Trabecular Micro-bypass Stent

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Introduction

Prevalence and Impact

Glaucoma is the second leading cause of blindness in the world. Its current worldwide prevalence in the population aged 40-80 years old is estimated to be 3.54% with the highest incidence in the African and Asian racial groups.[1] Glaucoma is projected to affect 76 million people by 2020. Although glaucoma is a progressive and irreversible disease, treatment can slow down its progression. Cataract and glaucoma frequently co-exist, especially in the elderly population. About 2.7 million cataract surgeries are performed each year, after which patients usually experience intraocular pressure (IOP) reduction.[2]

Background Information

Figure 1. First-generation iStent. The lumen lies proximally within the AC. The self-trephining end lies distally inside Schlemm’s canal. The retention arches ensure secure stability of the device within the canal of Schlemm.

IOP is determined by the inflow and outflow of aqueous fluid into and out of the anterior chamber (AC). A lower IOP deters glaucomatous progression.[3] The function of the aqueous humor is to provide nutrients and hydration to the AC while removing waste products. The aqueous humor is produced by the ciliary body epithelium and flows anteriorly to be drained through the trabecular meshwork (TM). It enters the Schlemm’s canal, passes through the scleral plexuses, and then flows into the episcleral veins.[4] Obstruction of flow leads to accumulation of aqueous humor in the anterior segment, with mechanical pressure transmission onto the vitreous humor and optic nerve.[5]

Figure 2. An illustration of the actual size of a first-generation (Left) and second-generation (Right) iStent devices in comparison to a penny.

The most common culprit in glaucoma is increased resistance at the level of the TM. The TM is a filter-like structure that drains the aqueous humor from the AC. Its 360˚ circumference is divided into segments of high and low flow regions and it is a critical structure in the regulation of aqueous outflow.[6]

Patients who have been medicated for mild-moderate glaucoma and who needed to undergo cataract surgeries were shown to experience reduction in IOP after cataract removal. There has been a number of theories attempting to explain this phenomenon. Phacoemulsification involves the use of ultrasound energy to break down the lens. During the process, phacoemulsification energy and the ensued inflammation likely induces TM ultrastructural changes (stimulating cell division, phagocytosis, glycosaminoglycan deposit and other alterations) that reduce resistance to outflow.[7] Other potential mechanisms might include anterior segment volumetric changes and widening of the angle structures.

Trabecular micro-bypass stents have emerged as a relatively novel technology (first device approved in the US for trabecular bypass) that can yield favorable IOP reduction in eyes with mild-moderate open angle glaucoma undergoing cataract surgery. Currently both procedures are performed simultaneously.

Design

Figure 3. A pre-loaded injector with a first-generation iStent device.

iStent (Glaukos Corp., Laguna Hills, CA) first generation trabecular micro-bypass implant is a snorkel-shaped (Figure 1) device that is surgically embedded through the TM into the Schlemm’s canal. It provides direct passage for aqueous flow from the pressurized AC in glaucomatous eyes through the dysfunctional TM. There are currently two generations of iStents in use.

The first generation iStent was FDA approved in 2012. Its dimensions are 1mm x 0.33mm x 120 microns (Figure 2). It is made of surgical grade nonferromagnetic heparin-coated titanium, featuring three retention arches, promoting stable placement within the TM. The inserter system functions as a preloaded single use inserter with a rotator grip (Figure 3). There are two versions for left and right-handed surgeons. The device features a self-trephining tip that facilitates access into the TM via a sideways sliding technique.

The second generation “iStent Inject” system was FDA approved in 2018. The model is smaller in dimension (Figure 2). It has three sections: the flange which sits in the AC, the thorax which traverses the TM, and the head which sits in the Schlemm’s canal. The head features four outlets that are 50 microns each (Figure 4).

Indications

Figure 4. Second-generation iStent device featuring four 50-microns outlets at the distal end, which is positioned within Schlemm’s canal.

The iStent is FDA approved in the U.S. and is indicated for use in conjunction with cataract surgery for the reduction of IOP in adult patients with mild to moderate open-angle glaucoma treated with topical hypotensive medication. Patients that could benefit from iStent implantation are those with primary open angle glaucoma (POAG), including pigmentary or pseudoexfoliative subtypes.[8] Although some evidence exists on use in patients with traumatic and steroid-induced glaucoma, POAG continues to be the most common approved indication.[9]

Contraindications

iStents are contraindicated in angle-closure with no access to the TM, neovascular glaucoma.[10] In addition it is not recommended or approved for patients with elevated episcleral venous pressure (such as thyroid eye disease and Sturge-Weber syndrome). It is also not studied for use in juvenile or childhood glaucoma, in eyes with chronic inflammatory disease, in patients with abnormal anterior segments, or in aphakic patients.

