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Majority of patients treated with embolization for symptomatic fibroids can avoid hysterectomy, 10-year EMMY trial results show
23rd September 2016
 
Jim Reekers.
Ten-year outcomes from the randomised controlled EMMY trial were presented at CIRSE 2016 (10–14 September, Barcelona, Spain) by Jim Reekers, Academic Medical Center, Amsterdam, The Netherlands. The results have also been published in July 2016 in the American Journal of Obstetrics and Gynecology by de Bruijn AM and colleagues.
EMMY is a Dutch, randomised controlled trial that set out to compare the clinical outcome and health-related quality of life in patients treated with either uterine artery embolization or hysterectomy for heavy menstrual bleeding caused by uterine fibroids.
 
 
The 10-year results show that the majority, around two thirds, of patients undergoing uterine artery embolization can side-step having a hysterectomy. Around 35% who underwent embolization went on to have a secondary hysterectomy, with just over 30% of these being patients who had had a successful uterine artery embolization procedure. These long-term data further contribute to the picture of the minimally invasive option being beset by the need for reintervention for symptom recurrence and control. Reintervention was not part of the trial and was considered a failure.
“After 10-years of follow-up, about two thirds of patients with symptomatic uterine fibroids, who undergo treatment with embolization can avoid a hysterectomy,” Reekers said, commenting on the results. “Health-related quality of life at 10 years after uterine artery embolization or hysterectomy remain comparably stable. Uterine artery embolization is a well-documented and good alternative to hysterectomy for symptomatic uterine fibroids, on which all eligible patients should be counselled,” he added.
Uterine artery embolization has been described as an alternative treatment to hysterectomy for patients with symptomatic fibroids since 1995. However, one of the barriers to its widespread uptake has been that women who are eligible for this treatment are often not informed about it.
Speaking on this aspect, ie women not being informed about embolization, Robert Vogelzang, chief of vascular and interventional radiology, Northwestern Memorial Hospital, Chicago, USA and a past president of the Society of Interventional Radiology, said in April this year: “Sadly, the patients who have fibroids are often not being told about embolization.”
Reekers told Interventional News: “Not informing patients about uterine fibroid embolization, when these 10-year data are available, is unethical. Uterine fibroid embolization is an interventional radiology procedure that has level one evidence to back its use. In this trial, we treated the worst end-stage scenario without any reintervention, so real world outcomes for embolization will be even better.” Importantly, he emphasised, “Surgical reintervention in the hysterectomy group after 10 years run as high as 17%.”
In the EMMY trial, 28 Dutch hospitals recruited patients with symptomatic uterine fibroids who were eligible for hysterectomy. Patients were then randomly assigned in a 1:1 ratio to receive either uterine artery embolization or hysterectomy. The researchers randomised 177 patients from 2002 to 2004. Of these, 81 received uterine artery embolization and 75 underwent hysterectomy. Twenty one patients withdrew from the trial. The 10-year questionnaire was mailed when the last patient enrolled had been treated 10 years earlier.
 At 10 years postintervention, the investigators assessed reintervention rates, health-related quality of life, and patient satisfaction, which were obtained through validated questionnaires. The study outcomes were analysed according to original treatment assignment on an intention to treat basis.
Questionnaires were received from 131 of 156 patients (84%). The mean duration of follow-up was 133 months. Ten years after treatment 28 of 81 (35%) had a secondary hysterectomy. Of these 24 out of 77 (31%) were after successful uterine artery embolization. The authors reported that secondary hysterectomies were performed for persistent symptoms in all cases but one, which was for a uterine prolapse.
De Bruijn AM and colleagues found that after the initial treatment, health-related quality of life improved significantly. “After 10 years, generic health-related quality of life remained stable, without differences between both groups. The urogenital distress inventory and the defecation distress inventory showed a decrease in both groups, without significant differences between study arms, but with a trend towards better outcome for uterine artery embolization. Satisfaction in both groups remained comparable. The majority of patients declared being very satisfied about the received treatment; 78% of the uterine artery embolization group vs. 87% in the hysterectomy group,” the authors write.
 
