by Stephen Black, M.D., Paul J. Gagne, M.D., Kelly O'Connell Ph.D.

Venous Disease Overview and Classification

VENOUS LEG ulceration (VLU) is a chronic, recurring condition with a prevalence of 1.5–3% in the general population¹ and accounts for 70% of all chronic leg ulcers. Chronic venous insufficiency (CVI) independent of arterial disease accounts for 40–70% of chronic leg ulcers.¹ 70% of VLUs are healed within 24 weeks, but up to 60–70% of VLUs may recur within 10 years, resulting in significant morbidity.³

Questions remain regarding potential differences in ulcer healing and recurrence rates in patients whose primary CVI etiology is from obstructions in the deep venous system, given that deep venous obstruction (DVO) is present in 37–69% of patients with chronic venous ulcers.^4–7 McDaniel et al. reported that in patients with venous ulcers, 66% of patients with underlying deep venous disease had their ulcers recur within 48 months after standard compression therapy, while only 29% of patients without any underlying obstruction had a recurrence within the same time period.⁸ This demonstrates that ulcer recurrence is high in patients who do not have their underlying deep venous disease treated and suggests that the interrogation and treatment of the deep venous system may be critical to improving ulcer healing times and lowering recurrence rates.

Treatment Strategies for Venous Disease

Treatment of chronic venous disease (CVD) varies based on the clinical stage of the disease. The Clinical (C), Etiology (E), Anatomy (A), and Pathophysiology (P) (CEAP) classification, developed by the American Venous Forum (AVF), provides a uniform grading system for the diagnosis of venous disease based on severity within each of its broad categories.⁹ Within the clinical category, the scale ranges from C0 (asymptomatic, no clinical signs) to C6 (skin changes with active venous ulceration). First-line therapy for venous disease is the use of compression therapy/stockings. Compression stockings aid in reducing venous reflux and improving calf muscle function; however, when rigorously studied, the compliance rate for compression therapy is poor, regardless of CEAP score.^{10, 11}

Studies of more invasive interventions for venous disease have focused on treating superficial venous reflux. The Early Venous Reflux Ablation (EVRA) trial evaluated the role of early endovenous ablation of superficial venous reflux in patients with venous leg ulcers.¹² The study randomized patients to receive either early endovenous ablation and compression therapy or to receive compression therapy alone, then compared ulcer healing times between those two groups. The results showed that the time to ulcer healing was shorter in the early ablation group compared to the compression therapy alone group. This was an important step forward in treating venous leg ulcers, as it suggested that intervention (in this case ablation of superficial venous reflux) to reverse CVI is an important therapy for healing ulcers that supersedes traditional compression therapy alone. Importantly, the EVRA study specifically excluded patients in whom deep venous disease may have played a role as well as ulcers of greater than six months’ duration. It has been identified that deep venous disease may play a significant role in ulcers of longer duration.¹³

Other studies have been conducted that demonstrate the utility of performing an intervention in the deep venous system for improving quality of life, lowering CEAP scores, and even improving ulcer healing.^14–17 In 2020, Lawrence et al. performed a retrospective study comparing different treatment algorithms for patients presenting with chronic venous ulcers and found that patients with DVO treated with stenting had a significant benefit in healing time compared to those treated with compression or superficial ablation alone.¹⁸ Another retrospective study found that over half of patients with venous ulcers had stenotic lesions and once stented, 58% of the ulcers healed even after failing to respond to other therapies.¹⁶

Others have found that C6 patients who received iliac vein angioplasty and stenting healed 100% of their ulcers and significantly lowered their venous clinical severity score (VCSS).¹⁵ These studies provide an important foundation of evidence that suggests that treating underlying deep venous occlusive disease, even after superficial disease has been treated, can improve venous ulcer healing times.

Current State of Imaging/Diagnostics

Imaging modalities used to assess CVD include computed tomography venography (CTV), magnetic resonance venography (MRV), and multi-planar venography (MPV). Whereas MRV is radiation-free, it has a significantly longer acquisition time compared to either CTV or MPV. Conversely, CTV and MPV require less time to perform; however, they expose the patient to radiation. Limitations of MPV include obscured lesions due to contrast stasis within thrombus or obstructive anatomy, decreased visualization in obese patients, exposure to multiple doses of radiation, and the necessity to administer contrast medium. In contrast to arteries, veins are elliptical in most cases and can be dynamic, with intravascular volume and respiratory variation affecting intraluminal pressure and vein morphology. This elliptical shape of large veins accounts for the inaccuracy in the detection and quantification of stenosis with two-dimensional imaging, such as MPV. Raju and colleagues¹⁹ reported that the diagnostic sensitivity of MPV for non-thrombotic iliac vein (NIVL) type lesions are poor, with a third to half of the cases missed if frontal projection venograms alone are used for diagnosis. The NIVL type lesions and post- thrombotic scar (PTS) lesions are the two most common deep venous occlusive lesions underlying non-healing VLUs.

