GLASS Classification Correlates with Primary Patency in Chronic Limb-Threatening Ischemia Patients Treated Endovascularly

Primary Limb-Based Patency for Chronic Limb-Threatening Ischemia Treated with Endovascular Therapy Based on the Global Limb Anatomic Staging System

Clinical question

In a large population and with long follow-ups, does the GLASS classification correlate with primary patency in patients with chronic limb-threatening ischemia who underwent endovascular therapy? And what were the risk factors for primary patency loss?

Take away point

GLASS classification may be an indicator of prognosis after intervention in patients with chronic limb-threatening ischemia.

Reference

Peng M, Li C, Nie C, Chen J, Tan J. Primary Limb-Based Patency for Chronic Limb-Threatening Ischemia Treated with Endovascular Therapy Based on the Global Limb Anatomic Staging System. J Vasc Interv Radiol. 2024 Jul 24:S1051-0443(24)00472-X. doi: 10.1016/j.jvir.2024.07.015. Epub ahead of print. PMID: 39059464.

Click here for abstract

Study design

Retrospective, observational, descriptive study

Funding Source

N/A

Setting

Chongqing University Three Gorges Hospital, Wanzhou, Chongqing, China (academic institution)

Figure

Kaplan-Meier curves for primary limb-based patency stratified by Global Limb Anatomic Staging System (GLASS) stage for limbs with chronic limb-threatening ischemia undergoing endovascular therapy. (a) At 1 year after intervention: GLASS Stage I versus II, 78.8% versus 69.5%; P = .232; GLASS Stage I versus III, 78.8% versus 41.6%; P < .001; GLASS Stage II versus III, 69.5% versus 41.6%; P = .001. (b) At the end of follow-up: GLASS Stage I versus II, 54.2% versus 38.6%; P = .042; GLASS Stage I versus III, 54.2% versus 10.5%; P < .001; GLASS Stage II versus III, 38.6% versus 10.5%; P < .001. G = grade; HR = hazard ratio.

Summary

The Global Limb Anatomic Staging System (GLASS) classification system, proposed in 2019, aims to standardize the assessment of limb anatomy in patients with critical limb threatening ischemia (CLTI) in order to guide treatment decisions. It consists of three stages, with Stage III representing the highest severity of disease. Prior studies were inconclusive regarding the ability of GLASS to predict limb-based patency. This study was conducted in order to assess the potential of the GLASS classification system to predict prognostic outcomes of patients with CLTI who underwent endovascular therapy with a larger patient population and longer follow-up.

Using a retrospective analysis, the investigators reviewed data from a total of 1,029 patients who underwent revascularization therapy for CLTI between January 1, 2018 and May 31, 2022 at the Chongqing University Three Gorges Hospital. After excluding patients with confounding variables, 231 patients (236 limbs) were included in the final analysis. The GLASS classification of the ischemic limbs was assessed using CTA or digital subtraction angiography prior to intervention. Of these patients, 52 (22%) were classified as GLASS Stage I, 59 (25%) were classified as GLASS Stage II, and 125 (53%) were classified as GLASS Stage III. Patients were followed up at 1-, 3-, 6-, and 12-months post-intervention and annually thereafter. Patient interviews, physical examinations, and vascular ultrasonography were used to assess patency at follow up.

The mean patient age was 74.45 years, with a predominance of male patients (76.7%). Notably, 36.9% of limbs were classified as clinical Stage IV according to the WIfI system, and common comorbidities included hypertension (64.8%) and diabetes (41.1%). For procedural details, 23.3% of limbs received no stents, while 58.1% were treated with bare nitinol stents. There were significant differences in the number of stents used across GLASS stages (P < .001) and in postoperative antithrombotic regimens (P = .004), but not in the type of stents used (P = 0.101). The median follow-up time was 1,279 days, with primary limb-based patency rates declining significantly with higher GLASS stages; for example, 1-year limb-based patency rates were 78.8% for Stage I and 41.6% for Stage III (P < .001). Univariate analysis identified GLASS stage III, diabetes, and smoking as independent risk factors for long-term patency loss, while male sex was associated with a lower risk. Multivariate analysis confirmed all these to be independent factors associated with limb-based patency.

The authors cited multiple prior studies that found evidence that the use of GLASS staging can predict limb-based patency rates in CLTI patients undergoing endovascular treatment. This study, which had a larger sample size and longer follow-up times than those cited, supports these findings and provides additional insight.