 
Two-year MAJESTIC data show sustained positive results for Eluvia drug-eluting stent
23rd September 2016
 
Stefan Müller-Hülsbeck. 
The MAJESTIC trial set out to evaluate the performance of the Eluvia paclitaxel-eluting vascular stent system (Boston Scientific) in the treatment of femoropopliteal artery lesions. Two-year results show a greater than 90% freedom from target lesion revascularisation rate.
Stefan Müller-Hülsbeck, director, Department of Diagnostic and Interventional Radiology/ Neuroradiology, Diako Hospital, Flensburg, Germany, presenting the results of the trial at CIRSE 2016 (10–14 September, Barcelona, Spain), said in terms of patient outcomes, the two-year MAJESTIC data showed that 91% of patients had no or minimal symptoms (ie, they were classified Rutherford Category 0–1). Further, the improvement that patients experienced in Ankle Brachial Index (ABI) was sustained to two years.
MAJESTIC is a prospective, single-arm, multicentre clinical study of 57 patients. Patients were eligible for enrolment if they had chronic lower limb ischaemia, defined as Rutherford categories two, three or four de novo or restenotic lesions (≥70% stenosis) in the native superficial femoral artery or proximal popliteal artery. Further, the reference vessel diameter needed to be between 4–6mm and the total lesion length ≥30mm and ≤110mm.
Patients were enrolled in 14 sites in Europe, Australia and New Zealand. In the trial, no centre could enrol >20% (11 patients) of the total study population. Long-term follow-up of the trial includes primary patency (ie, duplex ultrasound peak systolic velocity ratio ≤2.5 and absence of target lesion revascularisation or bypass) and safety assessments at two years as well as safety monitoring through three years.
The mean age of patients (83% were male) enrolled was 69±3 years. Of these, 35% had diabetes. The baseline Rutherford Category was two for 35%, three for 61%, and four for 4% of patients. The mean lesion length was 70.8±28.1mm and nearly 65% had severe calcification. Percent diameter stenosis was 86.3%±16.2%, and 46% had total occlusions.
“What is most important is that we have proved with the MAJESTIC data, showing a freedom from target lesion revascularisation rate of over 90% at 24 months, that the concept of combining a self-expanding nitinol stent with a polymer that controls paclitaxel release over time, is a concept that works. Boston Scientific has used a polymer that is well-established in the coronary drug-eluting stent world, and adapted it for use in the superficial femoral artery,” Müller-Hülsbeck told Interventional News.
Commenting on the difference in restenosis rates between superficial femoral artery and coronary territories, he added: “Restenosis following nitinol stenting in the superficial femoral artery peaks at around 12 months. Superficial femoral artery restenosis takes longer than restenosis after coronary stenting, which predominantly occurs within six months after stenting. The drug release for the Eluvia stent has been tuned so that there is a low burst of drug released in the implant phase and at one year, nearly 90% of the drug is released to coincide with the restenotic cascade in the superficial fermoral artery.”
He also explained freedom from target lesion revascularisation is a valid and relevant endpoint for patients. “We need to focus on what is of utmost importance to patients; this endpoint translates to the fact that the patient has no requirement for reintervention as their symptoms, if any persist, are mild and do not limit their lifestyle.”
Two-year results
At one year, primary patency was 96.1% (49/51) with a Kaplan–Meier estimate of 96.4%. The major adverse events rate was 3.8%; with the two events both being target lesion revascularisation and no stent fractures were identified. Müller-Hülsbeck noted that there were two additional target lesion revascularisations reported between one and two years making the freedom from target lesion revascularisation rate 92.5% (49/53) at two years.
When comparing the two-year data from the MAJESTIC trial with the two-year data from the ZILVER PTX randomised controlled trial that evaluated the Zilver PTX drug-eluting stent (Cook), Müller-Hülsbeck noted that the latter trial had a freedom from target lesion revascularisation rate above the 80% mark, while this was around 90% in MAJESTIC. “These results probably show that the concept of combining paclitaxel with a polymer for sustained drug release is a good concept in terms of patient safety and quality of life,” he said.
Keep endovascular approach simple
Commenting on drug-elution itself and the importance of using a drug as the antirestenostic agent, Müller-Hülsbeck outlined his approach when treating patient with superficial femoral artery lesions. “I think we should keep endovascular therapy as simple as possible. If lesion length and lesion location are not considered, once I have performed a percutaneous transluminal angioplasty, I then carry out an angiogram to determine how to proceed. If the vessel looks good, based on the trial data we have available, I would recommend using a drug-coated balloon. If there is any need for a stent, ie if there is elastic recoil or flow limiting dissection, then I would go ahead and use a drug-eluting stent—at this point, this could be Eluvia or Zilver PTX.”
 
