Novel Glaucoma Procedures

Transcription

1 Ophthalmic Technology Assessment Novel Glaucoma Procedures A Report by the American Academy of Ophthalmology Brian A. Francis, MD, 1 Kuldev Singh, MD, MPH, 2 Shan C. Lin, MD, 3 Elizabeth Hodapp, MD, 4 Henry D. Jampel, MD, MHS, 5 John R. Samples, MD, 6 Scott D. Smith, MD, MPH 7 Objective: To review the published literature and summarize clinically relevant information about novel, or emerging, surgical techniques for the treatment of open-angle glaucoma and to describe the devices and procedures in proper context of the appropriate patient population, theoretic effects, advantages, and disadvantages. Design: Devices and procedures that have US Food and Drug Administration clearance or are currently in phase clinical trials in the United States are included: the Fugo blade (Medisurg Ltd., Norristown, PA), Ex-PRESS mini glaucoma shunt (Alcon, Inc., Hunenberg, Switzerland), SOLX Gold Shunt (SOLX Ltd., Boston, MA), excimer laser trabeculotomy (AIDA, Glautec AG, Nurnberg, Germany), canaloplasty (iscience Interventional Corp., Menlo Park, CA), trabeculotomy by internal approach (Trabectome, NeoMedix, Inc., Tustin, CA), and trabecular micro-bypass stent (istent, Glaukos Corporation, Laguna Hills, CA). Methods: Literature searches of the PubMed and the Cochrane Library databases were conducted up to October 2009 with no date or language restrictions. Main Outcome Measures: These searches retrieved 192 citations, of which 23 were deemed topically relevant and rated for quality of evidence by the panel methodologist. All studies but one, which was rated as level II evidence, were rated as level evidence. Results: All of the devices studied showed a statistically significant reduction in intraocular pressure and, in some cases, glaucoma medication use. The success and failure definitions varied among studies, as did the calculated rates. Various types and rates of complications were reported depending on the surgical technique. On the basis of the review of the literature and mechanism of action, the authors also summarized theoretic advantages and disadvantages of each surgery. Conclusions: The novel glaucoma surgeries studied all show some promise as alternative treatments to lower intraocular pressure in the treatment of open-angle glaucoma. It is not possible to conclude whether these novel procedures are superior, equal to, or inferior to surgery such as trabeculectomy or to one another. The studies provide the basis for future comparative or randomized trials of existing glaucoma surgical techniques and other novel procedures. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2011;118: by the American Academy of Ophthalmology. The American Academy of Ophthalmology prepares Ophthalmic Technology Assessments to evaluate new and existing procedures, drugs, and diagnostic and screening tests. The goal of an Ophthalmic Technology Assessment is to systematically review the available research for clinical efficacy, effectiveness, and safety. After review by members of the Ophthalmic Technology Assessment Committee, other Academy committees, relevant subspecialty societies, and legal counsel, assessments are submitted to the Academy s Board of Trustees for consideration as official Academy statements. The purpose of this assessment is to provide an evidencebased summary of clinically relevant information about novel, or emerging, surgical devices and procedures for glaucoma. Devices that have US Food and Drug Administration clearance or are currently in phase clinical trials in the United States were included: the Fugo blade (Medisurg Ltd., Norristown, PA), Ex-PRESS mini glaucoma shunt (Alcon, Inc., Hunenberg, Switzerland), SOLX Gold Shunt (SOLX Ltd., Boston, MA), excimer laser trabeculotomy (ELT; AIDA, Glautec AG, Nurnberg, Germany), canaloplasty (iscience Interventional Corp., Menlo Park, CA), trabeculotomy by internal approach with the Trabectome (NeoMedix, Inc., Tustin, CA), and trabecular microbypass stent (istent, Glaukos Corporation, Laguna Hills, CA). If available, publications of proof of concept or in vitro evidence were also included. Materials and Methods Glaucoma surgical procedures for lowering intraocular pressure (IOP) can be divided into 2 main categories: outflow surgeries by the American Academy of Ophthalmology ISSN /11/$ see front matter Published by Elsevier Inc. doi: /j.ophtha

2 Francis et al Ophthalmic Technology Assessment scleral window approximately 1 mm 2 overlying the pars plicata (Fig 1). A smaller tip ( 100 m) is then inserted through this scleral window and used to create an opening through the pars plicata into the posterior chamber, thereby creating a posterior chamber filter. The procedure is designed to create external filtration of aqueous from the posterior chamber to the subconjunctival space. The theoretic advantages of the procedure are the posterior route of aqueous filtration, lack of use of antifibrotic agents, low relative cost, and shorter surgery time relative to trabeculectomy. The disadvantages are that it is an external filtration procedure with bleb formation, risk of overfiltration, and hypotony. Figure 1. Transciliary filtration with the Fugo blade (Medisurg Ltd., Norristown, PA). Note the scleral opening and the smaller opening through ciliary body into the posterior chamber. Aqueous flows from the posterior chamber through these openings into an external conjunctival bleb. Illustration by Brian A. Francis, MD. designed to increase the egress of aqueous humor from the eye and inflow surgeries designed to decrease the production of aqueous in the eye. The first category, outflow procedures, includes the most frequently performed operations: trabeculectomy, aqueous shunts, and their variations. This category can be subdivided into procedures designed to do the following: (1) increase outflow by creating a new outflow channel (Ex-PRESS glaucoma implant and Fugo blade transciliary filtration); (2) augment the conventional (trabecular) outflow pathway (Fugo blade goniotomy, Trabectome, canaloplasty, ELT, and trabecular micro-bypass stent); or (3) increase uveoscleral outflow (SOLX Gold Shunt). The therapeutic goal of the first subgroup should be to equal or surpass the efficacy and safety of the current standard, trabeculectomy with antifibrotic agents, with a lower complication rate. The second and third subgroups include procedures designed to increase aqueous humor outflow without the formation of an external filtering bleb. The goal in