location and geometry in order to promote optimal oxygen-supplemented wound healing,” the authors conclude.

Breakthrough Strategy to lead an international project to develop venous BIBA Briefings

thromboembolism clinical research standards

Breakthrough Strategy (BTS), working on behalf of the International Society on Thrombosis and Haemostasis (ISTH), is to lead a team of researchers to design a minimum standard data set to be used in research studies of venous thromboembolism. According to a press release, the data set is to be completed in 2019 and will simplify the process of identifying care data elements used in venous thromboembolism research studies and support cross-study comparisons and collaboration using agreed-upon standards.

Sam Walters, BTS founder and president, comments: “BTS is thrilled to work with ISTH to develop consistent venous thromboembolism research standards. Consensus-based data sets are key to powering collaborative healthcare research, increasing the power and magnitude of future venous thromboembolism clinical research projects globally.”

BIBA Briefings is a new platform that provides in-depth analysis of the latest market intelligence from BIBA MedTech Insights, which provides consulting and market analysis services to medical professionals and organisations in the medical device industry in Europe and North America. The platform also reviews data and news.

The aim of each report is to give an overview of the key information affecting the medical device industry, enabling those working in the industry to keep abreast of the latest developments and make knowledgeable decisions.

For more information about BIBA Briefings or BIBA MedTech Insights, please contact Laura James laura@bibamedical.com

Jan

Issue

19 09

Oral anticoagulants

Rivaroxaban trial finds significant VTE reduction in cancer patients

Results from the Phase 3 CASSINI study contributes new data on the use of oral anticoagulant rivaroxaban (brand name Xarelto, Janssen Pharmaceuticals) in the management and prevention of venous thromboembolism (VTE) in high-risk patients with cancer.

T

he composite primary endpoint of VTE occurrence did not reach statistical significance during the full study period. However, use of the anticoagulant resulted in a clinically meaningful and nominally significant 60% reduction of VTE events compared to placebo during active treatment time.

Bleeding rates were low, though higher with rivaroxaban. The results were presented at the 60th American Society of Hematology (ASH; 1–4 December) Annual Meeting in San Diego, USA. “We want patients to focus on treating their cancer and getting better, without the concern and burden of blood clots,” said Alok Khorana (Cleveland Clinic, Cleveland, USA) lead investigator on the trial. “Building on prior research supporting the use of rivaroxaban for the treatment of VTE in patients with cancer, this new CASSINI data signal the role of rivaroxaban in preventing blood clots.”

Khorana was compensated by Janssen for his role as chair of the CALLISTO advisory council and co-chair of the CASSINI steering committee.

Study Results

In the intent to treat (ITT) population, the primary efficacy composite endpoint (symptomatic or asymptomatic lowerextremity proximal deep vein thrombosis (DVT), symptomatic upper-extremity or distal lower-extremity DVT, symptomatic or incidental pulmonary embolism (PE), and VTE-related death) occurred during the study period in 8.79% of patients in the placebo group and in 5.95% of patients treated with 10mg rivaroxaban once daily; however, this result was not statistically significant (HR 0.66; 95% CI, 0.40–1.09; p=0.101).

Approximately 62.4% of patients completed the double-blind trial period from randomisation through the end of the study’s 180-day observation period, regardless of whether they discontinued the study medication. Withdrawal of consent and death were the primary reasons for discontinuation.

Researchers also examined the primary efficacy composite endpoint in all

randomised patients, during the time they were actively taking treatment, known as the ‘on-treatment’ period. For this pre-specified analysis, rivaroxaban was associated with a statistically significant 60% reduction in VTE events compared to placebo (2.62% vs. 6.41%; HR=0.40; 95% CI, 0.20–0.80; p=0.007). The primary safety outcome, International Society on Thrombosis and Haemostasis (ISTH) major bleeding, during the ontreatment period was low across both treatment arms and occurred in four out of 404 (0.99%) patients treated with placebo and eight out of 405 (1.98%) patients treated with rivaroxaban; this result was not statistically significant, though the study was not powered to detect a significant difference. (HR=1.96; 95% CI, 0.59–6.49; p=0.265).

