Peripheral arterial disease (PAD) remains a critical, independent predictor of coronary artery disease, cerebrovascular disease, and mortality.1 A subset of PAD patients progress toward a malignant form of disease known as critical limb ischemia (CLI).2,3 Vascular specialists and other providers alike cringe when the term ‘CLI’ is used, as the numbers ‘20/50’ come to mind: 20% of patients with CLI die within 6 months, while 50% of patients die within 5 years. MicroMedical is researching how to flatten this curve by changing outcomes at 6 months and beyond.
The goal of CLI treatment is direct: relieve pain, augment wound healing, improve quality of life, and prevent amputation and mortality. Unfortunately, comorbidities such as diabetes, renal failure, tobacco smoking, heart failure, and infection tend to accompany CLI, leading to major amputation and subsequently, increased mortality.
In order to understand the intent behind the pivotal STAND (Clinical Evaluation of the MicroSTent PeripherAl Vascular SteNt in Subjects with Arterial Disease Below the Knee) trial, it is important to comprehend the barriers of clinical success in below-the-knee (BTK) revascularization.
Barriers to Successful BTK Treatment
BTK disease is commonly composed of complex tandem, long-segmented lesions that require complicated revascularization techniques. Currently, there is no U.S. Food and Drug Administration (FDA)-approved stent for primary treatment of BTK disease. Thus, treatment of these complex, diseased vessels has been limited to angioplasty, recent atherectomy, and off-label use of drug-eluting coronary stents in the setting of matched luminal diameter and previously revered drug-coated technology. These treatment modalities, which are sometimes used as bailout options in limb salvage cases, do present challenges.
Despite angioplasty after optimal nominal balloon diameter selection, Baumann et al4 state that up to 97% of cases have a significant amount of vessel recoil in complex BTK lesions, thus only temporizing the luminal gain and inline flow achieved shortly after procedure completion. It is also well established that the microtrauma exhibited by plaque during angioplasty can lead to non-flow and flow-limiting dissections in approximately 20% to 30% of cases.5-7 Dissections often go untreated as many are underreported or missed, especially in the absence of intravascular ultrasound (IVUS). These tend to become a nidus for restenosis or occlusion.5-7
Atherectomy devices, including laser and orbital atherectomy, can decrease plaque burden in tibial vessels. However, their utility can be limited to vessel size compatibility and true lumen use depending upon the debulking method chosen. Even then, these therapies may need adjunctive therapy from percutaneous transluminal angioplasty (PTA) or stenting.
The use of off-label drug-eluting coronary stents BTK has been employed in complex limb salvage cases for years. Historically, size compatibility and drug-eluting technology made this a viable option to improve and maintain inflow in the BTK vessels, with favorable outcomes as demonstrated in the ACHILLES trial, which showed high patency rates at 1 year with balloon-expandable drug-eluting stents in BTK vessels compared to PTA.8 However, in lieu of the recent paclitaxel conundrum set forth in 2018, application of the once-prized chemotherapy agent in the treatment of PAD/CLI must now be evaluated on a case-by-case basis due to the possible increased mortality signal. In addition, due to their intended use, coronary stents are typically short (<4 cm in length) and are typically applied only to the proximal tibial vessels when feasible. Since they are balloon-expandable, these stents tend to have limited flexibility and have less radial strength than self-expanding stents, thus bringing a higher risk of extrinsic compression.
With the present challenges, it is imperative to use evidence-based medicine when forming a treatment algorithm for BTK revascularization. Historically, the BASIL trial simulated equal amputation-free survival at 6 months between patients undergoing PTA versus infrainguinal saphenous vein bypass to an above-the-knee or BTK arterial segment. The BASIL trial proved that an endovascular approach is as efficacious and less expensive than a surgery-first strategy for the treatment of infrainguinal disease in CLI.9
Subsequent studies, such as the meta-analysis by Caradu et al10, demonstrated no significant advantage in off-label use of balloon- expandable bare metal stents versus PTA in patency or wound healing, but highlighted good results with self-expanding stents for PTA bailout. However, no direct comparison was made to PTA in that analysis.
The randomized YUKON-BTX and DESTINY trials have demonstrated higher rates of freedom from target lesion revascularization (TLR) when comparing bare metal and drug-eluting stents BTK, but a clear clinical benefit has yet to be shown.11 There are conflicting conclusions on improvement in Rutherford class, a query on the economic benefit of drug-eluting stents, and no significant difference in major amputations or survival has yet to be demonstrated between bare metal stents and drug-eluting stents.12-14
Thus, in the U.S., use of BTK stenting has traditionally been reserved to combat recoil and dissections in complex CLI cases, especially in patients that are poor surgical bypass candidates.10 Although some of the trials that have led to such employment may have been limited by statistical power and short-term assessments, their findings may also be reflective of the existing technology and comprehension of CLI (from vessel histology to the pathological implications of this systemic disease) at that time, both of which have vastly evolved.
The current BTK revascularization outcomes thus far, in addition to the paclitaxel conundrum, suggests that the challenges in treating BTK disease in CLI have yet to be met. The meta-analysis of Romiti et al15 demonstrated more than 90% of patency failures and amputations occurred within 6 months after endovascular infrapopliteal treatment. This timeline parallels the average wound healing time seen after complex BTK revascularization.16,17 Keeping ‘20/50’ in mind, along with the poor outcomes described throughout this article, the efficacy that can flatten CLI mortality is apparent by 6 months. By establishing primary effectiveness and safety endpoints at 6 months, the STAND trial seeks to break down the barriers that have held us back from successful BTK treatment.