Clinic Evaluation

In order to determine candidacy for the iStent, a thorough glaucoma evaluation, including gonioscopy, must be performed. Gonioscopy will allow the clinician to assess angle structures and to examine the TM. It will also allow for the detection of peripheral anterior synechiae and rubeosis. The clinician needs to determine how wide the iridocorneal angle is, which has a bearing on whether to perform the iStent insertion before (when the cornea is clearest for most optimal intraoperative visualization) or after phacoemulsification (if the angle has a narrow approach, then it may be preferable to insert the iStent after phacoemulsification as lens removal tends to deepen the angle). Examining the TM for areas of increased pigmentation is important as some evidence suggests the proximity of a collector channel to those areas (anecdotal evidence).

Standard of care evaluations for glaucoma include IOP trends, past/present topical treatments, corneal thickness, and structure-function testing. Optical coherence tomography (OCT) of the optic nerve head and retinal nerve fiber layer provides noninvasive, cross sectional imaging of tissues. These measures, in addition to visual field testing, assist in determining the severity of disease (mild, moderate or severe). These factors have to be considered as the surgeon assesses the necessity and potential benefit of an iStent implantation.

Surgical Technique and Peri-operative Management

Figure 5. Gonioscopic view of an implanted first generation iStent (Red arrow) positioned in Schlemm’s canal with the back end (snorkel) in the anterior chamber.

Micro incisional glaucoma surgery (MIGS) relies on performing surgery through a small incision by utilizing the phacoemulsification incision. The goal is to lower IOP while keeping tissue manipulation to a minimum and thus enhancing the safety of the procedure, leading to a faster visual recovery compared to traditional incisional glaucoma surgeries. The iStent was the first MIGS procedure available to ophthalmologists.

Patients undergoing simultaneous cataract surgery and iStent implantation may be instructed to discontinue any ocular hypotensive medication in order to obtain a baseline washout IOP measurement if the severity of glaucoma allows (wash out period for different medication classifications as follows: one week for carbonic anhydrase inhibitors, two weeks for alpha-2 adrenergic agonists, and four weeks for either beta-blockers or prostaglandins).[11] Standard phacoemulsification is typically performed through a clear corneal (which is preferred over a limbal incision that is more likely to ooze blood making intraoperative gonioscopy more difficult due to blood in the interface between the cornea and the gonioscopy lens).

Key to the successful insertion of the iStent relies on the ability to visualize the AC angle during surgery. It is thus critical that surgeons familiarize themselves with the anatomy of the angle as well as with techniques for successful intraoperative gonioscopy. In the initial phases it is advantageous for surgeons to practice intraoperative gonioscopy skills during routine cataract surgery. As mentioned earlier, preoperative gonioscopy is essential before surgery.

Figure 6. An illustration of a second-generation iStent device implanted within the TM, re-establishing aqueous humor outflow into Schlemm’s canal.

iStent insertion can be performed prior to cataract extraction or after cataract removal. There are advantages and disadvantages to each approach. Performing MIGS prior to phacoemulsification allows for the best intraoperative view secondary to minimal corneal edema. On the other hand, the angle structures maybe more crowded particularly if the cataractous lens is intumescent with a larger volume and is pushing the iris forward. Performing MIGS after cataract extraction has the advantage of enhanced access to the TM due to angle deepening. However, the view maybe compromised by corneal edema.

For optimal intraoperative gonioscopy, the head of the patient has to be tilted away from the surgeon by approximately 30 to 45°. The operating microscope needs to be tilted in the opposite direction towards the surgeon by an equivalent angle. This would allow for the use of a direct gonioscopy lens to visualize the nasal angle.

The angle view has to be maintained throughout the procedure. Should the view be compromised due to patient movements, lens movements, or blood then the procedure should be halted. The surgeon should be mindful to avoid indenting the cornea with the gonioscopy lens as that would compromise visualization. The gonioscopy lens is typically removed from the cornea and the iStent inserter is introduced through the main corneal incision over the pupil. The gonioscopy lens is then reintroduced to the cornea. In the case of the first-generation implant, the TM is approached and engaged with the tip of the implant (at about 10-15° inclination) which is then advanced into the Schlemm’s canal and released (Figure 5). With the second-generation implant, the approach is direct (Figure 6). The protective sleeve is retracted once in the AC and the needle is used to engage the TM perpendicularly and then lightly dimple it before the implant is released. The process is repeated for the second implant.

