Novel Injection Methods

Number: 0777

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses novel injection methods.

1. Medical Necessity

   Aetna considers the following interventions medically necessary: 

   1. Suprachoroidal injection (i.e., triamcinolone acetonide injectable suspension [Xipere]) for the treatment of macular edema associated with uveitis when criteria are met in CPB 1000 Triamcinolone Acetonide Injectable Suspension (Xipere);
      
      Aetna considers suprachoroidal injection of all other pharmacologic agents experimental and investigational for all indications because the effectiveness of this approach has not been established.
      
      
   2. Subretinal injection of recombinant tissue plasminogen activator (rtPA) for the treatment of sub-macular hemorrhage.
      

2. Experimental and Investigational

   Aetna considers the Mercator Bullfrog micro-infusion device experimental and investigational for direct adventitial delivery of diagnostic or therapeutic agents via blood vessel walls because there is a lack of evidence regarding its safety and effectiveness.

3. Related Policies

   • CPB 0393 - Vitrectomy
   • CPB 0927 - Voretigene Neparvovec-rzyl (Luxturna) for subretinal injection of gene therapy
   • CPB 1000 Triamcinolone Acetonide Injectable Suspension (Xipere)

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Triamcinolone acetonide injectable suspension [Xipere] :
CPT codes covered if selection criteria are met:
67516	Suprachoroidal space injection of pharmacologic agent (separate procedure)
HCPCS codes covered if selection criteria are met:
J3299	Injection, triamcinolone acetonide (Xipere), 1 mg
ICD-10 codes covered if selection criteria are met:
H35.81	Retinal edema
Suprachoroidal delivery of all other pharmacologic agents:
CPT codes not covered for indications listed in the CPB:
67516	Suprachoroidal space injection of pharmacologic agent (separate procedure)
0699T	Injection, posterior chamber of eye, medication
HCPCS codes not covered for indications listed in the CPB:
C9759	Transcatheter intraoperative blood vessel microinfusion(s) (e.g., intraluminal, vascular wall and/or perivascular) therapy, any vessel, including radiological supervision and interpretation, when performed
Subretinal injection of recombinant tissue plasminogen activator (rtPA):
CPT codes covered if selection criteria are met:
0810T	Subretinal injection of a pharmacologic agent, including vitrectomy and 1 or more retinotomies
HCPCS codes covered if selection criteria are met:
Recombinant tissue plasminogen activator (rtPA)- no specific codes
ICD-10 codes covered if selection criteria are met:
H35.60 - H35.63	Retinal hemorrhage [sub-macular hemorrhage]

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Background

Suprachoroidal Injection of Pharmacologic Agents

Treatment of diseases of the posterior segment of the eye such as choroidal neovascularization presents a major challenge in ophthalmology. The posterior segment of the eye, including the retina, macula, and optic nerve, is difficult to access due to the recessed location within the orbital cavity.

Current drug delivery techniques to access the posterior segment of the eye include intra-vitreal injections, peri-ocular injections (i.e., subconjunctival, subtenon, or juxtascleral), and intra-vitreal implants. Drug delivery by injection into the suprachoroidal space is another technique that has recently been proposed in the treatment of posterior segment disease. The suprachoroidal space provides a potential route of access from the anterior region of the eye to the posterior region.

The iScience Surgical Ophthalmic Microcannula, or iTrack (iScience Surgical Corporation, Menlo Park, CA) is designed to access ocular structures such as schlemm's canal, subretinal space, vitreous cavity, and the suprachoroidal space. The iTrack received 510(k) clearance from the U.S. Food and Drug Administration on June 22, 2004 as a flexible microcannual for atraumatic cannulation of spaces in the eye such as the anterior chamber and posterior segment, for infusion and aspiration of fluids during surgery, including saline and viscoelastics. The microcannula incorporates an optical fiber to allow transmission of light to the microcannula tip for surgical illumination and guidance.

There is inadequate evidence regarding the clinical utility of supracoroidal injection of pharmacologic agents for the treatment of any ophthalmologic condition. Clinical outcome studies published in the peer-reviewed medical literature are needed to determine the value of this drug delivery method in the management of patients with diseases of the posterior segment of the eye.