these latter 2 groups is to lower IOP and decrease dependence on glaucoma medications while eliminating complications associated with external filtration. These complications include hypotony and its sequelae, as well as bleb-related problems such as bleb infection, endophthalmitis, and ocular discomfort. Thus, the second and third groups are generally not held to the same standard of lowering IOP as external filtration (i.e., trabeculectomy with antifibrotic agents). A description of these procedures and devices and an explanation of their desired effect and the available literature on clinical efficacy follow. Fugo Blade Transciliary Filtration The Fugo blade is an electrosurgical device that produces noncauterizing hemostasis and precise tissue cutting while minimally affecting the adjacent tissue and sterilizing the wall of the incision. (Information provided by Medisurg Ltd. and R. Fugo.) The blunt instrument produces a microscopic plasma cloud around a filament that dissolves the molecular bonds of the target tissue when activated. The instrument has several uses in ophthalmology, including treatment applications for cataract surgery (capsulorrhexis and pupillary membrane removal), pediatric eye disease, and glaucoma. In transciliary filtration with the Fugo blade, a conjunctival flap is made, and the 600- m tip is then used to create a full-thickness Fugo Blade Goniotomy Goniotomy ab interno with the Fugo blade is designed to create an opening directly from the anterior chamber into Schlemm s canal by removing segments of the trabecular meshwork (TM) (Fig 2). A limbal corneal incision is made, and an ophthalmic viscosurgical device (OVD) is injected into the anterior chamber. Under visualization with a 4-mirror goniolens, the 100- m Fugo blade tip is advanced across the anterior chamber and used to create 4 goniotomies approximately 0.3 mm deep and 0.6 mm wide. The probe is withdrawn, and the OVD is flushed out of the anterior chamber. The theoretic advantages of goniotomy with the Fugo blade are its internal filtration without the formation of an external bleb, the consequent lower risk of hypotony, the short surgical time, and the sparing of conjunctiva. The disadvantages include the fact that control of depth of ablation is not known, fibrosis over the opening is possible, and lowering of IOP is limited by episcleral venous pressure. Ex-PRESS Glaucoma Implant The Ex-PRESS mini glaucoma shunt is a miniature stainless steel shunt developed for use as an alternative procedure to trabeculectomy (Fig 3). The device comes in several models, including the R-50, P-50, and P-200. It is a nonvalved, flow-restricting implant with a 400- m (27-gauge) external diameter, a 50- m inner diameter (or 200 m in the P-200), and a rounded and beveled tip. A spur projection on the posterior surface prevents extrusion of the device from the eye, and a disc-like flange at the distal end Figure 2. Fugo blade goniotomy: An opening is made through the trabecular meshwork connecting the anterior chamber to Schlemm s canal. Illustration by Brian A. Francis, MD. 1467

3 Ophthalmology Volume 118, Number 7, July 2011 Figure 3. ExPRESS glaucoma implant (Alcon, Inc., Hunenberg, Switzerland): The metal shunt is placed in the angle, creating a pathway for aqueous to drain to the limbal conjunctival space to form a bleb. The device is now typically placed underneath a scleral flap. Illustration by Brian A. Francis, MD. prevents it from migrating into the anterior chamber. The P models have a cut-out channel from the external opening posteriorly to facilitate flow in this direction. Originally, the Ex-PRESS shunt was implanted near the corneal limbus underneath the conjunctiva, but because of cases of extrusion, it is now implanted beneath a scleral flap. The procedure is similar to a standard trabeculectomy. A fornix- or limbus-based conjunctival flap is made to expose the perilimbal area. A partial-thickness scleral flap is dissected, and an incision is made using a 25- to 27-gauge needle or sapphire/ diamond blade to enter the anterior chamber just anterior to and parallel to the iris. The implant is inserted through the opening by a preloaded introducer. The scleral flap is then sutured partially closed to allow some drainage of aqueous, and Tenon s capsule and conjunctiva are closed. After implantation, the device immediately begins to function, shunting aqueous humor from the anterior chamber to the subconjunctival space like a trabeculectomy and resulting in the formation of a conjunctival filtering bleb. The use of adjunctive agents, such as mitomycin-c (MMC) and 5-fluorouracil (5-FU), is similar to the use in trabeculectomy. The theoretic advantages of the procedure include a lower risk of hypotony and a shallow anterior chamber compared with trabeculectomy, with more uniform filtration control because of the flow restriction of the internal lumen. No peripheral iridectomy is performed, which may reduce inflammation. Disadvantages include the necessity of a filtration bleb and antifibrotic use, and fibrosis over the opening is possible. There are also possible device-related complications, such as exposure and trauma to internal ocular structures such as the corneal endothelium or iris. SOLX Gold Shunt The SOLX Gold Shunt (GMS) is designed to shunt aqueous from the anterior chamber to the suprachoroidal space for eventual drainage via the uveoscleral outflow pathway (Fig 4). This procedure takes advantage of a presumed pressure differential of 1 to 5 mmhg between these 2 spaces, resulting in unidirectional flow from the anterior chamber to the suprachoroidal space if the 2 are connected. The GMS is a nonvalved flat-plate drainage device made of 24-karat medical-grade gold. It is a rectangle 3.2 mm wide, 5.2 mm long, and 44 m thick. It is constructed of 2 plates welded together and has 2 rounded projections on the distal end for anchoring the device in the suprachoroidal space. The gently curved proximal end projects into the anterior chamber. Contained within the plates are 19 tubules (10 closed and 9 open) with a lumen width of 24 m and height of 50 m. The anterior side contains 60 holes that are 100 m in diameter and one 300- m hole through both plates to allow flow into the device. The posterior end of the shunt contains 117 holes, which are 110 m in diameter, to allow flow of fluid out of the device. A fornix-based conjunctival flap is made, and a 4-mm fullthickness scleral incision 2 mm posterior to the limbus is created to expose the