Intravascular ultrasound (IVUS) can also be used to detect and diagnose DVO. IVUS is a catheter-based imaging technology that captures a 360-degree, cross-sectional image providing the precise location of the lesion(s), the size of veins, and important abnormalities such as external compression, residual stenosis, thrombus, spurs, and webbing. This breadth of information facilitates the planning of deep venous therapy²⁰ while limiting exposure to radiation and contrast.²¹ The Philips-sponsored VIDIO (Venogram vs IVUS for Diagnosing Iliac vein Obstruction) trial, which enrolled 100 patients with clinical class C4 to C6 with suspected iliofemoral vein obstruction, demonstrated that IVUS can better characterize venous lesions compared to MPV, and this increased sensitivity resulted in revised treatment plans in 57% of cases.²² Further, a secondary analysis of the VIDIO trial reported that IVUS showed significant usefulness at predicting when stenting in the venous system would result in significant clinical improvement compared to venography alone, which had no predictive value.²³

Unmet Need

Despite the availability of data supporting the interrogation and treatment of deep venous occlusive disease in patients with unhealed venous ulcers, questions remain regarding the effectiveness of this therapy for promoting ulcer healing and decreasing ulcer recurrence rates compared to compression and superficial vein ablation.

As mentioned previously, multiple studies have shown clinical improvement in venous leg ulcer healing following angioplasty and stenting of DVO, but the variability in healing rates leaves uncertainty regarding which patients will benefit from deep vein interventional treatment.

The Philips Intravascular Ultrasound-Guided Intervention for Venous Leg Ulcers (IGuideU) trial is designed to address these concerns. This study aims to determine if patients with VLUs refractory to superficial venous ablation and compression have underlying DVO and if so, whether stenting of these VLUs promotes healing. The IGuideU trial will study the importance of evaluating for occlusive disease within the deep venous system with highly sensitive diagnostic imaging devices, like IVUS, in patients with nonhealing VLUs.

Philips IGuideU Clinical Trial

The Philips IGuideU clinical trial is a prospective, multi-center, randomized controlled trial in which up to 266 patients will be randomized 1:1 to either receive interrogation of the deep venous system (interrogation arm, n=133) or a deferred interrogation (n=133) at up to 30 clinical study sites in the US, UK, Germany, France, and Australia. In the interrogation arm, patients will first be evaluated with MPV followed by IVUS intervention as appropriate, once the prescribed course of treatment based on the MPV results has been documented. The deferred-interrogation arm will include a continuation of standard of care comprising of compression therapy with or without sclerotherapy under the ulcer bed, mechanical debridement, pain management medication (Trental [pentoxifylline]) and/or topical antimicrobials.

The primary objective of this study is to determine whether the interrogation of the deep venous system (iliac-common femoral veins) MPV plus IVUS, with subsequent interventional treatment determined and guided by IVUS, results in improved clinical outcomes when compared to deferred-interrogation of the deep venous system. The secondary objectives are to assess changes in treatment decision parameters made with MPV after further investigation with IVUS and to assess the long-term clinical and economic impact of IVUS-guided interventional treatment for venous leg ulcers compared to the deferred-interrogation group.

Patients are screened and must complete an index procedure visit that includes MPV and IVUS imaging for patients in the interrogation arm. Patients then return to the clinic for follow-up at one, three, six, and 12 months after the baseline visit/index procedure. Follow-up by phone call will occur at 18 and 24 months. The primary clinical endpoint is the difference in complete ulcer healing between the interrogation arm and the deferred-interrogation arm three months after the index procedure. The diagnostic endpoint is a composite of the difference in the detection of DVO and any subsequent changes in treatment plan informed by IVUS compared to MPV. Secondary endpoints include rate of ulcer healing, ulcer recurrence rate, change in the quality of life measured by the EQ-5D and SF-36, change in clinical score assessed using the VCSS and CEAP scoring systems, and medical resource utilization (MRU) and a health economic analysis.

Given the lack of consensus in the treatment of venous ulcers, the design of the IGuideU trial was complex and required consideration of several factors. Some members of the medical and payer communities remain skeptical of the benefit of interrogating the deep venous system in patients with venous leg ulcers. For those who do perform these interventions, there is a lack of consensus on the added benefit of using IVUS to evaluate DVO and to guide subsequent stenting procedures.

To help raise awareness of the benefit of treating DVO utilizing the increased diagnostic sensitivity of IVUS to guide treatment and to demonstrate improved ulcer healing, a randomized controlled trial was needed.

The first patient is expected to be enrolled in the IGuideU trial in early 2021, and the trial is expected to take approximately five years to complete, including a two-year follow-up. If the results of the IGuideU trial are positive, meaning that greater ulcer healing is observed in the interrogation group compared to in the deferred- interrogation group, this would suggest that deep venous disease is a large contributor to the development of venous ulcers and that interventionalists should consider interrogating the deep venous system in all patients with recalcitrant venous ulcers. Additionally, positive results will provide yet another piece of data to demonstrate the relatively poor diagnostic sensitivity and specificity of MPV compared to IVUS for identifying DVO and will emphasize the importance of using IVUS guided intervention and stenting for clinical improvement.

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