Of the total VTE events that occurred, approximately 39% were experienced by patients who had prematurely discontinued treatment. All-cause mortality, a secondary efficacy endpoint, was similar between both groups at the end of the 180-day observation period (20% for rivaroxaban vs. 23.8% for placebo; HR=0.83; 95% CI, 0.62–1.11).

Many patients died as a result of their cancer, with a small number of VTErelated deaths. Efficacy and safety outcomes were consistent across all prespecified subgroups.

Despite being largely preventable, blood clots remain the second leading cause of death in patients with cancer.

The risk of VTE, which comprises DVT and PE, is five times greater in people with cancer, and that risk is magnified in those receiving certain types of chemotherapy. VTE risk is also highest in the newly diagnosed and in those with more advanced, metastatic disease. Recent guidelines issued by the ISTH and the National Comprehensive Cancer Network (NCCN) recommend rivaroxaban as an option for the treatment of cancer-associated VTE. Currently, no medical therapy is approved for the primary prevention of VTE in high-risk, ambulatory cancer patients, due to limited clinical data.

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19 09

Venous leg ulcers

Venous occlusion and incompetence treatment algorithm needed for venous ulcer patients A recent study suggests that correction of both superficial and deep venous abnormalities improves venous leg ulcer (VLU) healing when compression fails. The investigators note, however, that an algorithm for treatment has not yet been established.

The study was carried out by Eric Hager (University of Pittsburg, Pittsburg, USA) and colleagues and presented by Peter F Lawrence, (University of California, Los Angeles, USA) at the recent VEITHsymposium (13–17 November, New York, USA).

T

he investigators make four main conclusions: firstly, that venous ulcers can be healed with an aggressive approach to incompetent or obstructed superficial, perforating, and deep veins. Secondly, while four main procedures—compression, laser ablation, radiofrequency ablation, and iliac stenting—contribute incrementally to ulcer healing, the optimal order needs to be determined. Additionally, the status of the ulcer is the “key” to determining if there is still ambulatory venous hypertension and, finally, if an ulcer is not healing with compression or heals and then recurs, there is a mechanical reason which must be found and treated.

Hager and colleagues aimed to evaluate the relative contribution of the correction of deep, superficial, and perforator vein abnormalities in the healing of VLUs. They found that the size of an ulcer is “critical” in that the bigger the ulcer, the harder it is to

heal. Results also showed that while an iliac stent had a particularly “positive impact” on ulcer healing, there is no one procedure that reliably heals all VLUs, and all endovenous interventions contribute to VLU healing in some patients.

Background

Lawrence noted various studies of compression and antibiotics, including Gohel et al (2007), van Gent et al (2006), and Mayberry et al (1991). An average of 15% of patients across these studies had recalcitrant venous ulcers.

In terms of endovenous laser treatment (EVLT), Lawrence notes one study which involved 44 CEAP 6 patients and took place between January 2004 and August 2007. Cumulative ulcer healing rates were 82.1% at one month, 92.5% at three months and six months, and 97.4% at 12 months.

A previous study by Lawrence et

al (2011) concluded that endovenous ablation of incompetent perforating veins is an effective treatment for recalcitrant venous ulcers. The study was conducted in a single institution and involved 45 patients, or 75 ulcers, with 86 incompetent perforating veins. Ninety per cent of the ulcers healed in patients with at least one successful ablation. The mean healing time was four months. Lawrence noted that at the time of this study, the deep vein system was “not considered to be significant” in treatment.

Finally, Lawrence pointed to a paper by Marston (2011), which was a prospective study of 78 CEAP 5/6 patients to assess incidence of proximal venous disease. Lawrence noted that Marston had not addressed the issue of treatment and whether or not that can heal ulcers. Thirty-seven per cent of patients in this study had iliocaval stenosis of over 50% and 23% had stenosis/occlusion above 80%.

