NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

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1 NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE INTERVENTIONAL PROCEDURES PROGRAMME Interventional procedure overview of ab interno supraciliary microstent insertion with phacoemulsification for primary open-angle glaucoma Primary open-angle glaucoma is a progressive condition that causes long-term increase of pressure within the eye. This damages the nerve that connects the eye to the brain (optic nerve) and may gradually lead to permanent loss of sight. In this procedure a tiny tube (stent) is inserted just below the surface of the eye, to create a drainage channel for excess fluid. The procedure is usually done during surgery for cataracts. The aim is to reduce pressure in the eye. Contents Introduction Description of the procedure Efficacy summary Safety summary The evidence assessed Validity and generalisability of the studies Existing assessments of this procedure Related NICE guidance Additional information considered by IPAC References Additional relevant papers Literature search strategy Introduction The National Institute for Health and Care Excellence (NICE) prepared this interventional procedure overview to help members of the interventional procedures advisory committee (IPAC) make recommendations about the safety and efficacy of an interventional procedure. It is based on a rapid review of the open-angle glaucoma Page 1 of 28

2 medical literature and specialist opinion. It should not be regarded as a definitive assessment of the procedure. Date prepared This overview was prepared in May Procedure name Ab interno supraciliary microstent insertion with phacoemulsification for primary open-angle glaucoma Specialist societies Royal College of Ophthalmologists. Description of the procedure Indications and current treatment Open-angle glaucoma is a chronic condition associated with elevated intraocular pressure. It leads to progressive damage to the optic nerve. Early stages are usually asymptomatic but as the condition progresses it causes visual impairment and, if untreated, blindness. Treatment is usually eye drops containing drugs that either reduce the production of aqueous humor or increase its drainage. Surgical procedures such as trabeculectomy, drainage tubes, deep sclerectomy, viscocanalostomy or laser trabeculoplasty may also be used. What the procedure involves Ab interno supraciliary micro stent insertion for primary open angle glaucoma aims to increase outflow using the suprachoroidal space, without manipulating the conjunctiva and sclera or creating a filtering bleb. It is usually done at the same time as phacoemulsification cataract surgery. Using local anaesthesia, a small incision is made in the cornea. For the phacoemulsification, a small probe that emits ultrasound waves is inserted into the eye to break the lens into pieces. The pieces are then removed and a small plastic lens is inserted. For the supraciliary microstent insertion, the anterior chamber of the eye is deepened using viscoelastic. Intraoperative gonioscopy is used to visualise angle structures. The microstent is then put into the supraciliary space, between the ciliary body and the sclera. Precisely how the stent is deployed into position varies according to the particular device being used. open-angle glaucoma Page 2 of 28

3 Efficacy summary Intraocular pressure In a randomised controlled trial (RCT) of 505 patients treated by cataract surgery with supraciliary micro stent insertion or by cataract surgery alone, there was a statistically significant difference in the proportion of patients with 20% reduction or more in unmedicated diurnal intraocular pressure at 24 month follow-up (73% compared with 58%, p=0.002 for intention to treat population) 1. The mean reduction in unmedicated intraocular pressure at 24 month follow-up was 30% in the stent group and 21% in the control group (p<0.001). The proportion of patients maintaining intraocular pressure between 6 and 18 mm Hg without medication at 24 month follow-up was 61% in the stent group and 44% in the control group (p<0.001, intention to treat population). Anti-glaucoma medication use In the RCT of 505 patients treated by cataract surgery with supraciliary micro stent insertion or by cataract surgery alone, 85% of patients in the stent group did not need rescue medication compared with 59% of patients in the control group (p value not reported) 1. In a case series of 142 patients divided into 2 cohorts according to baseline intraocular pressure (IOP), 65% (46/71) of eyes in the cohort with a baseline intraocular pressure less than 21 mm Hg were medication free at 12 month follow-up, compared with 4% (4/102) at baseline (p value not reported) 2. The mean number of IOP lowering medications reduced from 2.1 to 1.1 (p=0.0013) in the cohort of eyes with IOP 21 mm Hg or above and from 2.0 to 0.5 (p ) in the cohort of eyes with IOP less than 21 mm Hg. In a case series of 136 patients from the same study, the mean number of IOP lowering medications reduced from 2.2 to 1.0 (p=0.0265) in the cohort of eyes with IOP 21 mm Hg or above (n=23) and from 2.0 to 1.1 (p ) in the cohort of eyes with IOP less than 21 mm Hg (n=59) at 24 month follow-up 3. Visual acuity In the RCT of 505 patients treated by cataract surgery with supraciliary micro stent insertion or by cataract surgery alone, 98% of patients in both groups had 20/40 or better best corrected visual acuity (BCVA) at 24 month follow-up 1. In the case series of 142 patients, 87% (97/111) of eyes had a best corrected distance visual acuity (BCDVA) of 20/40 or better at 12 month follow-up, compared with 61% (100/165) of eyes at baseline (p value not reported) 2. Secondary glaucoma surgery Secondary glaucoma surgery was reported in 11% (15/136) of eyes in the case series of 136 patients 3. Additional surgical intervention was needed in 5% (9/184) of patients in the case series of 184 patients 5. open-angle glaucoma Page 3 of 28