supraciliary space. An anterior chamber maintainer is positioned, and the anterior chamber is entered at a depth of 90% scleral thickness using a crescent blade. The dissection is then carried out posteriorly into the supraciliary space for 2 to 3 mm. The anterior end of the GMS is introduced into the anterior chamber, and the posterior aspect is placed into the suprachoroidal space so that 1 to 1.5 mm of the device is present in the anterior chamber. The scleral incision is closed with 10-0 nylon sutures, and the conjunctiva is closed at the limbus. The theoretic advantages of the GMS are that it uses a novel aqueous outflow pathway without an external filtering bleb, and the risk of hypotony is low. Its disadvantages are the presence of a permanent implant in the anterior chamber and suprachoroidal space with the risk of erosion or exposure, and that the mechanism of action is not well delineated. Excimer Laser Trabeculotomy Ab interno ELT is designed to create several small holes in the TM and inner wall of Schlemm s canal to provide a direct pathway for aqueous humor to access the canal and the outflow collector channels (Fig 5). The energy is delivered using a quartz fiberoptic probe connected to a xenon chloride (XeCl) excimer laser (AIDA, Glautec AG, Nurnberg, Germany). This is a pulsed laser with a duration of 80 ns and a wavelength of 308 nm, delivering mean energy of 1.2 mj per pulse at a rate of 20 Hz. The quartz probe is mounted in a stainless-steel casing with an external diameter of 500 m. The probe tip is bevelled at 65 degrees to aid in placement against the angle. The eye is filled with an OVD, and the probe is advanced across the anterior chamber and placed in contact with the TM via gonioscopic or endoscopic guidance. Eight to 10 laser punctures Figure 4. SOLX Gold Shunt (SOLX Ltd., Boston, MA): The device is placed in the suprachoroidal space with the anterior aspect in the anterior chamber. Aqueous humor is shunted from the anterior chamber to the suprachoroidal space, presumably exiting via the uveoscleral pathway. Illustration by Brian A. Francis, MD. 1468

4 Francis et al Ophthalmic Technology Assessment Figure 5. Excimer laser trabeculotomy: The excimer laser probe is shown here ablating a hole through trabecular meshwork, thus creating a pathway for aqueous to enter directly into Schlemm s canal. Note the previously made ablation areas along the angle. Illustration by Brian A. Francis, MD. are evenly spaced over 90 degrees. During the laser ablation, whitening of the TM and bubble formation is visible. This is typically followed by some blood reflux from the laser opening, signifying that Schlemm s canal has been accessed. At the end of the procedure, the probe is withdrawn and the OVD is removed. The eye is pressurized to approximately 15 mmhg to decrease the amount of blood that enters the anterior chamber. The theoretic advantages of ELT are its internal approach, which spares the conjunctiva, the controlled ablation of TM without heat damage, the short operating time, and the ease of combination with phacoemulsification cataract extraction. Its theoretic disadvantages are that the multiple small openings may be more prone to closure than a larger opening, there is no circumferential flow in Schlemm s canal (thus limiting efficacy if the holes are not near a collector channel), and reduction of IOP is limited by Schlemm s canal resistance and episcleral venous pressure. Canaloplasty The canaloplasty procedure was designed to enhance the outflow of aqueous humor by dilating Schlemm s canal, establishing circumferential flow, and stretching out the TM (Fig 6). Conceptually, it is an extension of viscocanalostomy with the addition of catheter-aided dilation, the placement of a permanent suture under tension in Schlemm s canal, and the creation of an intrascleral reservoir. After creating a conjunctival flap, a parabolic scleral flap of approximately half-scleral thickness and 5 mm in width and length is constructed. A deep flap is then made within the margins of the superficial flap and dissected down to a depth just superficial to the ciliary body. This is advanced anteriorly until Schlemm s canal is exposed, or unroofed. The flap is carried further anteriorly to expose a small segment of Descemet s membrane to create a trabeculo-descemetic window. The exposed cut ends of Schlemm s canal are then identified to allow the introduction of the flexible microcatheter. The catheter is 250 m in diameter at the tip with a shaft diameter of 200 m. Its lumen allows the injection of an OVD to inflate the canal. The device also contains an optical fiber with a lighted beacon at the tip to indicate the course of the catheter. The microcatheter is advanced into Schlemm s canal and followed with the aid of this beacon until it has progressed 360 degrees and exits from the other ostium. One or two 10-0 polypropylene sutures are then tied to the distal end, and the microcatheter is withdrawn in the opposite direction from which it was introduced, thereby threading the sutures through Schlemm s canal. The deep scleral flap is removed to create a scleral lake, and the ends of the suture are tied with enough tension to distend the TM inside the eye. The superficial scleral flap is then tied tightly. A high-resolution ultrasound biomicroscopy system (iultrasound, iscience Interventional, Menlo Park, CA) may be used intraoperatively to assess the dilation of Schlemm s canal and verify suture placement and tension. The theoretic advantages of canaloplasty include the circumferential treatment of Schlemm s canal, the use of fiberoptics to confirm placement, the use of ultrasound biomicroscopy to confirm suture tension, and the ability to convert to trabeculectomy intraoperatively if needed. The possible disadvantages are the external dissection, which is more difficult and time-consuming than other angle-based procedures, and the conjunctival scarring that may increase the risk of failure of a subsequent trabeculectomy. Other potential risks are related to the use of antifibrotic agents by some surgeons and bleb formation in a minority of patients. The procedure does not provide a direct access to collector channels and the reduction of IOP is limited by Schlemm s canal resistance and episcleral venous pressure. In addition, the long-term effects of a foreign body in Schlemm s canal are not known. Trabectome Trabeculotomy by an internal approach with the Trabectome system is used to remove a strip of TM and inner wall