In a pilot study, Rizzo et al (2012) evaluated the safety, feasibility, and preliminary effectiveness of suprachoroidal drug delivery with a microcatheter for the treatment of severe subfoveal hard exudates (SHE) in retinal vasculopathies. A total of 6 eyes of 6 patients with central or branch retinal vein occlusion or diffuse diabetic macular edema accompanied by massive refractory SHE underwent a single treatment with bevacizumab and triamcinolone administered to the submacular suprachoroidal space via a microcatheter introduced at the pars plana and advanced posteriorly. The main outcome measures included best-corrected visual acuity, vascular leakage, macular thickness, extent of SHE, and complications. Mean follow-up was 12 months; 3 eyes had central retinal vein occlusion, 1 had branch retinal vein occlusion, and 2 had chronic diabetic macular edema. Best-corrected visual acuity improved by greater than or equal to 2 lines in 4 eyes and remained stable in 2 eyes. At 1 month to 2 months post-procedure, SHE was almost completely resolved in all eyes and macular edema was significantly reduced. There were no surgical or post-operative complications. The authors concluded that suprachoroidal infusion of drugs can be effective in reabsorbing massive SHE. The findings of this pilot study needs to be validated by well-designed studies.

Tetz et al (2012) examined the safety and feasibility of using a microcatheter for drug delivery in the suprachoroidal space in eyes with advanced, exudative, age-related macular degeneration (ARMD) unresponsive to conventional therapy. A unique microcatheter was used to deliver a drug combination consisting of bevacizumab and triamcinolone to the submacular suprachoroidal space. A total of 21 eyes of 21 patients with choroidal neovascularization (CNV) secondary to advanced, exudative ARMD were followed over a 6-month post-procedure period. The microcatheter was successfully and atraumatically inserted into the suprachoroidal space of all eyes. No serious intra-operative or postoperative complications including suprachoroidal hemorrhages were encountered. Post-surgically, complications consisted of 1 eye experiencing a transient elevation in intra-ocular pressure at 3 months, which was medically controlled, and 2 eyes (10.5 %) with an apparent increase in nuclear sclerotic cataracts. The authors concluded that suprachoroidal drug administration was achieved without serious complication using a novel microcatheter. They noted that direct drug delivery to the choroid can potentially increase local tissue drug levels and drug effectiveness for the treatment of ARMD and other diseases associated with CNV. These preliminary findings need to be validated by further studies.

Rai and colleagues (2015) stated that the development of safe and convenient drug delivery strategies for treatment of posterior segment eye diseases is challenging. Although intra-vitreal injection has wide acceptance among clinicians, its use is associated with serious side-effects. Recently, the supra-choroidal space (SCS) has attracted the attention of ophthalmologists and pharmaceutical formulators as a potential site for drug administration and delivery to the posterior segment of the eye. These investigators reviewed the major constraints of drug delivery to the posterior eye segment, key anatomical and physiological features of the SCS and drug delivery applications of this route with emphasis on micro-needles along with future perspectives.

Pearce and associates (2015) noted that emerging developments and research for drug delivery to the posterior segment of the eye offer a promising future for the treatment of vitreo-retinal disease. As new technologies enter the market, clinicians should be aware of new indications and ongoing clinical trials. These researchers summarized the advantages and shortcomings of the most commonly used drug delivery methods, including vitreous dynamics, physician sustainability and patient preferences. Currently available, intra-vitreal, corticosteroid-release devices offer surgical and in-office management of retinal vascular disease and posterior uveitis. The SCS offers a new anatomic location for the delivery of lower dose medications directly to the target tissue. Implantable drug reservoirs would potentially allow for less frequent intra-vitreal injections reducing treatment burdens and associated risks. Newer innovations in encapsulated cell technology offer promising results in early clinical trials. The authors concluded that although pars plana intra-vitreal injection remains the mainstay of therapy for many vitreo-retinal diseases, targeted delivery and implantable eluting devices are rapidly demonstrating safety and efficacy. They stated that these therapeutic modalities offer promising options for the vitreo-retinal therapeutic landscape.