4 Safety summary Transient loss of visual acuity Best corrected visual acuity (BCVA) loss of 10 letters or more was reported in 9% (33/374) of patients who had supraciliary micro stent insertion with cataract surgery and in 15% (20/131) of patients who had cataract surgery alone in a randomised controlled trial (RCT) of 505 patients (p=0.0466) 1. At 24 month follow-up, 1% of eyes in the stent group and no eyes in the control group had a BCVA that was 2 lines or more below the baseline value. Reduction of 2 or more lines of corrected distance visual acuity from baseline was reported in 1% (2/184) of patients in a case series of 184 patients 5. Increased intraocular pressure Transient intraocular pressure (IOP) higher than 10 mm Hg over baseline was reported in 4% (16/374) of patients who had supraciliary micro stent insertion with cataract surgery and in 2% (3/131) of patients who had cataract surgery alone in the RCT of 505 patients (p=0.4263) 1. High IOP (IOP higher than 30 mm Hg and baseline IOP plus 10 mm Hg) lasting more than 1 month was reported in 2% (3/167) of eyes in a case series of 142 patients 2. Transient IOP increase of more than 10 mm Hg from baseline was reported in 11% (19/184) of patients in the case series of 184 patients 5. Hypotony Hypotony (IOP less than 6 mm Hg) was reported in 3% (11/374) of patients who had supraciliary micro stent insertion with cataract surgery and in no patients who had cataract surgery alone in the RCT of 505 patients (p=0.0744) 1. Transient hypotony was reported in 14% (23/167) of eyes in the case series of 142 patients 2. Hypotony lasting more than 1 month was reported in 1 patient in the case series of 184 patients 5. Corneal effects Corneal abrasion was reported in 2% (7/374) of patients who had supraciliary micro stent insertion with cataract surgery and in 2% (2/131) of patients who had cataract surgery alone in the RCT of 505 patients (p=0.9999) 1. Corneal endothelial touch was reported in 1% (2/167) of eyes in the case series of 142 patients 2. Transient corneal oedema was reported in 4% (13/374) of patients who had supraciliary micro stent insertion with cataract surgery and in 2% (2/131) of patients who had cataract surgery alone in the RCT of 505 patients (p=0.3741) 1. Corneal oedema lasting more than 1 month was reported in 1 patient in the case series of 142 patients 2. open-angle glaucoma Page 4 of 28

5 Hyphema Transient, intraoperative hyphema was reported in 3% (10/374) of patients who had supraciliary micro stent insertion with cataract surgery and in no patients who had cataract surgery alone in the RCT of 505 patients (p=0.0706) 1. Transient hyphema was reported in 1% (2/167) of eyes in the case series of 142 patients 2. Postoperative hyphema, which resolved within 2 weeks, was reported in 1 patient in the case series of 184 patients 5. Subconjunctival haemorrhage Subconjunctival haemorrhage was reported in 2% (6/374) of patients who had supraciliary micro stent insertion with cataract surgery and in 1% (1/131) of patients who had cataract surgery alone in the RCT of 505 patients (p=0.6829) 1. Maculopathy Maculopathy was reported in 2% (6/374) of patients who had supraciliary micro stent insertion with cataract surgery and in 1 patient who had cataract surgery alone in the RCT of 505 patients (p=0.6829) 1. Cyclodialysis cleft greater than 2 mm circumference Cyclodialysis cleft greater than 2 mm circumference was reported in 2% (7/374) of patients who had supraciliary micro stent insertion with cataract surgery and in no patients who had cataract surgery alone in the RCT of 505 patients (p=0.1985) 1. This was not associated with hypotony or other sequelae and did not need stent replacement. Iritis and other inflammation Iritis was reported in 9% (32/374) of patients who had supraciliary micro stent insertion with cataract surgery and in 4% (5/131) of patients who had cataract surgery alone in the RCT of 505 patients (p=0.0809) 1. Inflammation was reported in 4% (7/167) of eyes in the case series of 142 patients; all cases resolved within 1 month 2. Inflammation or anterior chamber reaction lasting more than 1 month was reported in 4% (8/184) of patients in the case series of 184 patients 5. Micro-stent obstruction, explantation, migration or dislodgement Micro stent obstruction was reported in 2% (8/374) of patients in the RCT of 505 patients and in 9% (12/136) of eyes in the case series of 136 patients 1,3. Stent migration or dislodgement was reported in less than 1% (2/374) of patients who had supraciliary micro stent insertion with cataract surgery 1. Stent open-angle glaucoma Page 5 of 28

6 explantation was reported in 1 patient in the case series of 142 patients 2. Stent migration was reported in 1 patient in the case series of 136 patients 3. Malpositioning of stent Stent malpositioning was reported in less than 1% (2/374) of patients who had supraciliary micro stent insertion with cataract surgery in the RCT of 505 patients 1. Repositioning of the stent was reported in 1 patient in the case series of 184 patients 5. Anecdotal and theoretical adverse events In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never happened). For this procedure, specialist advisers listed the following anecdotal adverse events: small myopic shift because of anterior chamber shallowing, and poor pressure control. They considered that the following were theoretical adverse events: endothelial cell loss, infection, and damage to other structures in the eye. The evidence assessed Rapid review of literature The medical literature was searched to identify studies and reviews relevant to ab interno supraciliary microstent insertion with phacoemulsification for primary open-angle glaucoma. The following databases were searched, covering the period from 1 January 2006 to 7 March 2017: MEDLINE, PREMEDLINE, EMBASE, Cochrane Library and other databases. Trial registries and the Internet were also searched. No language restriction was applied to the searches (see appendix C for details of search strategy). Relevant published studies identified during consultation or resolution that are published after this date may also be considered for inclusion. The following selection criteria (table 1) were applied to the abstracts identified by the literature search. Where selection criteria could not be determined from the abstracts the full paper was retrieved. open-angle glaucoma Page 6 of 28