of Schlemm s canal to create a direct pathway for aqueous humor outflow from the anterior chamber to the collector channels in Schlemm s canal (Fig 7). The Trabectome consists of a disposable handpiece connected to a console with irrigation and aspiration, as well as an electrocautery generator. The handpiece is a 19.5-gauge instrument with a tip that incorporates an insulated footplate that is pointed for ease of insertion through the TM into Schlemm s canal. The target tissue is vaporized using bursts of high-frequency electrocautery. An aspiration port is located adjacent to the cautery electrode, and an irrigation port is located more distal to the surgical site to keep the anterior chamber formed and to dissipate heat. The device is controlled by a foot pedal with stepwise activation of irrigation, aspiration, and cautery. Figure 6. Canaloplasty: A deep sclerectomy is made under a superficial scleral flap to expose Schlemm s canal externally. The canal is cannulated with a fiberoptic probe, and a Prolene suture (Ethicon Inc., Somerville, NJ) is tied there to place the trabecular meshwork under tension. Illustration by Brian A. Francis, MD. 1469

5 Ophthalmology Volume 118, Number 7, July 2011 Figure 7. Trabectome (NeoMedix, Inc., Tustin, CA) (trabeculotomy internal approach): The Trabectome handpiece is used to ablate a strip of trabecular meshwork, thus creating a pathway for aqueous to directly enter Schlemm s canal. Illustration by Brian A. Francis, MD. In preparation for the procedure, the head and microscope are positioned to give a gonioscopic view of the angle. A 1.7-mm keratome is used to make a peripheral temporal corneal incision. An OVD is variably used to form the anterior chamber. The Trabectome handpiece is inserted and advanced nasally across the anterior chamber with the infusion on. A surgical gonioscopy lens is used to visualize the nasal TM as the instrument tip approaches the angle. The pointed tip of the footplate is inserted through the TM into Schlemm s canal, and a footswitch activates the aspiration and electrosurgical elements. The surgeon advances the instrument along the meshwork in the counterclockwise or clockwise direction using the limbal corneal incision as a fulcrum. The initial power setting of 0.7W to 0.8W is titrated up or down, depending on the desire to ablate a wider strip of TM or by charring of tissue, respectively. Aspiration of the OVD is performed with a Simcoe handpiece connected to the device tubing, and the incision may be closed with a 10-0 suture. Histopathologic analysis has been performed to confirm the ability of the Trabectome device to remove the target tissue and to compare it with simulated goniotomy. 1 Treated areas have been examined by confocal microscopy in 20 donor human corneoscleral rims that underwent treatment with a Trabectome device and 2 specimens that received goniotomy. All samples that underwent ablation at power greater than 0.7W (except 1 sample at 1.0W) showed disruption of the TM with separation of the severed ends. There was no evidence of thermal damage in any of the tissue samples deep to the TM or in the surrounding tissues. Coagulation was visible in 10 of 20 samples treated, which frequently affected the anterior TM more than the posterior TM. The theoretic advantages of the procedure are that it opens a large pathway for aqueous outflow from the anterior chamber to the collector channels with minimal heat damage or trauma to adjacent structures. The procedure spares the conjunctiva, and there is no bleb formation. It is also well suited for performance at the time of cataract surgery. The possible disadvantages are the lack of circumferential flow in Schlemm s canal (limiting outflow to the collector channels exposed by the area of treatment), the possibility of cleft closure, and the limitation of IOP reduction by episcleral venous pressure and Schlemm s canal resistance. Trabecular Micro-bypass Stent The trabecular micro-bypass stent is designed to create a permanent opening from the anterior chamber into Schlemm s canal (Fig 8). The Glaukos Trabecular Micro-Bypass Stent, also known as the istent, was designed to fit into and remain within Schlemm s canal. It is made of nonferromagnetic titanium and consists of an inlet (or snorkel ) end connected at a right angle to the implantation portion, which has a pointed end to facilitate entry into the canal and opens up to a half cylinder at the distal end to prevent blockage or fibrosis over the tip. The patient is positioned with the head and microscope tilted to provide a gonioscopic view of the angle. A 3-mm temporal corneal incision is made, the implant and applicator tip are rinsed with a balanced salt solution, and the anterior chamber is filled with an OVD. The surgical goniolens is placed on the cornea, and the applicator is inserted into the anterior chamber and advanced across to the nasal angle. The distal pointed tip of the device is used to perforate the TM and slides into the canal. The device is released by pushing a button on the applicator, and the tip of the applicator is used to gently push the device to ensure that it is seated within the canal with the snorkel tip parallel to the iris plane. The OVD is then removed with irrigation and aspiration, and the anterior chamber is reformed with balanced salt solution. Zhou and Smedley 2 explored the theory behind trabecular bypass using mathematic equations to calculate the expected effect on the outflow facility and IOP. They describe the reduction in IOP and outflow through TM, and the increase in outflow facility that would accompany a bidirectional trabecular bypass. Bahler et al 3 tested the device in cultured human anterior segments to determine in vitro reduction in IOP. The anterior segments from 21 cadaver eyes were placed in a perfusion culture and implanted with 1 to 4 stents. Mean IOP was decreased from a baseline of mmhg to mmhg after implantation of 1 stent and to mmhg after implantation of more than 1 stent. The authors concluded that implantation of a single stent in this cadaver eye model resulted in the greatest incremental reduction of IOP, and additional stents resulted in further lowering of IOP but to a lesser degree. The theoretic advantages of the trabecular bypass stent are that it opens a pathway from the anterior chamber to Schlemm s canal and maintains its patency by the stent. The internal approach by a clear corneal incision spares the conjunctiva. The possible disadvantages include the fact that the opening is limited to the size of the stent(s) placed and that access to Schlemm s canal collector channels is limited to the area adjacent to the stents. The permanent implantation of a device into the angle has unknown longterm effects. Figure 8. istent trabecular bypass stent (Glaukos Corporation, Laguna Hills, CA): The device is placed with one end in Schlemm s canal and the other end in the anterior chamber to shunt aqueous directly into the canal past the trabecular meshwork. Illustration by Brian A. Francis, MD. 1470