Venkatesh and Takkar (2017) noted that the prevalence of myopia and its severe/progressive visually impairing forms is increasing world-while. Most of the preliminary clinical research has focused on rehabilitation and treatment of its complications. Pharmacological prevention of myopic progression has shown encouraging results recently and currently the scleral structure is believed to be responsible for disease progression. These investigators hypothesized injecting a biological cement in the potential space between the choroid and the sclera to halt the progressive elongation of the eye ball while preventing complications related to myopia.

In a prospective cohort study within a randomized, controlled phase-II clinical trial, Willoughby and colleagues (2018) evaluated choroidal and supra-choroidal changes following supra-choroidal injection of triamcinolone acetonide injectable suspension (CLS-TA), in eyes with macular edema due to retinal vein occlusion (RVO). Enhanced depth imaging optical coherence tomography (EDI-OCT) images were analyzed from 38 eyes of 38 treatment-naive patients with macular edema due to RVO, enrolled in the prospective Suprachoroidal Injection of Triamcinolone Acetonide with Intravitreal Aflibercept in Subjects with Macular Edema Due to Retinal Vein Occlusion (TANZANITE) study who received either a supra-choroidal injection of CLS-TA with an intra-vitreal (IVT) injection of aflibercept (combination arm) or only an IVT injection of aflibercept (monotherapy arm), followed by monthly IVT aflibercept injections in both arms based on pro re nata criteria. Macular choroidal thickness measured to the outer choroidal vessel lumen (vascular choroidal thickness, VCT), outer choroid stroma (stromal choroidal thickness, SCT), or inner scleral border (total choroidal thickness, TCT) showed no significant changes over 3 months in both study arms (p = 0.231 to 0.342). Eyes that received combination therapy showed a trend toward thickening of the supra-choroidal space (SCS) compared with monotherapy alone (13.4 μm versus 5.3 μm at 3 months; p = 0.077). In the 15 eyes that showed a visible SCS at baseline, the SCS expanded significantly after supra-choroidal CLS-TA injection (16.2 μm to 27.8 μm at 3 months; p = 0.033). The authors concluded that supra-choroidal injection of CLS-TA did not alter choroidal thickness in eyes with macular edema due to RVO, but may result in expansion of the SCS.

Hartman and Kompella (2018) noted that even though the very thought of an injection into the eye may be frightening, an estimated 6 million IVT injections were made in the U.S. during 2016. With the introduction of new therapeutic agents, this number is expected to increase. In addition, drug products that are injectable in ocular compartments other than the vitreous humor are expected to enter the back of the eye market in the not so distant future. Besides the IVT route, some of the most actively investigated routes of invasive administration to the eye include peri-ocular, sub-retinal, and SC routes. While clinical efficacy is the driving force behind new injectable drug product development for the eye, safety is also being improved with time. In the case of IVT injections, the procedural guidelines have evolved over the years to improve patient comfort and reduce injection-related injury and infection. Similar advances are anticipated for other routes of administration of injectable products to the eye. In addition to procedural improvements, the design of needles, particularly those with smaller diameters, length, and controlled bevel angles are expected to improve overall safety and acceptance of injected ophthalmic drug products. A key development in this area is the introduction of microneedles of a length less than a millimeter that can target the SC space. In the future, needles with smaller diameters and lengths, potentially approaching nano-dimensions, are expected to revolutionize ophthalmic disease management.

Suprachoroidal Corticosteroid for the Treatment of Non-Infectious Uveitis / Chorio-Retinal Diseases

In a phase I/II open-label, clinical trial, Goldstein and colleagues (2016) evaluated the safety, tolerability, and preliminary efficacy of suprachoroidal injection of triamcinolone acetonide (TA) in patients with non-infectious uveitis. A single suprachoroidal injection of 4-mg TA in 100 μl was performed in the study eye of patients with non-infectious intermediate, posterior, or pan-uveitis, and follow-up obtained for 26 weeks. A total of 9 individuals with chronic uveitis were enrolled. There were 38 reported adverse events (AEs); most were mild or moderate in severity. Approximately 50 % the AEs were ocular. The most common AE was reported by 4 subjects who experienced ocular pain at or near the time of the injection. All systemic AEs were unrelated to study drug. No steroid-related increases in intra-ocular pressure (IOP) were observed and no subject required IOP-lowering medication. All 8 efficacy-evaluable subjects had improvements in visual acuity (VA); 4 subjects, who did not need additional therapy, had on average a greater than 2-line improvement in VA through week 26; 3 of 4 had macular edema at baseline, and 2 of 3 had at least a 20 % reduction in macular edema at week 26. The authors concluded that the safety and preliminary efficacy data support further investigations of suprachoroidally administered TA as a therapeutic option for the treatment of non-infectious uveitis.