7 Table 1 Inclusion criteria for identification of relevant studies Characteristic Publication type Patient Intervention/test Outcome Language Criteria Clinical studies were included. Emphasis was placed on identifying good quality studies. Abstracts were excluded where no clinical outcomes were reported, or where the paper was a review, editorial, or a laboratory or animal study. Conference abstracts were also excluded because of the difficulty of appraising study methodology, unless they reported specific adverse events that were not available in the published literature. Patients with primary open-angle glaucoma. Ab interno supraciliary microstent insertion with phacoemulsification. Articles were retrieved if the abstract contained information relevant to the safety and/or efficacy. Non-English-language articles were excluded unless they were thought to add substantively to the English-language evidence base. List of studies included in the IP overview This IP overview is based on approximately 850 patients from 1 randomised controlled trial and 4 case series 1 5. This may be an overestimate because there is likely to be some patient overlap between the studies. Other studies that were considered to be relevant to the procedure but were not included in the main extraction table (table 2) have been listed in appendix A. open-angle glaucoma Page 7 of 28

8 Table 2 Summary of key efficacy and safety findings on ab interno supraciliary microstent insertion with phacoemulsification for primary open-angle glaucoma Study 1 Vold S (2016) Details Study type Country Randomised controlled trial (COMPASS trial) US (multicentre; 24 sites) Recruitment period 2011 to 2015 Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding n=505 patients (505 eyes; 374 cataract surgery with microstent insertion versus 131 cataract surgery only) Patients with primary open angle glaucoma Mean 70 years (range 45 to 93); 53% (269/505) female Inclusion criteria: age 45 years, diagnosed or confirmed primary open angle glaucoma (Shaffer grade 3 in all quadrants of the study eye) within 90 days of screening, screening medicated intraocular pressure (IOP) 25 mmhg or unmedicated IOP between 21 and 33 mmhg, baseline unmedicated diurnal IOP between 21 and 33 mmhg and 3 mmhg higher than screening IOP, age-related cataract with best corrected visual acuity or acuity testing with a Brightness Acuity Meter of 20/40 or worse that was eligible for phacoemulsification cataract surgery with intraocular lens implantation. Exclusion criteria: >3 ocular hypotensive medications, significant risk associated with ocular hypotensive medication washout, previous corneal or glaucoma surgery (except laser trabeculoplasty), clinically significant ocular pathology other than cataract and glaucoma, diagnosis of acute angle closure or traumatic, congenital, malignant, uveitic, pseudoexfoliative, pigmentary, or neovascular glaucoma. All patients had phacoemulsification cataract surgery. Microstent device: CyPass Micro-Stent (Transcend Medical Inc., US). The microstent was implanted through a single phacoemulsification corneal incision. 24 months The study was supported by Transcend Medical Inc., US. The sponsor participated in study design, performance, analysis and reporting. Several authors received fees, research funding, or are consultants for Transcend Medical. One of the authors is an employee of Transcend Medical Inc., US. Analysis Follow-up issues: 95% (480/505) of patients completed the entire 24 month follow-up. Study design issues: Randomisation to microstent or control group was done centrally, stratified by site. Group assignment was revealed intraoperatively immediately after the completion of uncomplicated cataract surgery. Patients were blinded to treatment allocation throughout follow-up and IOPs were recorded by blinded technicians. The principal investigator at each study centre was not blinded to treatment allocation during patient follow-up examinations. The primary efficacy outcome measure was the proportion of eyes with unmedicated diurnal IOP reduction of 20% of more at 24 month follow-up compared with unmedicated baseline IOP. The primary safety outcome measure was the frequency and nature of any ocular adverse events. Per-protocol and intention-to-treat analyses were done. Study population issues: The 2 groups were similar with regard to baseline demographic and ocular parameters. Most patients (82%) were using 1 or more ocular hypotensive medications before the procedure (patients had a full glaucoma medication washout before a second baseline evaluation was done). open-angle glaucoma Page 8 of 28

9 Key efficacy and safety findings Efficacy Number of patients analysed: 505 (374 versus 131) Patients with 20% reduction or more in unmedicated diurnal IOP at 24 month followup (per-protocol [PP] analysis) Stent=77% Control=60%, p=0.001 Patients with 20% reduction or more in unmedicated diurnal IOP at 24 month followup (intention-to-treat [ITT] analysis) Stent=73% Control=58%, p=0.002 Mean unmedicated IOPs (mm Hg) Stent Control Baseline 24.4 (range 21.0 to 33.0) 24.5 (range 21.0 to 32.3) 24 month follow-up Mean unmedicated IOP change from baseline Stent Control p value Mean reduction at 12 months (mm Hg) % reduction at 32% 26% < months Mean reduction at 24 months (mm Hg) % reduction at 24 months 30% 21% <0.001 p<0.001 within each group versus baseline at both times Proportion of patients maintaining unmedicated IOP between 6 and 18 mm Hg at 24 month follow-up (PP) Stent=65% Control=44%, p<0.001 Proportion of patients maintaining unmedicated IOP between 6 and 18 mm Hg at 24 month follow-up (ITT) Stent=61% Control=44%, p<0.001 Safety Adverse events that occurred in at least 1% of patients in either group (24 month follow-up); n (%) Adverse event Transient BCVA loss 10 letters ( 30 days) Corneal abrasion Corneal oedema (transient) Stent n= (8.8%) 7 (1.9%) 13 (3.5%) Conjunctivitis 4 (1.0%) Cyclodialysis cleft >2 mm circumference (not associated with any sequelae) Transient, intraoperative hyphema Iritis (transient, resolved with topical steroids) Transient hypotony (IOP <6 mm Hg) Transient IOP 10 mm Hg over baseline Maculopathy, cystoid oedema Stent obstruction Subconjunctival haemorrhage Secondary ocular surgical intervention Visual field loss progression, confirmed 7 (1.9%) 10 (2.7%) 32 (8.6%) 11 (2.9%) 16 (4.3%) 6 (1.6%) 8 (2.1%) 6 (1.6%) 20 (5.5%) 25 (6.7%) Control n= (15.3%) p value (1.5%) (1.5%) (2.3%) (0%) (0%) (3.8%) (0%) (2.3%) (0.8%) (0.8%) (5.3%) (9.9%) There were 2 instances of malpositioning and 2 instances of stent migration or dislodgment. The authors noted that the majority of adverse events were transient and did not negatively affect functional outcomes such as visual acuity. open-angle glaucoma Page 9 of 28