Commentary

The results from this study, along with those referenced within it, provide a strong argument for using the GLASS staging criteria as a prognostic tool for patients with CLTI undergoing endovascular treatment. Systems like GLASS are important for personalized procedural strategy, post-procedural medical management, and follow-up schedule, and the questions addressed in this study contribute to holistic approaches around patients with CLTI.

While the study's methodology was robust with a large patient population and long follow-up, further evaluation of endovascular strategies (specific types of stents and balloons, as well as potential changes of certain strategies during the study period, i.e. paclitaxel-coated devices), antiplatelet/antithrombotic strategies (especially given statistically significant differences in antithrombotic medications post-procedural), and patient-relevant quality-of-life outcome measures will provide further insights to the endovascular community. Additionally, some patient groups were excluded from the analysis; one in particular was the group with hepatocyte growth factor therapy involved. Offering clear explanations for each exclusion would strengthen the validity of the findings by demonstrating how these decisions improved the overall rigor of the study.

The discussion of confounding variables raises an important consideration: should GLASS staging criteria incorporate some of these factors? Perhaps a scoring system, rather than a purely staging-based approach, would offer physicians a more comprehensive tool for making informed treatment decisions. At the minimal, the study can benefit from a discussion on the impact of the study’s results in daily clinical practice. Should patients with higher GLASS staging criteria receive more aggressive antithrombotic regimen or more frequent clinical follow-up for potential repeat revascularization? Or was there a cost-effective time point at which procedural intervention should be discouraged? Ultimately, this paper addresses a scientific question methodically but leaves room for future research regarding the practical aspects.

Post Author
Isabel Okinedo, BA
UMass Chan Medical School
@isabelokinedo

Eye90 Beads Provide Safe and Effective Direct Visualization in Radioembolization

Imageable Radioembolization Microspheres for Treatment of Unresectable Hepatocellular Carcinoma: Interim Results from a First-in-Human Trial

Clinical question 

Can radiopaque yttrium-90 microspheres safely and effectively treat unresectable hepatocellular carcinoma while providing real-time visibility of treatment?

Take away point 

Eye90, a radiopaque Y90 microsphere, enables real-time evaluation and treatment adjustment during radioembolization, potentially improving tumor targeting and serving as a tumor response biomarker. Initial study showed 50% complete response at 3 months with no severe adverse events.

Reference 

Abraham, R.J., Arepally, A., Liu, D., Lewandowski, R., Kappadath, S.C., Verma, A., Dobrowski, D. and Holden, A., 2024. Imageable Radioembolization Microspheres for Treatment of Unresectable Hepatocellular Carcinoma: Interim Results from a First-in-Human Trial. Journal of Vascular and Interventional Radiology, 35(10), pp.1464-1473.

Click here for article 

Study design 

Prospective, observational, descriptive study

Funding Source 

ABK Biomedical

Setting 

Auckland City Hospital, Auckland, New Zealand

Figure

A 53-year-old man with chronic hepatitis B. Axial contrast-enhanced computed tomography (CT) (arterial phase) demonstrated a 4.3-cm Segment 8 hepatocellular carcinoma (white arrow) adjacent to previous transarterial chemo- embolization scar (white arrowhead). CT image demonstrating radiopaque Eye90 microsphere distribution in hepatocellular carcinoma (arrow) and surrounding treated liver volume.

Summary

Current 90Y microspheres have limitations. Glass microspheres lack flexibility in quantity and activity customization, often necessitating multiple vials and kits for larger volumes. Resin 90Y provides quantity and activity customization, but at the cost of increased burden on nuclear medicine labs and operator risk. Both microspheres also have limitations in visibility, requiring post-treatment SPECT/ PET for assessing 90Y distribution, tumor targeting, and dosimetry.

Addressing these challenges, Eye90 Microspheres introduces radiopaque properties for direct CT visualization with a customizable dose with radioactivity between 0.4-9.6 GBq at 3 preset mass ranges: (a) small (100–200 mg), (b)medium (201–400 mg), and (c) large (401–600 mg). Personalized dose vial quantity and activity is determined using a 3-compartment partition model that considers various patient-specific factors based on the technetium-99m macro- aggregated albumin SPECT/CT. This personalized approach reportedly eliminates the need for dose-draw or multiple vials.