6 Francis et al Ophthalmic Technology Assessment Food and Drug Administration Status The information from the manufacturers submissions to the Food and Drug Administration for the procedures is listed in Table 1. Questions for Assessment The purpose of this assessment is to answer the following questions: What is the mechanism of action of the procedure and how is it performed? What is the efficacy in terms of lowering of IOP and decreasing glaucoma medications? What are the safety and complications related to the procedure? Description of Evidence Literature searches were conducted up to October 2009 in PubMed and the Cochrane Library databases with no date or language restrictions. The search strategy used the MeSH terms glaucoma, open-angle, and trabeculectomy and the text words trabectom (truncated), trabeculectom (truncated), internal, interno, canaloplast (truncated), Glaukos, trabecular bypass stent, trabecular micro-bypass stent, ExPRESS, Ex-PRESS, SOLX, gold shunt, Fugo blade, Schlemm (truncated), drain (truncated), and microcatheter. The searches yielded 192 citations. The first author reviewed the abstracts of these citations and selected 37 articles of possible clinical relevance for review by the panel. Abstracts of meeting presentations are not subject to peer review and were not included in the assessment. The panel deemed 23 of these articles to be sufficiently clinically relevant to review in full text. The panel methodologist reviewed these studies and assigned ratings of level of evidence to each. The rating scale is based on the one developed by the British Centre for Evidence-Based Medicine. A level I rating was assigned to well-designed and wellconducted randomized clinical trials; a level II rating was assigned to well-designed case-control and cohort studies and lesser quality randomized studies; and a level rating was assigned to case series, case reports, and poor-quality cohort and case-control studies. of the 23 articles rated by the methodologist fulfilled the criteria for level I evidence. One study compared the Ex-PRESS shunt with trabeculectomy and was rated as level II evidence. 10 Most articles were case series describing novel surgical techniques with some preliminary efficacy data and no control group, and thus they were categorized as level evidence. These articles varied with regard to sample size, with some including phacoemulsification and intraocular lens implantation combined with the novel glaucoma procedure. Although studies of canaloplasty, Ex- PRESS, and Trabectome procedures had larger sample sizes and longer follow-up, the absence of an adequate comparative group and lack of randomization generally limited the opportunity to draw meaningful conclusions regarding the overall effectiveness of these novel procedures relative to conventional glaucoma filtration surgery. Published Results Table 2 contains a summary of the results of the studies for novel glaucoma procedures that are included in the assessment. The results are described below for each device and procedure. Fugo Blade Transciliary Filtration A nonrandomized prospective case series of 60 eyes of 36 patients in a rural clinic of the Philippines was reported by Dow and devenecia. 4 In this study, a historical comparison was made with trabeculectomy and thermosclerostomy with the randomized clinical trial by Blondeau and Phelps. 5 The strengths of the study are the consecutive inclusion of all types of patients with glaucoma, a relatively large study population, the prospective design, and the historical comparison. Its weaknesses are the limited applicability of this patient population to the typical patient with primary open-angle glaucoma in developed countries and uncertainty about the data analysis. Specifically, although the number of eyes in the study is 60, the analysis of IOP results includes only 46 starting from day 1 after surgery. Although it is not known why, this may be accounted for by excluding the 14 failures from the analysis. In addition, only 28 Table 1. Manufacturers Submission Information for Food and Drug Administration Clearance for Marketing Device Ex-PRESS mini glaucoma shunt Optonol, Ltd., Duluth, GA* Fugo blade Medisurg Ltd., Norristown, PA SOLX Gold Shunt SOLX, Inc., Boston, MA istent Glaukos Corp., Laguna Hills, CA Canaloplasty catheter system iscience Interventional Corp., Menlo Park, CA Trabectome high-frequency generator/lp NeoMedix Corp., Tustin, CA Xenon chloride excimer laser AIDA, Glautec AG, Nuremberg, Germany 510(k) Number Date of Substantially Equivalent Decision K012852, K /11/02, 3/13/03 K /09/05 K /18/2008 K /18/06 Indication To reduce IOP in patients with glaucoma in whom medical and conventional surgical treatments have failed. Intraocular creation of iridotomies. (The Fugo blade for peripheral iridotomy is the same electronic system as the Fugo blade for capsulotomy.) Limited to investigational use in United States. Limited to investigational use in United States. For use in cannulation of Schlemm s canal in eye surgery. For use with compatible electrosurgical instruments in low-power microsurgical applications for the removal, destruction, and coagulation of tissue. Not cleared for marketing in United States. *Now owned by Alcon Inc., Hunenberg, Switzerland. 1471