10 Number of hypotensive ocular medications (ITT) Follow-up Stent Control p value Baseline months months <0.001 p value <0.001 <0.001 At 24 month follow-up, 1.1% of eyes in the stent group and no eyes in the control group had a BCVA that was 2 lines or more below the baseline value. Eleven patients died during the course of the study (10 in the stent group and 1 in the control group). None of the deaths were related to the Cypass device. 85% of patients in the stent group did not need rescue medication compared with 59% of patients in the control group. More than 98% of patients in both groups had 20/40 or better BCVA at 24 month follow-up. Abbreviations used: BCVA, best corrected visual acuity; IOP, intraocular pressure; ITT, intention to treat; PP, per-protocol open-angle glaucoma Page 10 of 28

11 Study 2 Hoeh H (2016) Details Study type Country Recruitment period Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Case series (CyCLE study) Germany, Canada, Spain, US Not reported n=142 (167 eyes) Patients with primary or secondary open-angle glaucoma and cataract. Mean 74 years; 59% (99/167) female Patients with primary or secondary open-angle glaucoma and visually significant cataract needing phacoemulsification surgery. Exclusion criteria: chronic angle closure or narrow angle (Schaffer grade I or II), uveitic or neovascular glaucoma, congenital anomaly of the anterior chamber and angle, known intolerance or hypersensitivity to topical anaesthetics, miotics, mydriatics, or polyimide materials. Combined phacoemulsification, with intraocular lens insertion, and microstent implantation into the supraciliary space. Device: CyPass Micro-Stent (Transcend Medical Inc., US). The CyPass device was implanted after completion of the phacoemulsification part of the surgery. The microstent was inserted into the anterior chamber through the phacoemulsification incision and then into the supraciliary space. The positioning of the microstent was evaluated using gonioscopy. At investigator discretion, positioning could also be evaluated by optical coherence tomography. Each investigator used their own standard regimen of postoperative antibiotics and steroids. IOP-lowering medications were discontinued or tapered immediately after the procedure. Mean 294 ± 121 days The study was supported by Transcend Medical Inc., US. The sponsor participated in all aspects of the study and preparation of the manuscript. Most of the authors were investigators for, consultants to, or employees of Transcend Medical Inc. Analysis Follow-up issues: By 12 months postoperatively, the attrition rate in number of eyes followed was 30%: 37 patients (41 eyes) were lost to follow-up and 14 patients (15 eyes) exited the study early because of the need for subsequent glaucoma surgical procedures or because the patient wanted to exit the study early. Study design issues: Prospective, multi-centre study. Patients were divided into 2 cohorts: those with IOP 21 mm Hg despite topical medication or prior surgical glaucoma treatment, and those with stable IOP<21 mm Hg with medical treatment. The primary outcome measure was the incidence of intraoperative and postoperative adverse events. Secondary outcome measures included change in IOP and the number of glaucoma medications needed for adequate IOP control as determined by the treating physician. Study population issues: Approximately 95% of patients were on at least 1 glaucoma medication before the procedure. The remaining patients were newly diagnosed and supraciliary microstent insertion was the primary treatment option. Other issues: There is likely to be a high degree of patient crossover with Hoeh H et al. (2013) and Höh H et al. (2014). open-angle glaucoma Page 11 of 28

12 Key efficacy and safety findings Efficacy Number of patients analysed: 142 patients (167 eyes) Visual acuity Proportion of eyes with best-corrected distance visual acuity (BCDVA) of 20/40: Baseline=61% (100/165) 12 month follow-up=87% (97/111) Of the 111 eyes with 12 month BCDVA recorded data, 84% had improvement over baseline. Mean intraocular pressure (IOP), mmhg All eyes Cohort 1 (baseline IOP 21 mm Hg) n=65 Cohort 2 (baseline IOP<21 mm Hg) n=102 Baseline 20.2± ± ± month follow-up p value 15.9± ± ±3.0 Not reported Not significant Mean number of IOP-lowering medications Cohort 1 (baseline IOP 21 mm Hg) Cohort 2 (baseline IOP<21 mm Hg) Baseline month follow-up p value At 12 month follow-up, 65% (46/71) of eyes in cohort 2 were medication free, compared with 4% (4/102) at baseline. Safety Adverse events and complications during the first 12 months after the procedure, n (%) Event High IOP (IOP>30 mm Hg and baseline IOP + 10 mm Hg) All eyes n=167 Cohort 1 (baseline IOP 21 mm Hg) n=65 IP 1531 [IPGXXX] Cohort 2 (baseline IOP<21 mm Hg) n=102 5 (3.0) 3 (4.6) 2 (2.0) 1 month 2 (1.2) 1 (1.5) 1 (1.0) >1 month 3 (1.8) 2 (3.1) 1 (1.0) Transient hypotony (IOP<6 mm) Transient hyphema Inflammation <1 month Inflammation >1 month Corneal oedema >1 month BCDVA loss possibly related to implant Endothelial touch Anterior chamber shallowing Obstruction of implant Secondary glaucoma surgery Repositioning of implant Explantation of implant Secondary cataract Macular oedema 23 (13.8) 4 (6.2) 19 (18.6) 2 (1.2) 2 (3.1) 0 (0) 7 (4.2) Not reported Not reported 0 (0) 0 (0) 0 (0) 1 (0.6) 0 (0) 1 (1.0) 0 (0) 0 (0) 0 (0) 2 (1.2) 1 (1.5) 1 (1.0) 0 (0) 0 (0) 0 (0) 9 (5.4) 1 (1.5) 8 (7.8) 10 (6.0) 6 (9.2) 4 (3.9) 1 (0.6) 0 (0) 1 (1.0) 1 (0.6) 1 (1.5) 0 (0) 3 (1.8) 2 (3.1) 1 (1.0) 1 (0.6) 0 (0) 1 (1.0) All cases of hypotony resolved within 4 weeks. Abbreviations used: BCDVA, best-corrected distance visual acuity; IOP, intraocular pressure open-angle glaucoma Page 12 of 28