The investigators highlight a number of remaining uncertainties. There is still ambiguity regarding what the order of procedures should be when treating ulcers. Lawrence noted that most surgeons treat superficial veins first because they are “easier”, but that this may not necessarily be the best starting point. He suggested that further study

is needed to recognise how proximal iliofemoral venous disease should be identified, whether by duplex ultrasound alone, with CT venogram or MR venogram, or with a catheter venogram or intravascular ultrasound (IVUS).

Furthermore, Lawrence noted that in cases where there are multiple levels of occlusion or reflux, it can be unclear which should be treated first.

Results

The multicentre study included nine institutions across the USA, enrolling patients with an active venous ulcer which had been treated between 2013 and 2016. Included patients were treated with compression, ablation, angioplasty and/or stenting. The index leg was the limb with the largest ulcer, and the index ulcer was the one with the largest surface area.

A total of 832 patients were enrolled, 46% female and 54% male, with a mean age of 62 years. The mean BMI of the patients was 33.4 and a 27% history of deep vein thrombosis (DVT).

According to the investigators, the level of venous reflux in deep, superficial and perforator veins was 34%, 92% and 87% respectively. The incidence of stenosis above 50% was 5% in the iliac vein and 3% in the femoral vein.

Jan

Issue

19 09

Market watch

17

Product News Merit Medical acquires assets of Vascular Insights

Merit Medical Systems, Inc. has announced that it has acquired substantially all of the assets of Vascular Insights, LLC, based in Quincy, USA. Vascular Insights’ primary assets are the ClariVein IC and ClariVein OC specialty infusion and occlusion catheter systems, which have been utilised in more than 120,000 cases to treat superficial venous disease, particularly below the knee (BTK), and in venous leg ulcers (VLU).

The ClariVein systems address a US$700 million global market. The ClariVein IC system has 510(k) clearance from the US FDA, the ClariVein OC system is CEmarked, and the systems are covered by 43 patents issued worldwide.

The purchase price was US$40 million plus additional milestone payments that could amount to an additional US$20 million if certain sales targets are achieved.

“We have had our eye on these products for some time,” says Fred P Lampropoulos, Merit’s chairman and CEO. “These products complement our existing peripheral intervention sales platform, add to our capability to provide many existing Merit products, such as our micropuncture and vascular access products, and increase our ability to customise the entire procedure for our customers. Additionally, our global sales footprint allows for expansion of sales in previously underserved areas.”

“We are excited to reach this agreement with Merit,” comments James (Chip) Draper, chief executive officer of Vascular Insights. “This acquisition will allow ClariVein to reach more patients in more ways and in more places with the commitment to treat venous disease.”

“I am thrilled that Merit and ClariVein will bring transformative relief to millions of venous disease sufferers worldwide, especially those suffering from debilitating venous leg ulcers,” says Michael Tal, inventor of the ClariVein systems and co-founder of Vascular Insights.

The effect of the Vascular Insights acquisition on Merit’s earnings for 2018 is expected to be dilutive to Merit’s earnings per share on a GAAP basis of approximately US$0.03 per common share and on a non-GAAP basis of approximately US$0.02 per common share, with both Merit’s GAAP, non-GAAP gross margins, and revenue contributions expected to be inconsequential for 2018.

BTG to begin European distribution of EKOS Control unit 4.0

BTG has announced that the first EKOS Control Unit 4.0 have been shipped from BTG’s facility in Bothell (Washington, USA) to Europe, where full commercial launch will begin. New features of the EKOS CU 4.0 include an interactive colour touchscreen, a built-in battery and separate ports for managing two EKOS devices simultaneously.

These improvements simplify bilateral treatment of pulmonary embolism and deep vein thrombosis (DVT). Using CU 4.0, physicians can treat both pulmonary arteries and can easily monitor and manage two EKOS devices at the same time.

European patients with pulmonary embolism and DVT have already successfully been treated with EKOS CU 4.0 during a limited release of the product.

Professor Nils Kucher, director of Clinic of Angiology at University Hospital in Zurich, Switzerland says, “I have used EKOS therapy for over 10 years. This latest innovation of the technology is a big step for simplifying thrombosis treatment.”