7 Ophthalmology Volume 118, Number 7, July 2011 Table 2. Results of Studies for Surgery Type, Study Level of Evidence Fugo blade transciliary filtration Dow et al 4 No. of Eyes (Patients) Study Design (follow-up) Inclusion Criteria Exclusion Criteria 60 (36) Prospective nonrandomized case series (Up to 12 months) Appropriate for glaucoma surgery Severe, advanced pathology Definition of Success (rate, time point) IOP 30 mmhg without meds (76.6% at 6 months) Fugo blade transciliary filtration Singh et al 6 Fugo blade goniotomy Singh et al 7 Ex-PRESS glaucoma implant Wamsley et al 8 Ex-PRESS glaucoma implant Dahan et al 9 Ex-PRESS glaucoma implant Maris et al 10 II 147 (147) Retrospective case series (Up to 6 months) 16 (16) Prospective case series Pilot study (Up to 6 months) 11 (11) Retrospective case series Pilot study ( weeks) 24 (23) Prospective case series (Mean 71 weeks [26-104]) 50 (49) 50 (47) Retrospective comparative (with trabeculectomy MMC matched controls) IOP 21 mmhg without meds No repeat surgery (125/147 at 6 months) Absolute glaucoma Compromised visual field Uncontrolled IOP, conjunctival scarring, or sclera thinning POAG, PXG, pigmentary glaucoma Failed medical treatment 3 months since prior surgery 18 years of age Mobile conjunctiva Uncontrolled IOP on max meds Angle closure, NTG, NVG Uveitis Cataract Prior surgery other than glaucoma or cataract IOP 21 mmhg (87.5% at 6 months) No further surgery Controlled IOP No device removal IOP 5 or 21 mmhg No further surgery or device removal (85.6% Trab MMC) (84.3% ExPRESS) Both at 15 months Ex-PRESS and CEIOL Traverso et al, (25) Prospective,, multicenter (up to 4 years) POAG Mobile conjunctiva 2 clock hours High IOP with meds Cataract Angle closure NVG Congenital Juvenile glaucoma Monocular IOP 21 mmhg with or without meds (94.4% at 2 years 76.9% at last followup) Ex-PRESS and CEIOL Rivier et al, (35) Prospective (up to 48 months) 18 years old POAG or PXG uncontrolled with meds Side effects meds Failed filtering surgery Angle closure NTG Congenital Juvenile glaucoma IOP 6-18 mmhg No further surgery (53.7% qualified, 32.7% complete at 4 years) SOLX Gold Shunt Melamed et al, (38) Prospective (up to 12 months) 21 years old POAG, PXG, pigmentary or uveitic glaucoma IOP 22 mmhg on max meds 60 days from prior surgery VF defect MD score 0dB VA worse CF Systemic steroids Conjunctival scarring in 4 quadrants IOP 5-22 mmhg with or without meds (79% qualified, 13.2% complete success last follow-up) 1472

8 Francis et al Ophthalmic Technology Assessment Novel Glaucoma Procedures Baseline IOP Meds Postop IOP Postop Meds (time, n) Complications Strengths of Study Weaknesses of Study mmhg (1 day, n 46), (1-3 months, n 41) (6-12 months, n 28). Hyphema (3/60) Reoperation (6/60) Consecutive inclusion Relatively large population Prospective Uncertain data analysis (n 60 but n 46 at postop day 1) Inexact inclusion and exclusion criteria Not typical of OAG in developed countries Range mmhg 132/ mmhg Choroidal effusion (2/147) Large population No inclusion or exclusion criteria No mean IOP data No patient demographics 53.6 mmhg (range ) 17.3 mmhg (6 months, n 16) Hyphema (3/16) Hypotony (1/16) size; 9 of 12 patients with both eyes included mmhg meds mmhg 14 on meds mmhg meds (end of follow-up mean ) mmhg (12 mo, n 21) mmhg (24 mo, n 8) 2 on meds Bleb needling (3/11) Device removal (1/11) Hypotony (10/11) AC reform (3/11) Choroidal hemorrhage (1/11) Hyphema (2/24) Hypotony (5/24) Choroidal effusions (2/24) Iris touch (3/24) AC reform (1/24) Device removal (1/24) Complete data and complications reporting Prospective Completeness of data size Retrospective size Inclusion criteria unclear (8/24 no prior surgery, 10/24 on no meds preop) ExPRESS mmhg meds Trab MMC mmhg meds ExPRESS mmhg meds Trab MMC mmhg meds mmhg mmhg at 1 year mmhg meds mmhg meds mmhg at 1 year mmhg at 2 years 0.9 meds at 4 years mmhg meds at last follow-up ExPRESS /Trab Device removal (1/50; 0/50) Bleb endophthalmitis (1/50; 0/50) Hypotony (2/50; 16/50) Choroidal (4/50; 19/50) Flat AC (1/50; 2/50) Hypotony maculopathy (2/50; 3/50) Hyphema (2/50; 2/50) Bleb leak (3/50; 4/50) Bleb needling (7/26) 5-FU (6/26) Hyphema (3/26) Choroidal (3/26) Iris touch (1/26) Granuloma (1/26) Device rotation (2/26) Malposition (2/26) Conjunctival erosion (3/26) Bleb needling with MMC (6/35) and without (4/35) Choroidal (5/35) Shallow AC with reformation (1/35) Conjunctival erosion (4/35) Tube obstruction (4/35) Device removal (10/35) Shunt exposure (1/38) Synechiae (1/38) Hyphema (8/38) Retinal detachment (1/38) Concurrent comparison group of matched controls (nonrandomized) Length of follow up Good retention at 1 and 2 years Complete data reporting Length follow-up Good retention Complete data reporting Good retention Complete data reporting Retrospective Limited follow-up Inclusion criteria not clear Repeat surgery for device failure? Noncomparative Technique no longer in use (no scleral flap) Short follow up Noncomparative (Continued) 1473

9 Ophthalmology Volume 118, Number 7, July 2011 Table 2. (Continued.) Surgery Type, Study Level of Evidence No. of Eyes (Patients) Study Design (follow-up) Inclusion Criteria Exclusion Criteria Definition of Success (rate, time point) Excimer laser trabeculotomy Wilmsmeyer et al, ELT 70 ELT CE 60 Prospective (up to 26 months) OHTN IOP 21 mmhg Glaucoma Cataract Advanced glaucoma (fixation threatening VF defects) IOP 40 1: IOP 21 mmhg and 20% reduction 2: IOP 18 mmhg and 30% reduction No further surgery Excimer laser trabeculotomy Babighian et al, Canaloplasty Canaloplasty and CE Lewis et al, Canaloplasty Canaloplasty and CE (same cohort as above) Lewis et al, (21) Prospective (2 years) 94 Prospective (1 year) 127 Prospective (2 years) Medically uncontrolled POAG IOP 21 mmhg POAG, pigmentary, PXG, MMG IOP 16 mmhg IOP 21 mmhg in past POAG, pigmentary, PXG, MMG IOP 16 mmhg IOP 21 mmhg in past Prior laser Prior glaucoma surgery 2 laser trabeculoplasty Chronic angle closure 2 laser trabeculoplasty Chronic angle closure IOP decrease 20% No additional meds or surgery (success 54%) Group 1 all (94) Group 2 successful suture placed (74) Combined CE 27 Group 1 all (127) Group 2 successful suture placed (84) Combined CE 24 Canaloplasty and CE Shingleton et al, Prospective (Up to 1 year) POAG, pigmentary, PXG, MMG IOP 16 mmhg IOP 21 mmhg in past 2 laser trabeculoplasty Chronic uveitis Anterior synechiae Angle closure Successful suture placed 40 (74%) Trabectome Minckler et al, Trabectome Minckler et al, (expanded from above cohort) Trabectome and CE Francis et al, Trabecular microbypass istent Spiegel et al, (37) Prospective pilot study (up to 13 months) 101 Prospective (up to 30 months) 304 Prospective (up to 21 months) 6 (6) Prospective pilot study (up to 12 months) High IOP POAG, or secondary OAG Age 18 years Open angle grade 2 High IOP POAG, or secondary OAG Age 18 years Open angle grade 2 High IOP POAG, or secondary OAG Age 18 years Open angle grade 2 OAG Clear cornea Open angle grade 3 Vision hand motion Shallow AC TM not clearly visible Neovascular iris or angle Vision hand motion Shallow AC TM not clearly visible Neovascular iris or angle Vision hand motion Shallow AC Cornea opacity preventing view TM not visible Neovascular iris or angle Split fixation Increased episcleral venous pressure NVG Chronic inflammation IOP 21 mmhg with or without meds No further surgery 20% IOP decrease Decrease in meds No additional surgery or meds (78% at 6 months, 64% at 1 year) 1474