Habot-Wilner and colleagues (2019) stated that delivery of pharmaceuticals to the posterior segment presents challenges that arise from the anatomy and clearance pharmacokinetics of the eye. Systemic and several local administration options [topical, peri-ocular, IVT and sub-retinal] are in clinical use, each with a unique benefit-to-risk profile shaped by factors including the administered agent, frequency of dosing, achievable pharmaceutical concentrations within posterior segment structures versus elsewhere in the eye or the body, invasiveness of the procedure and the inherent challenges with some administration methods. The use of the SCS, which is the region between the sclera and the choroid, is being explored as a potential approach to target pharmacotherapies to the posterior segment via a minimally invasive injection procedure. Pre-clinical data on agents such as vascular endothelial growth factor (VEGF) inhibitors and triamcinolone acetonide (TA) indicated that administration via suprachoroidal injection resulted in more posterior distribution of the pharmacologic agent, with higher exposure to the sclera, choroid, retinal pigment epithelium cells and retina, and lesser exposure to the anterior segment, than observed with IVT administration. Based in part on these findings, clinical trials have examined the safety and efficacy of suprachoroidal administration of pharmacologic therapies in conditions affecting the posterior segment. Data on a proprietary formulation of TA administered by suprachoroidal injection showed improvement in anatomic and visual outcomes in subjects with non-infectious uveitis, with the potential to mitigate the known risks of cataract and increased IOP associated with the use of intra-ocular corticosteroids. The authors concluded that suprachoroidal administration appeared to be a promising treatment modality and is also in the early stages of investigation for other possible applications, such as injection of anti-glaucoma agents into the anterior SCS for long-lasting control of elevated IOP, and as a mode of delivery for gene- or cell-based therapies for retinal disorders.

Price and colleagues (2020) noted that macular edema (ME) is the most common cause of visual deterioration in non-infectious uveitis (NIU).  The treatment of NIU with associated ME often includes locally or systemic administered corticosteroids, with long-term use limited by significant side effects.  The need for a treatment with an improved safety profile has driven the development of a novel ophthalmic therapy: a proprietary triamcinolone acetonide suspension (CLS-TA) administered in the supra-choroidal (SC) space (XIPERE; Clearside Biomedical, Alpharetta, GA).  Suprachoroidal delivery of corticosteroids allows higher steroid concentration in the posterior segment and decreases the risk of other ocular AEs.  Recent results from the PEACHTREE study, a phase-III clinical trial with 2 SC injections of CLS-TA at 0 and 12 weeks with follow-up lasting 24 weeks, showed the significant improvement in VA and reduction in retinal central subfield thickness (CST), all without increasing the risk of elevated IOP or accelerated cataract progression.

These researchers stated that the studies summarized in this review highlighted the SC injection drug delivery platform and potential niche of CLS-TA in the therapeutic armamentarium for retinal and inflammatory diseases.  The PEACHTREE study demonstrated promising visual and anatomical results in patients with uveitic ME.  It also showed a low risk of IOP elevation and minimal risk of cataract development with a favorable safety profile compared with sham.  These findings compared favorably with the reported literature related to intra-ocular and peri-ocular administration of corticosteroid for uveitic ME.  These investigators stated that basic and translational research is ongoing for additional disease indications that will further leverage the SC drug delivery technology.  Additional studies may provide ophthalmologists a novel therapeutic approach for posterior segment disease, including uveitis and retinal vascular disease conditions in the future.