EKOS is the only device to have both FDA clearance and a CE mark [0086] for the treatment of pulmonary embolism.

The system includes an ultrasonic device that uses acoustic pulses, which enable quick and safe dissolution of blood clots and restore blood flow in patients with pulmonary embolism, DVT and peripheral arterial occlusions.

EKOS

First patients enrolled in FLASH registry using the FlowTriever system for PE

Inari Medical has announced the enrolment of the first patient in the FlowTriever All-Comer Registry for Patient Safety and Hemodynamics (FLASH) using the company’s FlowTriever System for the treatment of pulmonary embolism (PE).

FLASH is a 500-patient prospective, multicentre registry study to evaluate real-world outcomes after treatment of patients with intermediate and high risk PE with FlowTriever. FLASH represents the latest investment in a robust pipeline of clinical studies and follows the completion of the FlowTriever Pulmonary Embolectomy (FLARE) clinical study early this year and the recent launch of the ClotTriever Outcomes Registry (CLOUT) evaluating outcomes after treatment of deep vein thrombosis (DVT) with Inari’s ClotTriever system.

“We are pleased to be the first site to enrol a patient in FLASH,” said Thomas M Tu, director of the Pulmonary Embolism Response Team (PERT) at Baptist Health Louisville, USA. “In our experience, the FlowTriever System consistently and safely removes large volumes of clot from the pulmonary arteries, allowing us to improve heart function while avoiding the need for thrombolytics drugs and their associated bleeding risk. FlowTriever is the only mechanical thrombectomy device indicated for the treatment of PE and has become our first line therapy.”

“Compared to the previous FLARE study, FLASH will allow us to evaluate both short- and long-term outcomes in a much broader group of patients,” says Catalin Toma, interventional cardiologist at UPMC Presbyterian in Pittsburgh, USA and principal investigator for FLASH. “In particular, the six-month follow-up will allow us to determine how significant clot removal improves cardiac haemodynamics, symptoms and quality of life metrics over the longer term.”

“FLASH reflects Inari’s commitment to the production of clinical data to help advance the understanding and treatment of PE and we look forward to working with a dedicated group of physician investigators to execute this important study,” says Bill Hoffman, Inari’s chief executive officer. “We are also pleased to announce the achievement of another important milestone having treated our 1,000th patient this month, a testament to our physician community’s dedication to non-lytic based treatment of venous thromboembolism patients.”

Flowtriever

First successful implantation of the bioconvertible Sentry IVC filter

The world’s first bioconvertible IVC filter commercially offered in the USA (Sentry; BTG) has been successfully implanted into the first patients outside of a clinical trial.

The Sentry filter is designed to provide protection from pulmonary embolism for the period of transient risk and then bioconvert to leave a patent, unobstructed inferior vena cava (IVC) lumen, eliminating the need to retrieve and addressing the typical filterrelated complications associated with conventional IVC filters, a press release reports.

Ayad K M Agha, director of Interventional Radiology and an interventional radiologist at Cardiovascular Interventional Radiology Centers in Phoenix, USA, who performed the procedure on one of his patients, says: “Traditional IVC filters are sometimes associated with a variety of concerns. Placing the Sentry filter gives me confidence in reducing potential complications seen with conventional filters. Using the Sentry IVC filter only requires one visit which means my patient does not have to worry about coming back to make sure the filter is retrieved. This is better for the patient and their families and removes the risk of any complications that may arise on a follow up procedure” The Sentry bioconvertible filter is supported by two years of data available through the SENTRY trial, recently presented on podium at the Vascular Interventional Advances conference (VIVA; 5–8 November, Las Vegas, USA) and demonstrated no instances of filter tilt, migration, embolization, fracture or IVC perforation through 24-months of imaging-intensive follow up.

Sentry Bioconvertible IVC filter two-year results show zero tilt or migration

Two-year results for the SENTRY trial were presented at the Vascular Interventional Advances conference (VIVA; 5–8 November, Las Vegas, USA). The prospective, multicentre trial of the Sentry (BTG), a bioconvertible IVC filter, found that in addition to providing protection against pulmonary embolism during the transient risk period, the device also had zero instances of tilt, perforation, migration and embolisation through two years of imaging-intensive

18

Jan

Product News follow-up.