 
Three-year IN.PACT SFA trial results demonstrate durability, safety and efficacy for IN.PACT Admiral
20th September 2016
 
IN.Pact Admiral
Medtronic reinforced the durability, consistency, and safety of the IN.PACT Admiral drug-coated balloon in patients with peripheral arterial disease with new data presented in a series of late-breaking clinical trial presentations at the Vascular Interventional Advances (VIVA) Annual Conference 2016 (18–22 September, Las Vegas, USA). These included three-year results from the pivotal IN.PACT SFA trial and one-year, real-world results from the full clinical cohort of the IN.PACT Global study.
IN.PACT SFA Trial
The three-year outcomes from the IN.PACT SFA trial were presented today by Prakash Krishnan, assistant professor of medicine and director of endovascular intervention, Mount Sinai Heart, New York, USA. The results demonstrated the sustained, long-term clinical benefits of IN.PACT Admiral drug-coated balloon compared to plain balloon angioplasty. “The IN.PACT Admiral is the only drug-coated balloon to-date with superior performance supported by three-year data,” said Krishnan. “In line with the one- and two-year data, we saw a consistently low clinically-driven target lesion revascularisation rate and high patency rate. These durable, long-term outcomes reinforce the shift we are seeing in adoption of IN.PACT Admiral drug-coated balloon as the primary treatment option for superficial femoral artery treatment.” The IN.PACT SFA trial enrolled 331 patients at 57 sites across Europe and the United States who were randomised to treatment with either the IN.PACT Admiral drug-coated balloon or plain balloon angioplasty (percutaneous transluminal angioplasty). The data demonstrate strong durability through three years with superior performance in both primary patency (69.5% compared to 45.1% percent in the angioplasty group [p<0.001]) and clinically-driven target lesion revascularisation (15.2% compared to 31.1% in the angioplasty group [p=0.002]). Additionally, of the patients who received a repeat procedure within three years, those in the IN.PACT Admiral group did not require a second procedure as soon as those in the angioplasty group (542.9 days for IN.PACT Admiral on average vs. 302.9 days for angioplasty, p<0.001). The data also continue to demonstrate the long-term safety benefits of the IN.PACT Admiral, with no major target limb amputations in the IN.PACT Admiral DCB group.
IN.PACT Global study
In a separate session, Michael R Jaff, medical director, Mass General Vascular Center, Massachusetts General Hospital and professor of medicine at Harvard Medical School, Boston, USA, presented new one-year results from the full clinical cohort of the IN.PACT Global study. The results continue to underscore the consistent performance in both safety and efficacy for the IN.PACT Admiral.
The IN.PACT Global Study has enrolled over 1,500 patients across 27 countries, including the 1,406 patients in the full clinical cohort presented today, to characterise the performance of IN.PACT Admiral in treating real-world patients with challenging and complex lesions. The study included external monitoring and adjudication of events by an independent clinical events committee. Additionally, it included core lab evaluations for pre-specified imaging subsets for subjects with long lesions (≥15 cm) (n=157), chronic total occlusions (≥ 5 cm) (n=126) and in-stent restenosis lesions (n=131), as recently presented at international conferences.
“Despite the complexity of these challenging lesions and patients, the outcomes were consistent across all patients, including the imaging subsets,” said Jaff. “Complex lesion types, including long lesions, chronic total occlusions and in-stent restenosis, remain challenging to treat with no clearly superior treatment options. These results demonstrate the effectiveness of the IN.PACT Admiral drug-coated balloon as a primary therapy in treating these challenging patients who we routinely see in clinical practice.” The one-year data demonstrated a low clinically-driven target lesion revascularisation rate of 7.5% in a population with a mean lesion length of 12.09cm, 18% in-stent restenosis lesions, and 35.5% in occluded lesions. Additional safety and efficacy outcomes also included low rates of thrombosis (2.9%), occurrences of major target limb amputation (0.2%), and clinically-driven target vessel revascularisation (8.1%) within one year.
In a press release Medtronic noted that IN.PACT Admiral is the only drug-coated balloon to have published two year data from a pivotal randomised trial and also the first to have presented three-year data.
 