13 Study 3 Höh H (2014) Details Study type Country Recruitment period Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Case series (CyCLE study) Germany, US Not reported n=136 (136 eyes) Patients with primary or secondary open-angle glaucoma and cataract. Mean 74 years; 60% (81/136) female Patients with primary or secondary open-angle glaucoma and visually significant cataract needing phacoemulsification surgery. Only patients who has reached the 24-month postoperative time point were included. Combined phacoemulsification, with intraocular lens insertion, and microstent implantation into the supraciliary space. Device: CyPass Micro-Stent (Transcend Medical Inc., US). 24 months All of the authors were investigators for, or employees of Transcend Medical Inc. Analysis Follow-up issues: At the 24-month follow-up visit, 19% (26/136) of patients were lost to follow-up, 5 had died and 15 had stopped early because they needed secondary incisional glaucoma surgery. An additional 3 patients withdrew by their own choice and 5 were discontinued for other reasons (none because of a device-related adverse event). Therefore, data were available for 60% (82/136) of patients who were originally enrolled in the study. Study design issues: Prospective, multi-centre study. Patients were divided into 2 cohorts: those with IOP 21 mm Hg despite topical medication or prior surgical glaucoma treatment, and those with stable IOP<21 mm Hg with medical treatment. Study population issues: Approximately 95% of patients were on at least 1 glaucoma medication before the procedure. Other issues: There is likely to be a high degree of patient crossover with Hoeh H et al. (2013) and Hoeh et al. (2016). open-angle glaucoma Page 13 of 28

14 Key efficacy and safety findings Efficacy Number of patients analysed: 136 for safety, 82 for efficacy Mean intraocular pressure (IOP), mmhg Cohort 1 (baseline IOP 21 mm Hg) n=23 Cohort 2 (baseline IOP<21 mm Hg) n=59 Baseline month follow-up p value < Not significant Mean number of IOP-lowering medications Cohort 1 (baseline IOP 21 mm Hg) n=23 Cohort 2 (baseline IOP<21 mm Hg) n=59 Baseline month 1.0± ±1.1 follow-up p value For cohort 1, 9% of patients needed 3 or more medications at 24-month follow-up and 35% of patients did not need any medication. In cohort 2, 14% of patients were on 3 or more medications and 42% needed no medication. Safety Adverse events or complications in the study eye considered to be related to the micro stent device or the implantation procedure, n (%) Event n=136 Transient hypotony (IOP<6 21 (15.4) mm) Obstruction of implant 12 (8.8) High IOP (IOP>30 mm Hg 6 (4.4) and baseline IOP + 10 mm Hg) 1 month onset 2 (1.5) >1 month onset 4 (2.9) Secondary glaucoma 15 (11.0) surgery Inflammation 5 (3.7) Inflammation >1 month 5 (3.7) onset Endothelial touch 5 (3.7) Hospitalised for IOP 4 (2.9) monitoring only Transient hyphema ( 1 2 (1.5) month onset) Secondary cataract 2 (1.5) Corneal oedema >1 month 1 (0.7) Corneal oedema >3 months 1 (0.7) to 12 months duration Chronic eye pain 1 (0.7) Migration of implant 1 (0.7) Repositioning of implant 1 (0.7) Explantation of implant 1 (0.7) Macular oedema 1 (0.7) Ectropion 1 (0.7) Retinal disease progression 1 (0.7) All cases of hypotony resolved in the follow-up period and none needed surgical intervention. Most cases of obstruction happened within the first 3 months. One patient with hyphema had posterior capsular rupture during the surgery, with anterior chamber bleeding and increased IOP; these events resolved within 4 days. Abbreviations used: BCDVA, best-corrected distance visual acuity; IOP, intraocular pressure open-angle glaucoma Page 14 of 28