Post-operative Management

The cataract removal and iStent procedure require topical anesthesia in the majority of patients and is performed as an outpatient surgery. The eye is protected with a shield at night after surgery. Postoperatively restrictions are minimal and include strenuous work or physical labor that may increase intraocular pressure or venous pressure. Additionally, the patient should avoid any activities that may involve foreign contact to the eye such as contact sports and swimming.

After surgery, topical antibiotic and anti-inflammatory (steroid, NSAID) medications are used (some surgeons inject intracameral medications). Depending on the stage of the glaucoma and the individual target IOP for a patient, topical glaucoma therapy maybe reduced or withheld after surgery. In order to determine the efficacy of the surgical intervention, a washed out IOP may be necessary. As such, withholding glaucoma medication(s) may be advantageous if it is safe to do so for an individual patient (for example early glaucoma and/or IOP on target postoperatively). During postoperative follow up the need for topical glaucoma medications is determined based on IOP control and medications maybe resumed or discontinued as needed.

Complications

iStent implantation is considered generally safe. A randomized controlled trial of 240 eyes showed that iStent implantation combined with cataract surgery did not compromise vision for the 2-year study’s duration.[12][13] The most common complications reported post-operatively were malpositioning and obstruction by blood or iris. Management for such complications ranged from observation to stent repositioning/replacement. Of note, the incidence of such events was 3% to 4%. This may vary by surgeon experience, technique and type of implant.

Hyphema can be observed intraoperatively and early postoperatively.[14][15] It is often secondary to blood refluxing through the iStent. It is not regarded as a serious complication (but can hinder the view in surgery and should be cleared with viscoelastic injections before proceeding with the procedure) and can rather be an indication that the distal pathway is patent. The hyphema itself tends to resolve within days-week after the procedure and may affect visual acuity until its resolution.

Recurrent or persistent hyphema might compromise vision. One report has described recurrent hyphema 5 months post-operatively.[16] Gonioscopic examination revealed that the implant was malpositioned, being posteriorly angled toward the vasculature-rich ciliary body. The iStent had to be removed to resolve the hyphema. The stent’s malpositioning has not been a rarely reported complication; Fernandez-Barrientos et al. noted 17.6% cases of malpositioned iStent. Fea et al. similarly reported that 16.7% of their subjects experienced a malpositioned stent.[17][18] None of these patients, however, required another revision procedure.

There currently are no standard guidelines that define malpositioned stents. Confirmatory observations of the stent’s positioning can vary widely with different tools utilized. Gillmann et al. have recently shown that a significantly larger proportion of iStents (45.7%) tend to be completely burrowed within the trabeculum than observed gonioscopically, highlighting the value of anterior segment OCT in exploring the iStent’s location.[19] Adhering to proper technique during insertion will minimize those adverse events.

In rare circumstances, implanted iStents might not be locatable. In these cases, studies have shown that ultrasound biomicroscopy tend to locate the hidden stent more reliably than B-scan ultrasonography or OCT.[20][21]

Outcomes

iStent Implantation with Cataract Surgery

The effect of cataract surgery on IOP reduction is well-studied. Peräsalo et al. reported 3.1 mmHg reduction in IOP 12 months post-phacoemulsification in 182 patients.[22] Mathalone et al. found a mean IOP reduction of 1.5 mmHg and 1.9 mmHg at 12 and 24 months, respectively.[23] They also observed a statistically significant reduction in ocular hypotensive medications at both follow-up time periods. The Ocular Hypertension Treatment Study Group conducted a larger (n=806 eyes), controlled, case series study to further evaluate the impact of cataract surgery on IOP.[24] They reported a statistically significant difference between pre- and post-operative IOP measurements (P < 0.001); the mean decrease in IOP was 4.0 mmHg (95% CI, 3.4-4.7). 39.7% of eyes that underwent surgery experienced ≥ 20% IOP reduction. They observed that the difference in IOP from baseline was still significant at 36 months post-operatively.

As the first MIGS device approved in the US, the IOP lowering effect of iStent implantation with cataract surgery has been extensively studied. Spiegel et al. provided one of the earliest reports.[25] Their study comprised 47 subjects with POAG and IOP above 18 mmHg, medicated with at least one ocular hypotensive medication. At 6 months follow-up, average IOP was reduced by 5.7 mmHg (± 3.8), a 25.4% decrease from baseline (P < 0.001). Such a reduction is greater than values previously reported in the literature for solo phacoemulsification procedure.