In a prospective, open-label, multi-center study, Henry and associates (2022) examined the safety of CLS-TA injections in patients with NIU.  A total of 38 patients with NIU, with and without ME were included in this trial.  Treatment consisted of 2 SC injections of 4-mg CLS-TA, 12 weeks apart.  Best-corrected visual acuity (BCVA), AE assessment, ophthalmic examinations and optical coherence tomography (OCT) were conducted every 4 weeks for 24 weeks.  Blood samples were analyzed for plasma TA concentrations.  The main outcome measure was frequency of AEs.  Other endpoints included plasma TA concentrations, change in signs of inflammation, BCVA and retinal CST.  Based on a CST of greater than 300 µm, 20 out of 38 subjects had ME at baseline.  Mean IOP was 13.3 mm Hg at baseline and 15.2 mm Hg at week 24 in the study eye.  A total of 6 (15.8 %) subjects had an IOP rise of greater than 10 mm Hg compared with baseline, in the study eye, and 2 (5.3 %) subjects had IOP  of greater than 30 mm Hg (maximum 34 mm Hg at week 8 and 38 mm Hg at week 20).  Cataract formation AEs were reported in 4 study eyes; 1 of which was deemed treatment-related.  No serious ocular AEs in the study eye occurred in the study.  Quantifiable post-injection TA plasma concentration was less than 1 ng/ml.  Efficacy parameters showed improvement over the 24-week study period.  The authors concluded that suprachoroidally administered CLS-TA was safe and well-tolerated over the 24-week, open-label study in NIU patients with and without ME.

The authors stated that the AZALEA study had several drawbacks, including the small number of subjects (n = 38 patients), the open-label study design and the lack of a control group.  Nevertheless, CLS-TA showed meaningful promise, noted from pre-clinical testing through clinical studies, including AZALEA.  In pre-clinical studies, SC injection of TA demonstrated favorable ocular distribution with greater concentrations in the chorio-retinal tissues than anterior tissues, along with prolonged therapeutic tissue levels.  Furthermore, pre-clinical uveitis models showed the potential benefits of targeted delivery to affected tissue, as SC injection of TA was as effective as intravitreal injection of TA at 1/10th the dose.  This prolonged targeted compartmentalization and pre-clinical efficacy correlated to results from AZALEA and its companion study, PEACHTREE, demonstrating clinically meaningful safety and efficacy manifested by both low IOP and cataract AEs.  These researchers stated that in the future, CLS-TA may represent an additional promising local corticosteroid option for NIU.

Haim and Moisseiev (2021) noted that the SCS, a potential space between the sclera and choroid, is becoming an applicable method to deliver therapeutics to the back of the eye.  In recent years, intensive research in the field has been performed, with new discoveries in different areas of interest, such as imaging, drug delivery methods, pharmacokinetics, pharmacotherapies in pre-clinical and clinical trials and advanced therapies.  The SCS can be visualized via advanced techniques of optical coherence tomography (OCT) in eyes with different pathologies, and even in healthy eyes.  Drugs can be delivered easily and safely via hollow micro-needles fitted to the length of the approximate thickness of the sclera.  SCS injections were found to reach greater baseline concentrations in the target layers compared to IVT injection, while agent clearance was faster with highly aqueous soluble molecules.  Clinical trials with SCS injection of TA were executed with promising findings for patients with NIU, NIU implicated with ME and diabetic ME (DME).  Gene therapy is evolving rapidly with viral and non-viral vectors that were found to be safe and effective in pre-clinical trials.  The authors concluded that it appeared that the SCS is a promising route of drug delivery that will likely become an integral part of the treatment of retinal diseases.

The authors stated that challenges and open issues remain and necessitate more research in the field.  First, the fast clearance of aqueous soluble particles via the SCS deserves the invention and examination of new formulations that extend the time periods in order to enable longer intervals of drug administration.  Second, not all the material injected to the SCS near the limbus flows to the posterior parts -- more studies on better targeting with SCS injection are needed.  Third, clinical trials included small groups, and more clinical trials with larger groups are needed.  Fourth, the TANZANITE clinical trial for treatment of CLS-TA in combination with IVT aflibercept found promising results that were not repeated by subsequent clinical trials; thus, it might be relevant to study the role of SC CLS-TA in retinal vein occlusion again.   Fifth, the current clinical trials were carried out with only 1 agent injected into the SCS (namely CLS-TA), since it has a favorable distribution and clearance profile; and although bevacizumab was found to be cleared fast from the SCS in pre-clinical studies, more studies are needed to find ways to inject anti-VEGF therapies to the SCS efficiently.  Sixth, there is plenty to discover regarding the safety, efficacy, biodegradability, immunity and inflammatory characters of advanced therapy methods for better understanding and applicability of clinical trials.