15 Study 4 Hoeh H (2013) Details Study type Country Recruitment period Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Case series Germany, Canada, Austria, US Not reported n=184 patients (184 eyes) Patients with primary or secondary open-angle glaucoma and cataract. Mean 73 years; 57% female Visually significant cataract needing uncomplicated phacoemulsification surgery, and the presence of primary or secondary open-angle glaucoma (Shaffer grade 3 or 4) assessed by clinical gonioscopy. Exclusion criteria: angle closure or Shaffer grade 1 or 2 angles, uveitic or neovascular glaucoma, discernible congenital anomalies of the anterior chamber and angle, and known intolerance or hypersensitivity to topical anaesthetics, miotics, mydriatics, or polyimide. Combined phacoemulsification, with intraocular lens insertion, and microstent implantation into the supraciliary space. Glaucoma medications were stopped at the time of surgery. Device: CyPass Micro-Stent (Transcend Medical Inc., US). The CyPass device was implanted after completion of the phacoemulsification part of the surgery. The micro stent was inserted into the anterior chamber through the phacoemulsification incision and then into the supraciliary space. The positioning of the micro stent was evaluated using gonioscopy. At investigator discretion, positioning could also be evaluated by optical coherence tomography. Each site used its own standard regimen of postoperative antibiotics and steroids. 6 months 8 of the 9 authors are clinical investigators for Transcend Medical Inc., 1 of whom is also a consultant to Transcend Medical Inc., and the remaining author is an employee of Transcend Medical Inc. Analysis Follow-up issues: Only 53% (98/184) of patients were available for evaluation at 6 months, after accounting for early terminations and follow-up census. Study design issues: Prospective, multi-centre study. Patients were divided into 2 cohorts: those with IOP 21 mm Hg despite topical medication or prior surgical glaucoma treatment, and those with stable IOP<21 mm Hg with medical treatment. The primary outcome measure was the incidence of intraoperative and postoperative adverse events. Secondary outcome measures included change in IOP and the number of glaucoma medications used. An intent-to-treat analysis was done for the safety assessment. Study population issues: 51% of patients had a baseline IOP 21 mm Hg and 13% of patients had a previous intervention for glaucoma (incisional or non-incisional). 34% of patients were taking 3 or more IOP-lowering medications at baseline. Other issues: This is an interim report of an ongoing safety study. There is likely to be a high degree of patient crossover with Hoeh H et al. (2016). open-angle glaucoma Page 15 of 28

16 Key efficacy and safety findings Efficacy Number of patients analysed: 184 Intraocular pressure (IOP) Cohort 1 (IOP 21 mm Hg at baseline despite topical medication or prior surgical glaucoma treatment), n=91 at baseline and n=57 at 6 month follow-up Mean IOP at 6 month follow-up=15.6±0.53 mm Hg (p<0.001 compared with baseline) Mean change from baseline at 6 month followup=-36.9% (p<0.001) Mean number of medications used at 6 month followup=0.9±0.15 (p<0.001 compared with baseline) In patients with uncontrolled glaucoma before the procedure, the mean IOP was reduced by more than 30% from baseline at 6 months and patients were taking a mean of 50% fewer medications. Safety Adverse events and complications occurring at any time since implantation Adverse event/complication n (%) Inflammation/anterior chamber reaction >1 month 8 (4.4) Early hypotony (<1 month) 25 (13.8) Hypotony >1 month (<6 mm Hg) 1 (0.5) Shallow anterior chamber (no central touch) 1 (0.5) Transient IOP increase >10 mm Hg from baseline Postoperative hyphema (resolved within first 2 weeks; excludes minor transient intraoperative reflux bleeding from cyclodissection) 19 (10.5) 1 (1.1) Device repositioning 1 (0.5) Reduction of 2 lines of CDVA from baseline 2 (1.1) Need for additional surgical intervention 9 (5.0) Cohort 1 (stable IOP<21 mm Hg at baseline with medical treatment), n=93 at baseline and n=41 at 6 month follow-up Mean IOP at 6 month follow-up=15.6±0.68 mm Hg (p value not reported) Mean number of medications used at 6 month followup=0.6±0.07 (p<0.001 compared with baseline) In these patients, IOP remained controlled at below 21 mm Hg. There was a significant reduction (71.4%) in the mean number of IOP-lowering medications. No micro stent needed explanting. There were no cases of hypotony maculopathy, corneal oedema lasting for more than 1 month, suprachoroidal haemorrhage, other choroidal changes, retinal detachment, iris atrophy or endophthalmitis. The single case of device repositioning was in the early postoperative period. The device was originally inserted in a suboptimum position and was subsequently tapped further into the supraciliary space and locked into position. Abbreviations used: CDVA, corrected distance visual acuity; IOP, intraocular pressure open-angle glaucoma Page 16 of 28

17 Study 5 Saheb H (2014) Details Study type Country Case series Canada Recruitment period 2008 to 2010 Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding n=35 Patients with open-angle glaucoma. Mean 69 years Not reported The procedure was done with cataract surgery in 22 patients and as a single procedure in 13 patients. Device: CyPass Micro-Stent (Transcend Medical Inc., US). 12 months The study was supported by Transcend Medical Inc. One of the 3 authors is a clinical investigator for Transcend Medical Inc., 1 is a consultant for Glaukos and Transcend Medical Inc. and the third is an employee of Transcend Medical Inc. Analysis Study design issues: Retrospective case series. Ocular Coherence Tomography (OCT) images were obtained at followup by diagnostic technicians not otherwise involved in the clinical care of the patients. Assessments included microstent position in the supraciliary space, presence of microstent lumen, and morphology of the surrounding supraciliary space and ciliary body tissue. Fluid accumulation around the microstent was evaluated in the area lateral to the microstent (circumferential lake), between the microstent and the sclera (tenting) and posterior to the distal end of the microstent (posterior lake). Each image was graded with a score of 0 to 4 for the 3 morphological features. The composite score was the mean of the grades for all the anatomical features at each time point. The image grader was masked to all clinical outcome measures, as well as the postoperative timing of the OCT images. Study population issues: Baseline mean intraocular pressure was 21.9±6.1 mm Hg on average of 3.0 topical medications. open-angle glaucoma Page 17 of 28

18 Key efficacy and safety findings Efficacy Number of patients analysed: 35 Safety No safety outcomes were reported. Anatomic outcomes Follow-up Feature scored 1 month 6 months 12 months Tenting % of patients with score 1 96 (24/25) 90 (19/21) 79 (15/19) Mean score 2.8± ± ±0.99 Posterior fluid % of patients with score 1 79 (15/19) 65 (11/17) 60 (9/15) Mean score 1.6± ± ±0.70 Circumferential fluid % of patients with score 1 89 (8/9) 100 (13/13) 64 (7/11) Mean score 1.9± ± ±1.50 Composite score 2.5± ± ±1.05 Serial OCT imaging did not show any significant changes in stent position or patency over time. The supraciliary space showed accumulation of aqueous within, around, and posterior to the microstent in the majority of patients. However, the OCT modality was limited with increasing depth of imaging into the supraciliary space. open-angle glaucoma Page 18 of 28