In 2011, an investigational device exemption (IDE) trial was conducted to determine the efficacy of solo cataract surgery (control) compared to simultaneous placement of iStent with phacoemulsification in lowering IOP.[26] A total of 116 patients were randomized to the stent arm, while 123 patients participated in the control arm. Patients in both groups presented with mild to moderate glaucoma. The study showed that 61% of the stent group exhibited unmedicated IOP ≤ 21 mmHg at 24 months post-operatively compared to 50% in the control group (P = 0.036). Long-term follow-up displayed similar safety profiles in both groups.

Around the same time, Samuelson et al. conducted a similarly structured (but larger; n=240) randomized controlled trial comprising 29 US investigational sites with a follow-up period of 12 months.[27] Inclusion criteria were primarily a need for cataract surgery with a best corrected visual acuity (BCVA) of 20/40 or worse, mild-moderate open angle glaucoma, and a medicated IOP of ≤ 24 mmHg. Main exclusion criteria were the presence of severe glaucomatous field defects, prior glaucoma surgeries other than iridectomy, monocular subjects, and glaucoma of other etiologies than primary open-angle. With both groups unmedicated at 12 months, 72% of patients who underwent iStent displayed IOP ≤ 21 mmHg compared to 50% in the cataract-only group (P < 0.001). A secondary efficacy outcome of the study was the proportion of patients with ≥ 20% IOP reduction at one year without ocular hypotensive medications. The difference between both groups’ outcomes was still statistically significant (P= 0.003) with 66% of the iStent group achieving the outcome, compared to 48% in the cataract-only group.

The iStent phacoemulsification approach has not only shown more favorable IOP outcomes (than cataract surgery alone) but also lead to a significant reduction in the number of hypotensive medications used in the long run. An Italian study of 36 patients with follow-up at 1 day,[28] 1 week, and 1, 2, 3, 6, 9, 12, and 15 months post-operatively. At 15 months, the mean IOP for the iStent phacoemulsification group was 14.8 ± 1.2 mmHg, while that for the phacoemulsification group was 15.7 ± 1.1 mmHg (P= 0.031). By 15 months, the average numbers of ocular medications for the combined surgery and control groups were 0.4±0.7 and 1.9±1.0, respectively (P= 0.007). The reduction in IOP and number of glaucoma medications was reproduced in another smaller long term study (53 months) after combined phacoemulsification/iStent implant procedure.[29]

A meta-analysis comprised of 17 studies (n=2495) showed that both solo phacoemulsification and combined iStent/cataract surgery displayed significant decrease in IOP and long-term number of medications used.[30] The combined surgery approach led to a statistically greater reduction in IOP than the cataract-only surgery. Solo cataract surgery caused an average decrease of 4% in IOP, the addition of the iStent produced a 9% reduction. The addition of a second iStent (still with phacoemulsification) reduced IOP by a mean of 27%.

iStent Implantation as a Solo Surgery

Standalone iStent implantation has been studied in case series of patients with POAG who underwent only first generation iStent implantation (without cataract extraction) with a 24% IOP reduction from a baseline average IOP of 20.2 mmHg (± 6.3).[31] Another case series confirmed the results and reported 27.3% reduction 12 months post-operatively.[32]

Ahmed et al. included 39 phakic eyes with POAG in a non-randomized study to explore the efficacy of simultaneous implanting of 2 iStents.[33] All subjects were on two IOP medications before surgery. With an average baseline IOP of 22.2 mmHg, one month and 12 months assessments showed IOP reduction to a mean of 14.0 mmHg (± 2.2) mmHg and 13.0 mmHg (± 2.4), respectively; all patients showed IOP <18 mmHg by one year.

Fea et al. investigated whether Solo iStent placement yielded more favorable glaucoma management on the long run than chronic hypotensive medications.[34] They conducted a multicenter, randomized study at eight European investigational sites (Italy, Spain, Poland, Germany, United Kingdom, and Armenia; n=192). The trial compared the stent group to a matched group of patients treated with a prostaglandin/beta-blocker combination. The study’s primary efficacy measure was the percentage of subjects achieving IOP reduction of ≥ 20% at one-year. 94.7% of the unmedicated eyes in the stent group achieved the primary efficacy measure, compared to 91.8% in the medicated group, which was not statistically significant. An analysis of a subset of patients who achieved ≥ 50% decrease in IOP, however, revealed a statistically significant difference of 17.5% in favor of the stent group (P=0.02).