Suprachoroidal Hyaluronic Acid Hydrogel for the Treatment of Glaucoma

Chae and colleagues (2020) stated that glaucoma is the leading cause of irreversible blindness.  Current treatments use drugs or surgery to reduce IOP.  In this study, a drug-free, non-surgical method is developed that lowers IOP for 4 months without requiring daily patient adherence.  The approach entailed expanding the SC space (SCS) of the rabbit eye with an in situ-forming hydrogel injected using a micro-needle.  These researchers tested the hypothesis that SCS expansion increases the drainage of aqueous humor from the eye via the unconventional pathway; thus, lowering IOP.  SCS injection of a commercial hyaluronic acid (HA) hydrogel reduced the IOP of normotensive rabbits for more than 1 month and an optimized HA hydrogel formulation enables IOP reduction for 4 months.  Safety assessment by clinical ophthalmic examinations indicated the treatment was well-tolerated.  Histopathology showed minor hemorrhage and fibrosis at the injection site.  Further analysis by ultrasound (US) bio-microscopy demonstrated a strong correlation of IOP reduction with SCS expansion.  Outflow facility measurements showed no difference in pressure-dependent outflow by the conventional pathway between treated and untreated eyes, supporting the hypothesis.  The authors concluded that SCS expansion with an in situ-forming hydrogel can enable extended IOP reduction for treating ocular hypertension and glaucoma without drugs or surgery.  These researchers stated that with further research and development in human trials, this drug‐free, non-surgical approach has the potential to be used for the low‐cost treatment of ocular hypertension and glaucoma without the need for daily patient adherence or invasive surgical interventions.

Suprachoroidal CLS-TA plus Intravitreal Aflibercept for the Treatment of Diabetic Macular Edema

In a prospective, controlled, double-masked study, Barakat and colleagues (2021) examined the potential safety, efficacy, and durability advantages of CLS-TA, administered suprachoroidally in conjunction with intravitreal aflibercept compared with aflibercept monotherapy for treatment of DME.  Subjects were treatment-naive DME patients with best-corrected visual acuity (BCVA) of 20 to 70 letters and retinal CST of more than 300 μm; and they were randomized 1:1 to CLS-TA and aflibercept (active) or aflibercept monotherapy (control); and evaluated over 24 weeks.  Subjects in the active group (n = 36) received CLS-TA and aflibercept at baseline and week 12; subjects in the control group (n = 35) received aflibercept at baseline, week 4, week 8, and week 12.  To mask both groups, sham SC and intravitreal injections were utilized.  All patients were eligible to receive aflibercept as needed at weeks 4, 8, 16, and 20 per pre-specified criteria.  Main outcome measure was mean change in BCVA from baseline.  Treatment differences were evaluated with a 2-sided significance level of 0.10.  Mean BCVA changes from baseline to week 24 were not statistically different in the active and control groups (intention-to-treat [ITT] population: +11.4 letters and +13.8 letters [p = 0.288]; per protocol [PP] population: +12.3 letters and +13.5 letters [p = 0.664]; respectively).  Greater improvement in CST was observed in the active versus control group (ITT population: -212.1 μm and -178.6 μm [p = 0.089]; PP population: -226.5 μm and -176.1 μm [p = 0.035]; respectively).  Compared with the control group, eyes in the active group received fewer treatments (scheduled plus as-needed treatments averaging 4.6 versus 2.6, respectively).  No treatment-related serious AEs were observed.  Ocular AEs were low for both arms.  Cataract events, all evaluated as unrelated to treatment, and events of elevated IOP trended higher in the active group.  The authors concluded that CLS-TA administered suprachoroidally in conjunction with intravitreal aflibercept for treatment of DME provided similar visual benefit at 24 weeks' follow-up compared with aflibercept monotherapy, was well-tolerated and demonstrated modest anatomic benefit with potential to reduce treatment burden.  Moreover, these researchers stated that future studies of larger sample sizes and longer durations, possibly with a different regimen, are needed to establish the safety and effectiveness of this approach.