19 Validity and generalisability of the studies Evidence was only included when the supraciliary microstent was inserted at the same time as a phacoemulsification procedure for cataract; the cataract surgery alone may affect intraocular pressure. There is a lack of long-term follow-up data. The longest follow-up in the published studies is 2 years. None of the evidence was from patients treated in the UK. The large RCT only included patients with primary open-angle glaucoma but 3 of the case series (all from 1 study) included a proportion of patients with secondary open-angle glaucoma. All the evidence was based on 1 specific device. Three reports included patients who were enrolled in the same study, with results at different follow-up periods 2,3,5. It is not clear how much patient overlap there is between these case series. Existing assessments of this procedure There were no published assessments from other organisations identified at the time of the literature search. Related NICE guidance Below is a list of NICE guidance related to this procedure. Interventional procedures Ab externo canaloplasty for primary open-angle glaucoma. NICE interventional procedure guidance 591. Available from Trabecular stent bypass microsurgery for open-angle glaucoma. NICE interventional procedure guidance 575 (2017). Available from open-angle glaucoma Page 19 of 28

20 Trabeculotomy ab interno for open angle glaucoma. NICE interventional procedure guidance 397 (2011). Available from NICE guidelines Glaucoma: diagnosis and management. NICE clinical guideline 85 (2009). Available from Additional information considered by IPAC Specialist advisers opinions Specialist advice was sought from consultants who have been nominated or ratified by their Specialist Society or Royal College. The advice received is their individual opinion and is not intended to represent the view of the society. The advice provided by Specialist Advisers, in the form of the completed questionnaires, is normally published in full on the NICE website during public consultation, except in circumstances but not limited to, where comments are considered voluminous, or publication would be unlawful or inappropriate. Three Specialist Advisor Questionnaires for ab interno supraciliary micro stent insertion for primary open-angle glaucoma were submitted and can be found on the NICE website. Patient commentators opinions NICE s Public Involvement Programme will send questionnaires to NHS trusts for distribution to patients who had the procedure (or their carers). When NICE has received the completed questionnaires, these will be discussed by the committee. Company engagement A structured information request was sent to 2 companies who manufacture a potentially relevant device for use in this procedure. NICE received 1 completed submission. This was considered by the IP team and any relevant points have been taken into consideration when preparing this overview. Issues for consideration by IPAC Ongoing trials: open-angle glaucoma Page 20 of 28

21 An Observational Multicenter Clinical Study to Assess the Long-Term Safety of the CyPass Micro-Stent in Patients With Primary Open Angle Glaucoma Who Have Completed Participation in the COMPASS Trial (NCT ); case control study; US; Estimated enrolment 300; Study start date March 2016; Estimated study completion date March open-angle glaucoma Page 21 of 28

22 References 1. Vold S, Ahmed IIK, Craven ER, et al. (2103) Two-Year COMPASS Trial Results: Supraciliary Microstenting with Phacoemulsification in Patients with Open-Angle Glaucoma and Cataracts Ophthalmology 123: Hoeh H, Vold SD, Ahmed IK, et al. (2016) Initial Clinical Experience With the CyPass Micro-Stent: Safety and Surgical Outcomes of a Novel Supraciliary Microstent Journal of Glaucoma 25: Höh H, Grisanti S, Grisanti S et al. (2014) Two-year clinical experience with the CyPass Micro-stent: safety and surgical outcomes of a novel supraciliary micro-stent. Klinische Monatsblatter fur Augenheilkunde 231: Hoeh H, Ahmed, II, Grisanti S, et al. (2013) Early postoperative safety and surgical outcomes after implantation of a suprachoroidal micro-stent for the treatment of open-angle glaucoma concomitant with cataract surgery Journal of Cataract & Refractive Surgery 39: Saheb H, Ianchulev T and Ahmed, II (2014) Optical coherence tomography of the suprachoroid after CyPass Micro-Stent implantation for the treatment of open-angle glaucoma British Journal of Ophthalmology 98: open-angle glaucoma Page 22 of 28

23 Additional relevant papers The following table outlines the studies that are considered potentially relevant to the IP overview but were not included in the main data extraction table (table 2). It is by no means an exhaustive list of potentially relevant studies. Article Number of patients/ follow-up Direction of conclusions Reasons for non-inclusion in table 2 Bailey AK, Sarkisian Jr SR and Vold SD (2014) Ab interno approach to the suprachoroidal space Journal of Cataract and Refractive Surgery 40: Review Although glaucoma filtration surgery options are generally effective means of surgically lowering intraocular pressure (IOP), complications have driven innovators to develop novel approaches to the lowering of IOP. Using the suprachoroidal space has been one novel way to avoid these complications. This article reviews how recent innovation has exploited this space to lower IOP. Old review, which does not include recently published studies. Brandao LM and Grieshaber MC (2013) Update on Minimally Invasive Glaucoma Surgery (MIGS) and New Implants Journal of ophthalmology 2013: Review The drawback of MIGS is that some of these procedures produce a limited IOP reduction compared to trabeculectomy. Currently, MIGS is performed in glaucoma patients with early to moderate disease and preferably in combination with cataract surgery. Old review, which does not include recently published studies. Conlon R, Saheb H and Ahmed IIK (2016) Glaucoma treatment trends: A review Canadian Journal of Ophthalmology 52: Review A new class of glaucoma procedures, termed microinvasive glaucoma surgery, has emerged, which aims to fill the gap between conservative medical management and more invasive surgery. General review on treatment of glaucoma. Cornel S, Mehdi B, et al. (2015) Current options for surgical treatment for glaucoma. Romanian Journal of Ophthalmology 59: Review Surgery offers a better control of intraocular pressure than medical therapy. Only 1 relevant study is included, which is in table 2. Gigon A and Shaarawy T (2016) The Suprachoroidal Route in Glaucoma Surgery Journal of Current Glaucoma Practice 10: Review Most clinical studies seem to currently point toward the direction that there are actual benefits in suprachoroidal surgeries by avoiding bleb-related complications. Nevertheless, even suprachoroidal implants may be subject to scarring and failure. More data are still needed, especially concerning long-term effects, although the approach does seem appealing. All the relevant studies are already included in table 2. open-angle glaucoma Page 23 of 28