10 Francis et al Ophthalmic Technology Assessment Baseline IOP Meds ELT mmhg meds ELT phaco mmhg meds Postop IOP Postop Meds (time, n) Complications Strengths of Study Weaknesses of Study ELT mmhg meds (success 46% definition 1; 27% definition 2) at 1 yr at 2 yr ELT phaco mmhg meds (success 66% definition 1; 42% definition 2) at 1 yr at 2 yr Synechiae (2/130) Fibrin (3/130) CRVO (1/130) possibly unrelated Large sample Good follow-up at 1 year Noncomparative Loss of follow-up at 2 years Inclusion and exclusion criteria vague, includes OHTN mmhg Decrease mmhg at 2 yrs Microhyphema (?/21) Length of follow-up Good retention Vague inclusion and exclusion criteria Group mmhg Group mmhg Combined CE mmhg Group mmhg Group mmhg Combined CE mmhg mmhg meds Group mmhg Group mmhg at 1 year Combined CE mmhg at 1 year Group mmhg Group mmhg Combined CE mmhg at 2 years mmhg meds at 1 year Bleb formation (11/94) Unable to place suture (20/94) Hyphema (3/94) Descemet s detachment (1/94) Hypotony (1/94) Choroidal (1/94) Suture exposure (1/94) Bleb formation (4/127) Unable to place suture (43/127) Hyphema (20/127) Hypotony (1/127) Suture exposure (2/127) Bleb formation (3/54) Descemet s detachment (1/54) Hyphema (18/54) Iris prolapse (1/54) Wound hemorrhage (1/54) Large sample Complete data Multiple analyses including CE, suture distension of TM Large sample Complete data Multiple analyses including CE, suture distension of TM Complete data Moderate loss of follow-up Moderate loss of follow-up Moderate loss of follow-up mmhg meds mmhg meds at 1 year Corneal epithelial defect (6/37) Hyphema (22/37) PAS (9/37) IOP spike (2/37) Complete data Well-defined inclusion and exclusion Limited follow-up mmhg mmhg at 1 year mmhg at 2 years Corneal epithelial defect (3/101) PAS (14/101) IOP spike (5/101) Hypotony (1/101) Complete data Well-defined inclusion and exclusion Large sample Limited follow-up mmhg meds mmhg meds at 21 months Iris injury (4/304) Lens capsule damage (2/304) IOP spike (26/304) Complete data Large sample Inclusion and exclusion criteria vague Incomplete follow-up mmhg meds mmhg meds at 1 year Iris synechiae (1/6) CRVO (1/6) likely not related Defined inclusion and exclusion criteria Limited follow-up Data presentation limited (Continued) 1475

11 Ophthalmology Volume 118, Number 7, July 2011 Surgery Type, Study Level of Evidence Trabecular microbypass istent and CE Spiegel et al, Trabecular microbypass istent and CE Spiegel et al, (continuation of above study) No. of Eyes (Patients) 48 (48) Prospective (6 months) 48 (48) Prospective (12 months) Study Design (follow-up) Inclusion Criteria Exclusion Criteria POAG, PXG, or pigmentary IOP 18 mmhg x 2 Scleral spur visible by gonioscopy POAG, PXG, or pigmentary IOP 18 mmhg x 2 Scleral spur visible by gonioscopy Cloudy cornea Prior glaucoma filtration surgery Incresed episcleral venous pressure Ocular surface disease Eye trauma Refractive eye surgery Cloudy cornea Prior glaucoma filtration surgery Increased episcleral venous pressure Ocular surface disease Eye trauma Refractive eye surgery Table 2. (Continued.) Definition of Success (rate, time point) 5-FU 5-fluorouracil; AC anterior chamber; CE cataract extraction; CEIOL cataract extraction, intraocular lens implantation; CF count mitomycin C; MMG mixed mechanism glaucoma; NTG normal tension glaucoma; NVG neovascular glaucoma; OAG open angle glaucoma; trabeculectomy; VA visual acuity patients reached the long-term follow-up of 6 to 12 months (a time period that many would describe as intermediate term). The first published report of transciliary filtration with the Fugo blade was a, retrospective analysis of 147 cases with a maximum follow-up of 6 months. 6 The strength of this study is its large population. However, there are many limitations, including a lack of any inclusion or exclusion criteria, short follow-up, and a paucity of data presented. Specifically, patient demographics and mean IOP before and after surgery are not reported. With this lack of data, it is difficult to form an analysis of the quality of the study and to verify the results. Fugo Blade Goniotomy A small, case series of goniotomy ab interno with the Fugo blade was reported on 16 eyes of 16 patients at the Department of Ophthalmology, S.N. Medical College and Hospital in Agra, India, by Singh et al. 7 The strength of this study is its prospective design. Its limitations include the small study sample, lack of specified inclusion and exclusion criteria, short follow-up, and brevity of data presented. Some demographic information is included, such as age and gender, but type of glaucoma, severity of disease (although all are described as absolute glaucoma ), and use of glaucoma medications are not reported. In the brief description of the procedure, it is unclear how the depth of penetration is controlled and exactly what tissue is being removed with the Fugo blade. One assumes that the desired effect is opening Schlemm s canal by removing the TM and inner wall of Schlemm s canal, but this is not stated. The measurement of IOP is via Schiotz or noncontact tonometry, which is not the standard for glaucoma clinical trials, and it is not known if the same technique was used for all patients. All of the above studies using the Fugo blade were categorized as level evidence in support of the procedure. Ex-PRESS Glaucoma Implant The first report of the Ex-PRESS mini glaucoma shunt was a, retrospective case series of 11 patients by Wamsley et al 8 in 2004, which was categorized as level evidence. The procedure was performed with an Ex-PRESS miniature glaucoma shunt (model not specified, presumably R-50) implanted under the conjunctiva. This study has several limitations, including the small number, retrospective data collection, and design. The strength is the completeness of the reporting of results and complications for a case series of this nature. A, prospective, interventional pilot study with 24 eyes of 23 patients undergoing the Ex-PRESS glaucoma implant underneath a scleral flap was reported in 2005 by Dahan and Carmichael. 