Accompanying the Eye90 Microspheres is the Eye90 delivery device, which utilizes a dual-syringe system to achieve a controlled uniform delivery concentration of 60 mg/mL. The delivery device also allows the users to pause, assess microcatheter location with contrast media, examine microsphere distribution using CT modalities, and resume administration as needed.

This study reports 6-month safety, effectiveness, and imageability results for Eye90 in 6 subjects with unresectable HCC (median size of 3.1 cm, range: 1.2 – 4.3 cm). Subjects underwent planning procedure (90Y mapping) followed by selective treatment (≤2 segments) using partition dosimetry by SurePlan LiverY90 aiming to deliver at least 205 Gy and preferably > 250 Gy to the tumor. Post-therapy SPECT/CT, unenhanced lung CT, and 4-phase liver CT within 24 hours of treatment were obtained to correlate microsphere radiopacity with radioactivity. Follow-up were scheduled on days 21, 42, 90, and 180 after treatment.

Post-treatment SPECT/CT demonstrated mean and median dose of 283 Gy and 132 Gy to the tumor, respectively. Microsphere density within the tumor was calculated at 26,988 per mL. All subjects reported adverse events, but no treatment-related Grade ≥3 AEs occurred. At 90 days, 50% achieved complete response (CR) and 33.3% partial response (PR). At 180 days, 50% maintained CR and 16.7% PR. The other patient with PR, and the patient with stable disease at 90 days, underwent TACE and could not be evaluated. Qualitative analysis showed agreement between microsphere radiopacity on CT and radioactivity on SPECT/CT, with CT revealing heterogeneous dose distribution, and absence of radiopacity in the region of a particular tumor despite SPECT/CT activity noted throughout this region. This particular tumor did not respond to treatment.

Commentary 

Eye90 Microspheres represent another advancement in transarterial radioembolization, offering direct visualization of microsphere and tumor targeting on CT modalities. This capability could lead to more precise treatment execution, real-time therapy adjustments, and potentially serve as a biomarker for predicting tumor response and a foundation for more accurate dose-response relationships. The dual-syringe administration system allows for customized quantity and activity of microspheres, enhancing treatment personalization.

While the initial results are promising, the small sample size, short follow-up period, lower-than-planned tumor doses, and mediocre treatment response necessitate further research. The ongoing U.S. Pivotal IDE Route90 trial will provide more comprehensive data on a larger cohort. If these results hold up in larger studies, Eye90 Microspheres could redefine the standard of care in HCC treatment. The potential for improved precision, personalization, and real-time assessment makes this a technology to watch closely in the coming years.

Post author
Leila Haghani, MD 

Research Fellow 

University of Massachusetts Chan Medical School
@dr_Leila_IRad

Paclitaxel Containing Devices in Femoropopliteal Arterial Disease: The Trees and the Forest

An Up To Date Meta-Analysis on Paclitaxel Containing Devices in Femoropopliteal Arterial Disease, And A Commentary On The Entirety of the Data to Date.

Clinical question

Is paclitaxel safe when used in drug eluting stents and drug coated balloons for revascularization of the femoropopliteal artery?

Take away point

Paclitaxel containing devices are safe and effective devices, especially in their current usage and at their current generation. Previous versions of the devices may have conveyed some mortality risk, but it’s important to understand both the meta-analyses and the individual studies that comprise the data reporting, and how clinical practice is nuanced and so does the literature..

Reference

Katsanos, K. (2024). Paclitaxel meta-analyses in the lower limbs: Missing the trees for the forest. Journal of Vascular and Interventional Radiology.
Click here to access article

Briody, H., Kearns, C. A., & Lee, M. J. (2024). Mortality, safety and efficacy of paclitaxel-containing balloons and stents in the femoropopliteal artery: systematic review and meta-analysis of randomized controlled trials since 2018. Journal of Vascular and Interventional Radiology. 

Click here to access article

Study design

Meta-analysis, commentary/perspective

Setting

Meta-analysis was performed at Beaumont Hospital, Dublin Ireland and the Royal College of Surgeons in Ireland.
Commentary is from University Hospital Patras, School of Medicine, Rio, Greece.