24 Kammer JA and Mundy KM (2015) Suprachoroidal devices in glaucoma surgery Middle East African journal of ophthalmology 22: Kerr NM, Wang J, and Barton K (2016) Minimally invasive glaucoma surgery as primary stand-alone surgery for glaucoma. Clinical & Experimental Ophthalmology, doi: /ceo Manasses DT and Au L (2016) The New Era of Glaucoma Micro-stent Surgery Ophthalmology and Therapy 5: Richter GM and Coleman AL (2016) Minimally invasive glaucoma surgery: current status and future prospects Review Review Review Review While conventional glaucoma filtration surgery provides excellent intraocular pressure (IOP) lowering effect, this comes at the expense of significant risks. As the physiology of the suprachoroidal space has become better understood, its potential as a source for aqueous drainage has generated significant interest. This has resulted in the creation of several suprachoroidal glaucoma devices with excellent IOP lowering ability and a much more favourable side effect profile. New studies have shown that primary ab interno trabeculectomy (Trabectome, NeoMedix Inc., US), trabecular micro-bypass stent insertion (istent and istent Inject, Glaukos Corporation, US), canalicular scaffolding (Hydrus, Invantis Inc., US), the ab interno gel Implant (XEN, Allergan, Ireland) or supraciliary stenting (CyPass Micro-Stent, Alcon, US) may lower the lowering intraocular pressure and/or topical medication burden in phakic or pseudophakic patients with glaucoma. This effect seems to last at least 12 months but reliable costeffectiveness and quality of life indicators have not yet been established by investigatorinitiated randomised trials of sufficient size and duration. A CyPass stent is unlikely to match the pressure-lowering effect of a trabeculectomy, but it may prove to be the equivalent of more than one drop. Given the widely recognised dissatisfaction and disadvantages with long-term drop therapy, the benefit from this should not be underestimated. These disadvantages are tolerated, by ophthalmologists at least, because of the relative safety of drops, but in many cases a patient might decide to accept a slightly higher risk profile to reduce or eliminate their drops. Further work will need to be done on patient-reported outcomes as well as on clinical effectiveness. Minimally invasive glaucoma surgery (MIGS) technology has the potential to solve a variety of problems in current glaucoma management. These include More recent studies are included. Only 1 relevant study is included, which is in table 2. All the relevant studies are already included in table 2. All the relevant studies are already included in table 2. open-angle glaucoma Page 24 of 28

25 Clinical Ophthalmology 10: Saheb H, Ahmed I (2012) Micro-invasive glaucoma surgery: current perspectives and future directions. Current Opinion in Ophthalmology 23: SooHoo JR, Seibold LK, Radcliffe NM, et al. (2014) Minimally invasive glaucoma surgery: current implants and future innovations Canadian Journal of Ophthalmology 49: Vinod K and Gedde SJ (2017) Clinical investigation of new glaucoma procedures Current Opinion in Ophthalmology 28 (2): Review Review Review minimising patient adherence problems, increasing quality of life for patients with ocular toxicity, and potentially reducing lifetime costs of expensive glaucoma medications, all while preserving the conjunctiva if additional, more invasive glaucoma surgeries are necessary in the future. There are several limitations to the current state of MIGS. These include limited quality and duration of evidence, lack of study standardisation, lack of costeffectiveness data, and incomplete knowledge of ideal patient selection. Micro-invasive glaucoma surgery (MIGS) procedures offer reduction in IOP, decrease in dependence on glaucoma medications and an excellent safety profile. Their role within our glaucoma treatment algorithm continues to be clarified and differs from the role of more invasive glaucoma surgeries such as trabeculectomy or glaucoma drainage devices. Filtering procedures, such as trabeculectomy and glaucoma drainage devices, are effective in lowering IOP, but they have significant associated adverse events and rates of failure. For these reasons, a new group of surgical procedures has emerged that seeks to decrease IOP with lower associated rates of complications. The acronym MIGS, usually described as minimally invasive glaucoma surgery, has been coined to describe this group of procedures. As new devices become available, MIGS procedures will help to fill the gap between conservative medical and laser therapy and invasive surgical treatment of glaucoma to offer patients an earlier and safer transition to surgical management of their disease. Newer glaucoma procedures targeting different aqueous outflow pathways have improved the safety profile of glaucoma surgery while preserving modest efficacy. Most can be combined with phacoemulsification, allowing for simultaneous treatment of comorbid cataract and glaucoma. Old review, which does not include recently published studies. Old review, which does not include recently published studies. All the relevant studies are already included in table 2. open-angle glaucoma Page 25 of 28

26 Well-designed randomised clinical trials with extended follow-up remain necessary to evaluate the long-term efficacy and late complications of these novel procedures. open-angle glaucoma Page 26 of 28