The MicroMedical Solutions MicroStent
The MicroMedical Solutions MicroStent is a self-expanding nitinol stent designed with the intent to treat BTK vessels in CLI and combat the alarming amputation and death rates. With the goal of limb salvage, the stent has been tailored to meet the challenges that come with diseased tibial vessels. The woven nitinol composition makes the scaffold highly conformable without excessive outward force. This is advantageous as it allows for the following:
(1) Precise deployment. The lesion length is matched to the predicted stent length upon deployment based on vessel diameter. With help from the 3 French (Fr) MicroGuide catheter, this ensures reliable and accurate stent selection by the operator and precise delivery.
(2) Optimal stent opposition. The stent adheres to varying eccentric plaque morphologies as seen on IVUS, permitting luminal gain in lesions that normally recoil after angioplasty, for example. Notably, the integrated platinum core provides unequivocal visualization on follow-up intra- and extravascular ultrasound. Outcomes are enhanced with the use of IVUS, considered “best practice” in the ongoing STAND trial. IVUS helps to characterize the lesion in three dimensions, and evaluate flow and optimal stent apposition post deployment.
(3) “Gentle” luminal gain. As excessive chronic outward force between the intima and stent can propagate inflammation promoting in-stent restenosis (ISR),18 especially in small-caliber arteries, this stent's self-expanding scaffold negates elastic recoil with gentle outward radial resistive force to decrease the rates of ISR.
Lastly, the stent comes in varying sizes to treat vessel diameters ranging from 2.5 to 4.5 mm, and lengths from 8 to 60 mm, delivered on the 3 Fr MicroGuide catheter. Catheter delivery lengths are available in 40 cm and 120 cm, permitting retrograde and antegrade deployment. These evolutions in design aim to provide successful long-term outcomes in CLI patients after primary stenting. How does this low-profile, flexible, easy-to-use delivery system translate clinically for our patients?
MicroMedical Solutions MicroStent Feasibility Study
Here we provide a brief overview of the results from the feasibility study performed in 2018. The study consisted of 15 patients of Rutherford classification IV-V with tibial disease. Average lesion length was 40.6 mm (42.7 mm on core lab analysis), with an average of 93% stenosis (74.8% on core lab analysis). One hundred percent technical success (defined as stent full expansion, deployment without deformation, and lesion coverage as intended) was achieved in all cases, based upon independent analysis from a core laboratory. Clinical Events Committee and core lab-adjudicated primary patency was 91.7% at 30 days in device-related analysis. The safety endpoint, a composite of freedom from major adverse limb events (MALE) and freedom from perioperative death at 30 days, was 100%. At 6 months, the gold standard in order to ensure optimal wound healing was 90.9% primary patency and 100% primary safety.
After promising results from the initial cohort, the FDA approved the pivotal STAND trial to evaluate the MicroStent for primary instruction-for-use stenting in tibial vessels. STAND is a randomized, multicenter, clinical study of the MicroStent device versus PTA in up to 177 patients across 25 sites in the United States. Cadaver lab training was provided to operators. The study aims to demonstrate that the MicroStent is superior to PTA alone in achieving and maintaining vessel patency and improved blood flow.
Primary efficacy endpoint: Primary patency at 6 months. Primary patency is a composite of freedom from occlusion, clinically driven TLR, and major amputation.
Primary safety endpoint: Freedom from perioperative death and MALE at 30 days and 6 months, respectively, based on the FDA primary safety endpoint for CLI trials adopted from Conte et al.19
Hypothesis-tested secondary endpoints include the reduction in size of ischemic wounds at 6 months.
As mentioned previously, outcomes success for endovascular treatment of infrapopliteal lesions is largely apparent by 6 months post procedure. The STAND trial’s primary endpoints are 6 months, but long-term follow-up will continue for 3 years.
The STAND trial is in the early enrollment phases with the first patient enrolled in early April 2020. Figure 1 describes this case, which mirrors the high-risk demographic #CLIFighters evaluate and treat to prevent amputation and thus reduce mortality. We look forward to the 30-day follow-up, which is pending at the time of authorship.
As our globe battles the challenges brought forth by COVID-19, enrollment in the STAND trial has been temporarily paused to ensure the safety of physicians and patients. The MicroStent is also under investigation in Europe through the HEAL registry, which began enrollment in October of 2019. The HEAL registry is an open-label, all-comers registry in Italy, Belgium, Germany, Netherlands, and Austria, seeking to characterize the real-world use of the MicroStent, with open inclusion and exclusion criteria. Furthermore, as regards real-world experience, the registry places no parameters on adjunctive therapy, permitting evaluation of the MicroStent in conjunction with additional treatments. The primary effectiveness endpoint is primary patency at 6 months post procedure, as defined by freedom of target lesion occlusion and clinically driven TLR. The safety endpoint is freedom from major adverse limb events. Additional enrollment and analysis are forthcoming.
As our world heals from the impacts of the COVID-19 pandemic and research continues, we remain enthusiastic in our view of how the MicroStent will contribute to the dynamic limb salvage treatment landscape, with its goal of clinically effective change by 6 months. n
Disclosure: Dr. Beasley reports the following disclosures: Speaker/Trainer for Abbott Vascular, BSCI (also, Medical Advisory Board), Cardinal Health/Cordis, Cook Medical, CR BARD/Becton Dickinson (also, Medical Advisory Board), CSI, Endologix, Inari, Medtronic, Micro Medical Solutions, Philips/Volcano/Spectranetics, Penumbra, Terumo/Bolton, WL Gore. Dr. Oliveri reports that he is an unpaid speaker for Penumbra. The remaining authors report no disclosures.
Address for correspondence: Robert E. Beasley, MD, Chief of Vascular and Interventional Radiology and the Director of the Wound Healing Center at Mount Sinai Medical Center in Miami Beach, Florida. Email: email@example.com
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