“The trial shows no device-related pulmonary embolism and zero stability complications. Physicians can have the peace of mind that they are protecting their patients from the devastating consequences of pulmonary embolism (PE) while reducing complications often associated with IVC filter retrieval. This device eliminates the need to retrieve and that truly makes it a next-generation device,” says BTG chief commercial officer John Sylvester.

The findings were presented by principal investigator Michael Dake (Stanford, USA). In the long-term data, 85 patients were followed for 24 months using computed tomography (CT) or CT venography imaging. The rate of freedom from new symptomatic PE through 60 days was 100% and there continued to be no cases of devicerelated new symptomatic pulmonary embolism through 24 months.

The results, as reported at VIVA, showed that there were no instances of filter tilt, migration, embolisation, fracture or IVC perforation through 24-months. Two patients developed symptomatic caval thrombosis during the first month, however neither experienced recurrence after successful interventions and no further instances of symptomatic caval thrombosis occurred at 24 months. Filter bioconversion was successful for 95.7% of patients at six months, 96.4% at 12 months, and 96.5% at 24 months. No IVC stenosis was reported.

American College of Phlebology adopts new name: American Vein and Lymphatic Society

The members of the American College of Phlebology (ACP) have voted to change their name to the American Vein and Lymphatic Society (AVLS). The

name change is a part of the Society’s mission and vision to provide advocacy efforts, research opportunities and superior education to members and the field of venous and lymphatic medicine.

A press release from the society states that it is important for the identity of the society and its members to address and provide appropriate treatment to lymphatic patients, as well as venous patients. Thus, the leadership of the organisation determined a name change was essential for the AVLS’ continued growth as a medical society. In addition, the American College of Phlebology Foundation will become the Foundation for Venous and Lymphatic Disease.

“Our goal with this name change is for our members and the medical world at large to better understand who we serve and how we will serve them,” says Marlin Schul, president of the AVLS. “We are a society; a place for venous and lymphatic healthcare professionals to gather, exchange ideas, research and learn from each other.”

While the ACP had strong recognition within the field of vein disease, outside of the field the term “phlebology” was less known, the society press

realease says. As the society worked to increase recognition within the AMA and with public and private payors, the leadership realised a switch in terminology would help the society continue to grow in these arenas.

The board of directors and other leaders spent several months discussing in depth what their name means and what elements in a name are essential.

After hours of discussions, member surveys and conversations with our membership, the board of directors unanimously voted to change the name to American Vein and Lymphatic Society. The membership was informed at the 2018 ACP Annual Congress in Nashville, USA and received the news with a standing ovation. The announcement was followed by a member vote that passed by an overwhelming majority.

“This is a pivotal moment in the identity of our Society,” says Dean J Bender, executive director of the AVLS. “We are embracing both venous and lymphatic medicine as well as expanding our influence to include not only education, but also advocacy and research in our field.”

Calendar of events 20–25 January LINC: Leipzig Interventional Course Leipzig, Germany linc2019.com

23–25 January Winter Days Meeting Cortina d’Ampezzo Italian Alps, Italy vwinfoundation.com

Issue

19 09

Events

19–22 February AVF: American Venous Forum Annual Meeting Rancho Mirage, USA veinforum.org

10–12 March EVC: European Vascular Course Maastricht, the Netherlands vascular-course.com

12–13 March LINC Asia-Pacific Hong Kong linc-around-the-world.com

5–7 April Venous Symposium New York, USA

12–15 June SVS Vascular Annual Meeting London, UK

venous-symposium.com

vascular.org

15–18 April Charing Cross Symposium (CX) London, UK

17–19 June Royal Society of Medicine Venous Forum London, UK

cxsymposium.com

25–27 April IVC: International Vein Course Miami Beach, USA ivcmiami.com

rsm.ac.uk/venous-forum

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

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