The Mercator Bullfrog Micro-Infusion Device

The Mercator Bullfrog micro-infusion device is a system designed to inject therapeutic agents directly, non-systemically and safely via blood vessel walls into adventitial tissues. The Bullfrog micro-infusion device is tipped with a balloon-sheathed micro-needle, and is compatible with 0.014-inch guide-wires and 5 to 7 French (Fr) introducer sheaths. The closed balloon provides a protective covering for a tiny, perpendicular-oriented injection needle as it is guided safely through the vasculature to target vessels with diameters of 2 to 8 mm. When the desired injection site is reached, the balloon is inflated to 2 atmospheres (ATM) with saline and radio-opaque contrast, securing the system for injection and sliding the micro-needle through the vessel wall. This low pressure inflation does not cause trauma to the vessel wall, unlike standard angioplasty balloons that operate at 8 to 20 ATM. The Bullfrog device has received 510(k) marketing clearance from the Food and Drug Administration (FDA); and it is indicated for use in selective areas of peripheral and coronary vessels for the infusion of diagnostic and therapeutic agents into the vessel wall, peri-vascular area, or intra-luminally. However, there is a lack of evidence regarding the safety and effectiveness of the Mercator Bullfrog micro-infusion device.

Brahmbhatt and Misra (2016) stated that peripheral arterial disease (PAD) affects over 8 million people in the United States alone. Although great strides have been made in reducing the burden of cardiovascular disease, the prevalence of PAD is expected to rise with the age of global population. Peripheral arterial disease is characterized by narrowing of arterial blood vessels, and can be asymptomatic or cause limb-threatening claudication. It has been classically treated with bypass, but these techniques have been supplanted by endovascular therapy. Plain old balloon angioplasty has been successful in helping re-vascularize lesions, but its effect has not been durable because of re-stenosis. This prompted the creation of several technologies aimed at reducing re-stenosis. These advances slowly improved outcomes and the durability of endovascular management. Among the main tools used in current endovascular practice are drug-delivery devices aimed at inhibiting the inflammatory and proliferative pathways that lead to re-stenosis. These researchers examined the current drug-delivery technologies used in the superficial femoral artery (SFA). They stated that the major tools used to prevent stenosis today rely on endothelial drug delivery; however, there is also the possibility of adventitial delivery. This would target the fibroblast migration towards the intima as well as diffuse into the more interior layers. The benefits of peri-vascular drug delivery are the less invasive nature of the procedure leading to less endothelial denudation, stretch trauma and likely less systemic drug effects. Furthermore, this approach would lack complications such as migration, fracture, embolic effects, etc. Several animal studies had examined peri-vascular delivery of a variety of compounds, cells, particles in many methods, nano-spheres, gels, scaffolds, sponges, viral particles etc. There are few in human trials looking at stem cells, gene therapy. Percutaneous delivery of allogeneic endothelial cells has shown promise in a small safety study of 21 patients applied at the SFA after angioplasty and stenting. In another safety study, 20 patients received adventitial delivery of dexamethasone endovascularly through a micro-catheter and micro-needle system. Both of these studies showed promising results during short-term follow-up periods. These studies demonstrated technical feasibility and suggested that adventitial delivery is a promising therapeutic modality.

Subramanian and colleagues (2018) noted that PAD is a cause of significant morbidity and mortality, affecting over 200 million people world-wide. Many exciting technologies have emerged to address the unique challenges endovascular specialists face when treating lesions in this vascular bed. One of the enduring challenges has been re-stenosis after initial intervention. These researchers high-lighted a new technology, direct drug delivery, to address this challenge and exciting prospects. Direct drug delivery constitutes delivering drug directly to the vessel wall through a needle with a micro-infusion catheter. This device has the potential to expand the types of therapies that can be delivered in a targeted fashion and allow endovascular specialists to individualize treatment for patients.

Subretinal Injection of Recombinant Tissue Plasminogen Activator (rtPA) for the Treatment of Sub-Macular Hemorrhage

The American Academy of Ophthalmology (AAO)’s Ophthalmic Pearls on “Management of submacular hemorrhage” (Wong et al, 2018) listed subretinal injection of recombinant tissue plasminogen activator (rtPA) as a therapeutic option for sub-macular hemorrhage.

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References