 
VAPOUR trial produces robust new evidence for vertebroplasty
1st September 2016
 
William Clark
The VAPOUR trial proves that vertebroplasty is effective in patients with severe pain and fractures of less than six weeks’ duration, when an adequate amount of cement is injected. Subgroup analysis suggests that benefits are maximal in thoracolumbar fractures, writes William Clark, Sydney, Australia.
There have been few more debated topics in medicine over the last decade than percutaneous vertebroplasty. Two masked, randomised trials1,2 published in 2009, showed vertebroplasty to be no more effective than a placebo. Two open label randomised trials of vertebral augmentation, the FREE trial3 of kyphoplasty and VERTOS II4 trial of vertebroplasty, showed efficacy for both techniques compared to usual care. Because masked trials constitute a higher level of evidence than open label trials, it was necessary to prove the efficacy of vertebroplasty within a masked trial format.
The VAPOUR trial5 (Vertebroplasty for acute painful osteoporotic fractures) used the same trial methodology as the previous masked trials but with different patient selection and procedural technique. Selection criteria were Numeric Rated Scale (NRS) pain ≥7/10, pain duration <six weeks, MRI evidence of recent fracture, and both hospital inpatients and outpatients included. This was very different to previous masked trials which were exclusively outpatient trials, with pain >3/10, with the duration of pain up to 12 months. We targeted patients with the most painful acute fractures of less than six weeks duration.
The trial team included four centres in Sydney, Australia, an independent data collection agency and independent statisticians. Data was collected over a six-month period. Patients, data collectors, and data remained masked until trial completion. Independent statisticians then unmasked and analysed the data. This is a robust trial framework at low risk of bias.
Randomisation was provided by the National Health and Medical Research Council by automated telephone service once the patient was in the procedure room. All patients received intravenous midazolam and fentanyl before the procedure. Vertebroplasty was performed with AVAmax kits (CareFusion, whose vertebral augmentation portfolio was bought by Stryker earlier this year) using a “vertebral fill approach”, distributing polymethyl methacrylate (PMMA) cement from the top to bottom, side to side and from anterior cortex to posterior third of vertebral body. The treating radiologist had no other role in the trial after the procedure. Placebo intervention simulated a vertebroplasty with skin incision, subcutaneous lidocaine and verbal and tactile cues suggesting that a vertebroplasty was being performed.
Between November 2011 and December 2014, we enrolled 120 patients and all underwent the treatment they were randomised to. Mean cement volume was 7.5cc (compared to 2.7cc in previous sham trials). The primary endpoint was the proportion of patients with low NRS pain scores (<4/10) at 14 days. A significantly greater proportion of patients in the vertebroplasty group achieved the primary outcome compared with the control group (44% vs 21%; between-group difference 23 percentage points, 95% CI 6–39; p=0.011). The advantage in this outcome for vertebroplasty remained similar at every data collection time point to six months, with a maximum between-group difference at four weeks of 33% (95% CI, 17 to 50) (Figure 1).
 
 
Figure 1. Primary outcome of VAPOUR trial. Enrolment required Numeric Rated Scale pain?7/10 at baseline. The graph shows the proportion of patients in each group with pain intensity <4/10 at three days, one month, three months and six months post intervention. The black vertical lines represent 95% confidence intervals.
There were also positive secondary outcomes in the vertebroplasty group. Mean NRS pain score was lower at every time point, Roland Morris Disability score was lower from one month to six months, analgesic use was lower at three months and six months, median duration of hospitalisation was lower by 5.5 days, and fractured vertebral body height was 36% greater than placebo at six months. The reduction in hospital stay shows the procedure to be cost effective.
There were two serious adverse events in the vertebroplasty group. The first was hypoventilation following intravenous sedation, before the procedure commenced, and this was reversed and the procedure re-scheduled two days later. The second was a humerus fracture sustained during transfer into the prone position, and this was treated with plaster cast successfully. Two patients in the placebo group developed spinal cord compression due to continued vertebral collapse and fracture retropulsion in the weeks following randomisation. One had successful spinal decompressive surgery and the other became paraplegic. Neither had significant retropulsion at the time of enrolment.
Subgroup analysis of the primary endpoint was performed according to spinal segments—thoracic (T5–T10), thoracolumbar (T11–L2), and lumbar (L3–L5). Logistic regression analysis showed significantly greater benefit in the thoracolumbar segment than in the other segments (p=0.001).
In conclusion, the VAPOUR trial proves that vertebroplasty is effective in patients with severe pain and fractures of less than six weeks’ duration if adequate amount of PMMA is injected. Subgroup analysis suggests that benefits are maximal in thoracolumbar fractures.
The study was funded by an unrestricted research grant from CareFusion Corporation, who had no role in trial design, conduct, analysis or publication.
William Clark is director, Interventional Radiology, St George Private Hospital, Sydney, Australia. Clark has reported no disclosures pertaining to this article.
References
  1. Kallmes DF, Comstock BA, Heagerty PJ, et al. A randomized trial of vertebroplasty for osteoporotic spinal fractures. N Engl J Med 2009; 361: 569–79
  2. Buchbinder R, Osborne RH, Ebeling PR, et al. A randomized trial of vertebroplasty for painful osteoporotic vertebral fractures. N Engl J Med 2009; 361: 557–68.
  3. Wardlaw D, Cummings SR, Van Meirhaeghe J, et al. Efficacy and safety of balloon kyphoplasty compared with non-surgical care for vertebral compression fracture (FREE): a randomised controlled trial. Lancet 2009; 373: 1016-24.
  4. Klazen CA, Lohle PN, de Vries J, et al. Vertebroplasty versus conservative treatment in acute osteoporotic vertebral compression fractures (Vertos II): an open-label randomised trial. Lancet2010; 376: 1085-92
  5. Clark W, Bird P, Gonski P, et al. Safety and efficacy of vertebroplasty for acute painful osteoporotic fractures (VAPOUR): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2016; published online 17 August.
 