Another similarly structured long term clinical trial investigated the 5-year efficacy and safety of 2 stents implantation in comparison to a matched group of patients medicated with once daily topical prostaglandin.[35] The study incorporated 101 phakic eyes diagnosed with POAG who were randomly assigned to each treatment arm. At the conclusion of the study the mean diurnal IOP was similarly reduced in both groups (35.3% [iStent] and 35.1% [prostaglandin]). 17% of the stent implanted eyes had required additional medication to control IOP by 5 years, compared to 44% in the prostaglandin-treated eyes (P=0.017). Whereas 77% of the stent group maintained an IOP of 6-18 mmHg at the study’s conclusion without additional medications, only 54% from the prostaglandin-treated group did (P= 0.04). Both groups displayed comparably favorable safety profiles.

Another study examined the efficacy of adding a third iStent as standalone surgery.[36] Subjects received one, two, or three iStents, with 30 patients in each group. The single iStent group experienced 31% IOP reduction at 6 months post-operatively. On the other hand, both groups that received two or three iStents exhibited an identical 41% IOP reduction.

A meta-analysis comprised of 248 subjects examined five studies, one of which explored the efficacy of three iStents implantation.[37] The study concluded that there were significant reductions in IOP with 1, 2, or 3 iStents. Analysis revealed 22% weighted mean IOP reduction after the implantation of a single iStent at 18 months. Evaluation at the end of the same time period showed 30% and 41% decrease in IOP with 2 implants and 3 implants, respectively.

Cost-Efficacy of MIGS vs Topical Treatment

The iStent has been studied from a cost-efficacy stand point as a long-term solution for IOP control compared to topical treatment. Surgical treatments like iStent implantation circumvent some of the non-adherence challenges in patients on chronic medical treatment. In addition, the iStent effects on cost of therapy and quality of life measures by reducing chronic dependency on topical drops has been studied.

One study looked at a comparative cost analysis between iStent implantation and topical medical treatment in Canada.[38] The study was performed over a 15-year horizon on patients with mild to moderate POAG (83% and 17% respectively). Direct medical costs such as ophthalmology visits and diagnostic exams as well as indirect costs such as transportation and nursing care were considered. The cost of drops was calculated using the Ontario Drug Benefit Formulary for all existing glaucoma medications (taking into consideration waste, dispensing fees, and predicted markup value). It was found that over the study’s time frame, the iStent led to healthcare costs totaling C$9,394.1, compared to C$12,302.4 in matched patients treated with medications alone.

Data were also measured in incremental cost-utility ratio (difference in costs of treatment divided by difference in quality-adjusted life-years [QALY]) for iStent and Cataract extraction vs. Cataract surgery alone (control). Results showed that over a 15-year period, iStent showed a higher QALY score compared to the control group. Using a probabilistic analysis, it was concluded that iStent with cataract surgery would promote more savings and increase the QALY score and was an economically favorable treatment.

A similar study was performed to compare three types of treatments: iStent, laser trabeculoplasty, and topical combination medications (timolol/dorzolamide/brimonidine, timolol/dorzolamide/latanoprost, and timolol/dorzolamide/bimatoprost) in a Colombian healthcare payer system.[39] The analysis was done over a lifetime horizon with a patient baseline age of 40 years. Patients in this study had glaucoma stages ranging from mild to severe. The analysis of QALYs related to economic cost and loss of visual acuity was measured. It was shown that over a lifetime horizon, the iStent was expected to have a the most discounted QALY score followed by topical treatment then laser trabeculoplasty. Over a 40-year period across the study population, the iStent was $13,252,318 lower than the cost of laser trabeculoplasty and $6,403,534 lower than that of timolol/dorzolamide/brimonidine, $22,311,064 lower than that of timolol/dorzolamide/latanoprost, and $29,156,113 lower than that of timolol/dorzolamide/bimatoprost. The study concluded iStent was cost effective for preventing disease progression and increasing savings.

Future Direction

Pipeline trabecular micro-bypass products are expected in the coming years. The third-generation implant is planned to be a stand-alone iStent that does not require combined cataract surgery. Its predicted release date is approximately 2022-2023. Future technology also includes the iStent infinite which includes more than 2 implants and is geared towards patients with more advanced glaucoma.

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