9 The procedure followed the standard protocol as previously described, with the additional application of MMC 0.05% under the scleral flap. This pilot study has the expected limitations of small numbers, loss of follow-up at later time points, and design. The inclusion criterion of failed medical and surgical treatment is questionable, because 8 of 24 patients had not undergone prior surgery, and 10 of 24 patients were not receiving glaucoma medications before surgery. The strengths of this study are the prospective follow-up of patients and relatively complete presentation of data. This study was also categorized as level evidence. A retrospective, comparative study of the Ex-PRESS shunt and trabeculectomy was reported in 2007 by Maris et al. 10 The Ex- PRESS shunt implant was inserted underneath a scleral flap, and both surgeries were performed with application of MMC 0.4 mg/ml for 1 to 2 minutes. The trabeculectomy controls were matched for age and sex, and the procedure was combined with phacoemulsification cataract extraction. The limitations of this study include its retrospective design and limited follow-up time. Although it is nonrandomized, a strength is that a concurrent comparison group of matched controls undergoing trabeculectomy is included, and thus the study was rated as level II evidence in support of the procedure. The baseline and demographic data are similar between the 2 groups. It is unclear how the decision was made to perform Ex-PRESS shunt versus trabeculectomy, because the dates of inclusion are concurrent. The data reporting is complete. 1476

12 Francis et al Ophthalmic Technology Assessment Baseline IOP Meds mmhg meds Postop IOP Postop Meds (time, n) Complications Strengths of Study Weaknesses of Study mmhg meds at 6 months Stent obstruction (7/48) Stent removal (2/48) Stent repositioning (1/48) Defined inclusion and exclusion criteria Good retention Limited follow up time mmhg meds 16.9 mmhg (no SD) 0.4 meds (no SD) at 12 months Vitreous wick obstruction (1/48) Stent malposition (9/48) Stent removal (2/48) Stent repositioning (1/48) Corneal paracentesis for high IOP (1/48) Defined inclusion and exclusion criteria Good retention Limited follow-up time fingers; CRVO central retinal vein occlusion; ELT excimer laser trabeculotomy; IOP intraocular pressure; MD mean deviation; MMC OHTN ocular hypertension; POAG primary open-angle glaucoma; PXG pseudoexfoliation glaucoma; SD standard deviation; Trab Ex-PRESS Glaucoma Implant Combined with Cataract Extraction Two studies have published results of an Ex-PRESS implant combined with phacoemulsification cataract extraction. The first was by Traverso et al 11 in 2005 and included 26 eyes of 25 patients undergoing implantation of the R-50 device under the conjunctiva. The study was a, multicenter, prospective, interventional trial with a follow-up of up to 4 years. This pilot study has the usual limitations of small numbers and design. The inclusion criteria are unclear, because they are defined as primary open-angle glaucoma with visual field loss, but 1 case of ocular hypertension is included (pseudoexfoliation glaucoma is also included, but this is a secondary open-angle glaucoma). The definition of failure does not include further bleb procedures, such as needling or 5-FU injection, and it is not known whether repeat surgery to the device is similarly excluded, because it is not listed as a criterion for failure. There is some confusion in the reporting of IOP, because the text in the results and abstract do not match the table describing efficacy long-term IOP summary. The strengths of this study are the length of follow-up and excellent retention at 1 year, with good retention at 2 years. The reporting of data is complete and includes a description and resolution of complications. Another trial of the Ex-PRESS shunt combined with cataract extraction was reported by Rivier et al in In this, prospective, interventional trial, the R-50 implant was inserted underneath the conjunctiva in a nonconsecutive group of 35 eyes of 35 patients who were followed for up to 48 months. The limitations of this study include its design and small numbers of subjects. The inclusion criteria are somewhat confusing, because they are described as medically uncontrolled glaucoma, but they included eyes that required good IOP control without medications. Otherwise, the inclusion and exclusion criteria are straightforward. The length of follow-up is excellent, and there is good retention of subjects. The reporting of data, including complications, is also complete. The surgical method used a subconjunctival implantation of the device, which has been replaced by implantation under a scleral flap. Both of the above studies assessing the use of the Ex-PRESS implant with cataract surgery were rated as level evidence in support of the procedures. SOLX Gold Shunt A prospective, case series of 38 patients undergoing surgery with the GMS was reported by Melamed et al 13 in This can be considered a pilot study of the GMS device and is the first published report in the literature. As such, it has the usual limitations of small numbers of patients, relatively short duration, and design. However, the inclusion and exclusion criteria are clearly delineated, there is good retention in follow-up, and data reporting seems complete. Overall, the study was categorized as level evidence in support of the procedure. Excimer Laser Trabeculotomy A, interventional, prospective case series of ELT was reported by Wilmsmeyer et al. 14 This study included consecutive patients undergoing ELT alone (n 70) and those undergoing ELT and cataract extraction by phacoemulsification (n 60) with up to 26 months of follow-up. The strengths of this study are the prospective design, relatively larger numbers, and follow-up of 1 year with good retention. There is a large decrease in available data points at the 2-year time point. The limitations include the design, especially when examining combined ELT and phacoemulsification, because the latter may have IOP-lowering effects on its own. The inclusion and exclusion criteria are somewhat vague, and the inclusion of ocular hypertension is questionable, although these account for only 6 patients in the ELT group and 1 patient in the combined group. A smaller trial of 21 patients undergoing ELT was reported by Babighian et al 15 in This, interventional case series had a mean follow-up of more than 2 years. The strengths of this study are the prospective design and length of follow-up with good retention of subjects. The limitations include the small number of subjects, the vague inclusion and exclusion criteria, and the design. 1477