 
Understanding dosimetry in order to develop personalised treatment plans
19th August 2016
 
With transarterial radioembolization, one area that continues to be shrouded in debate is the concept of dosimetry and dose, writes David Liu.
David Liu
As we develop a deeper understanding of the power and potential of transarterial radioembolization (TARE), we have continued to refine both the strategy of patient selection, and improve upon the tactical execution of its delivery. Clearly, with the refined protocols and dedicated devices that are available, we are doing better. However, the one area that continues to be shrouded in debate is the concept of dosimetry and dose.
Although the term ‘dose’ within the radioembolization vernacular refers to the administration of a vial or vials of radioactive microparticles, and this is incorrect.
We can only address the issues of dose by understanding some basic physical principles.
The particle itself is essentially a benign carrier. When performing TARE, activity (measured in decays per seconds, or Becquerel [Bq]) is administered intra-arterially, resulting in deposition into the terminal vascular bed of the said vessel. Not all of the spheres arrive at the tumour, and as a result, additional collateral damage to the liver parenchyma, lungs, and in some cases other non-targeted tissue (such as stomach) occurs, resulting in these unintended compartments receiving different amounts and distribution of activity. Dose is dependent on four fundamental factors: activity, volume, distribution and susceptibility of the exposed tissue and can be derived for the tumour, liver parenchyma and other volumes of tissue (eg lung). When these four basic factors are taken into account, we may derive the dose (measured in absorbed radiation in tissue, with Gray (Gy) as the most commonly used unit of measurement) and this practice is termed dosimetry. When introducing these concepts to those that are new to dose, I describe these factors as fundamental roots in the creation of a ‘dosimi-tree’ (Figure 1).
Figure 1: The Dosimi-tree illustration depicting the concept of dose rooted in four basic principles of activity, volume, distribution and tissue susceptibility.
The aforementioned physical principles are not incorporated into the commonly used methods of determining the amount of radioactivity to inject. The Medical Imaging Radiation Dose (or MIRD), and Body Surface Area (BSA) methods do not accurately account for distribution, and susceptibility of tissue to radiation. Thus, controversial issues distill into arguments of conjecture (eg too many particles/too few particles, how to adjust for damaged liver, and more/less activity being more/less effective). When one examines the physical differences between commercially available glass (ie More radiation per particle, more overall radiation injected during a procedure, and less particles overall) and commercially available resin (ie Less radiation per particle, less overall radiation injected during a procedure, and more particles overall), the concept of dose becomes more complex. This situation is clearly demonstrated when more advanced methods of dose calculation (using the Partition method) result in the high variation of what is considered a tumouricidal dose. Wide ranges of optimal tumour dose, from 100–120Gy for resin, to 200–500Gy for glass are reported, all generally resulting in very similar response and survival (at least in hepatocellular carcinoma).
In summary, the activity is fundamentally bound to the particle, so the particle dictates the distribution, and only when this is married with the target tissue susceptibility, and target volume, may dose be derived. In this next level of discussion, apps such as the iOS Dosimetry & Activity Visualizer for Y90 Radioembolization [DAVYR] (available for free download on the Apple App Store for iOS Devices, search term: DAVYR) will be essential to developing personalised treatment plans. As we continue to mature TARE, progress to a common lexicon and common goals must be recognised: we must minimise non-targeted radiation (protect the liver, and protect the lungs), minimise overall activity to be injected (As Low As Reasonably Acceptable [ALARA]), and optimise (not maximise) dose to tumour.
David Liu is a clinical associate professor, Faculty of Medicine, University of British Columbia, Vancouver, Canada. He has acted as a consultant for Sirtex Medical and BTG.