Figure

Summary

In revascularization efforts for peripheral arterial disease, paclitaxel has proven to be an excellent anti-restenotic agent in the femoropopliteal artery when used in drug coated balloons and drug eluting stents in multiple randomized controlled trials. While effective, its safety profile was called into question in a 2018 meta-analysis. The meta-analysis, published by Katsanos et al, found statistically significant increases in all-cause death in patients with paclitaxel coated devices, and urged further investigations. In 2023, a patient level, industry funded meta-analysis concluded there was no excess mortality. Based on this study, the FDA published their official statement that there is no discernible excess of mortality.

The current meta-analysis was performed to provide an independent analysis of safety and effectiveness outcomes, including but not limited to mortality. The literature search was performed from 2018 (a choice made so this study would act as an update of the aforementioned Katsanos study) and included 19 randomized controlled trials for a total of 4,284 participants. When selecting studies, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was utilized (see figure). Effectiveness outcomes were primary patency which was analyzed using risk ratios via inverse variance, random-effects model. Safety outcomes were all cause mortality, target limb amputation, target lesion revascularization, clinically driven target lesion revascularization, and thrombosis. These were also analyzed using risk ratios via inverse variance, random effects model, as well as heterogeneity assessment via visual inspection of forest plots, chi squared test and I^2 statistic.

The results found no evidence for all-cause mortality in paclitaxel containing devices in the femoropopliteal region from 12 to 60 months, nor did they find any other safety concerns. The study redemonstrated the effectiveness of paclitaxel devices in maintaining primary patency with a pooled risk ratio of 1.55. Taken together, this meta-analysis concluded that paclitaxel containing devices work, and are safe to use. They compare this study directly to the Katsanos study due to its similar methodology and design, however they offer no suggestions as to the source of the different findings.

In response to the multiple meta-analyses looking at the use of paclitaxel containing devices in the femoropopliteal arteries with no evidence of increased all-cause mortality, Dr. Konstantinos Katsonas provided a companion commentary. In the piece, he presents 27 studies from 2008-2021 which show an increase in all-cause mortality in the paclitaxel containing device arm, arguing that the recent studies demonstrate dilution of the mortality signal, but do not eradicate it completely. He presents a meta-regression of long-term risk ratio of all cause death against publication year and shows that the observed mortality risk decreases with publication year, which would seem to suggest earlier generation devices or clinical practices may be the cause for the mortality signal. He further subgroups the studies by paclitaxel dosage and shows that the relative mortality risks may be different among the different devices with variable paclitaxel dosing. He concludes that the reader must not miss the trees for the forest, meaning that the individual studies may have points of interest that become diluted in meta-analysis.

Commentary

The academic discussion around paclitaxel can make it difficult for providers to know if these devices are safe or not. This most recent meta-analysis is an excellent consolidation of the most recent literature on paclitaxel containing devices in femoropopliteal artery treatment. The results add to the body of evidence that these paclitaxel devices are safe and effective tools in peripheral arterial disease, especially at their current generations. Providers can use these devices and expect good outcomes for their patients without an increased mortality risk.

That being said, Dr. Katsonas does raise interesting questions. The 2018 Katsonas et al meta-analysis did show a significant increase in all-cause mortality. In his commentary, this effect appeared again when looking at all studies from 2008-2021. While there were shortcomings in the Katsonas paper, the fact remains that a mortality signal was present and hasn’t been fully accounted for. The fact that it seems to disappear when looking at studies from only 2018 onward could be indicative of the root cause. Moreover, the more recent studies did not subgroup based on device or paclitaxel dosing. The data he presents on the decrease of all-cause mortality risk over the years, as well as the trend of lower risk ratios with lower paclitaxel dosing, are suggestive that the mortality signal may be device-, device-generation, and/or paclitaxel dosage-dependent. Of course, this is only speculation based on available data, but could make excellent areas of inquiry should the question of safety in paclitaxel containing devices remain.

Dr. Katsonas’ final point is to not miss the “trees” (individual studies) for the “forest” (meta-analysis), as individual studies can yield insights that may be diluted in meta-analyses. However, he doesn’t really support this in his commentary, as most of his points are made by using grouping statistics based on multiple studies. Regardless, it is an important point to keep in mind when reading meta-analyses. Procedural practice and published literature are nuanced, and evidence-based medicine should be supported by both high-level meta-analyses as well as individual studies that befit the patient population and institutional experience.

Post Author
Sean Rogers, MD
Interventional Radiology Fellow, PGY-6
University of Massachusetts Chan Medical School