Canaloplasty: Circumferential viscodilation and tensioning of Schlemm canal using a flexible microcatheter for the treatment of open-angle glaucoma in adults - PDF Document

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  1. ARTICLE Canaloplasty: Circumferential viscodilation and tensioning of Schlemm canal using a flexible microcatheter for the treatment of open-angle glaucoma in adults Two-year interim clinical study results Richard A. Lewis, MD, Kurt von Wolff, MD, Manfred Tetz, MD, Norbert Koerber, MD, John R. Kearney, MD, Bradford J. Shingleton, MD, Thomas W. Samuelson, MD PURPOSE: To evaluate 2-year postsurgical safety and efficacy of canaloplasty (circumferential vis- codilation and tensioning of the inner wall of Schlemm canal) to treat open-angle glaucoma (OAG). SETTING: Multicenter surgical sites. METHODS: This international prospective study comprised adult OAG patients having glaucoma surgery or combined glaucoma–cataract surgery. Qualifying preoperative intraocular pressure (IOP) was at least 16 mm Hg and historical IOP, at least 21 mm Hg. The full circumference of the canal was viscodilated and a trabecular tensioning suture placed with a microcatheter. Primary outcome measures included IOP and glaucoma medication use. RESULTS:At24months,all127eyes(127patients)hadameanIOPof16.0mmHgG4.2(SD)and mean glaucoma medication use of 0.5 G 0.8 (baseline values 23.6 G 4.8 mm Hg and 1.9 G 0.8 medications). Eyes with canaloplasty alone had a mean IOP of 16.3 G 3.7 mm Hg and 0.6 G 0.8 medications (baseline values 23.2 G 4.0 mm Hg and 2.0 G 0.8 medications). Eyes with combined glaucoma–cataract surgery had a mean IOP of 13.4 G 4.0 mm Hg and 0.2 G 0.4 medications (baseline values 23.1 G 5.5 mm Hg and 1.7 G 1.0 medications). The IOP and medication use results at all time points were statistically significant versus baseline (P <.001). The late postoper- ative follow-up identified 3 patients with elevated IOP. No other serious ocular or nonocular com- plications were reported. CONCLUSION: Canaloplasty was safe and effective in reducing IOP in adult patients with OAG. J Cataract Refract Surg 2009; 35:814–824 Q 2009 ASCRS and ESCRS bleb poses an ongoing risk for infection or hypotony and may require treatment or surgical revision to maintain function.9–14 Surgical methods to restore the natural aqueous out- flowsystemandthetrabeculocanalicularoutflowpath- way to treat OAG have long been of interest.15–17Such methods would obviate the need for a subconjunctival bleb and might reduce the complications associated with penetration of the intraocular space and shunting aqueous to nonphysiologic routes. However, such methodstypicallytreatonlyasegmentofthedistalout- flow pathway and lower IOP less than trabeculectomy and there are difficulties with surgical consistency.18–22 Open-angle glaucoma (OAG) is a disease in which the physician often observes a gradual loss of vision in a patient on medical therapy until surgical interven- tion is necessary to preserve the remaining vision. Tra- ditionally, a surgical procedure, trabeculectomy, is performed to penetrate the anterior chamber and shunt the aqueous humor to a subconjunctival bleb to reduce intraocular pressure (IOP). Although trabe- culectomy can achieve a large reduction in IOP and successfully preserve vision in most patients,1,2the acute postsurgical complications of the procedure are frequent and may in themselves cause loss of vi- sion.3–8In addition, the resulting subconjunctival 814 Q 2009 ASCRS and ESCRS 0886-3350/09/$dsee front matter Published by Elsevier Inc. doi:10.1016/j.jcrs.2009.01.010

  2. 815 CANALOPLASTY FOR OAG Recent advances in technology have allowed glau- coma surgeons to use a flexible microcatheter to access the lumen of Schlemm canal along its entire length.23 The treatment approach led to the development of a nonpenetrating surgical procedure called canalo- plasty, which involves catheterization and viscodila- tion of the entire length of the canal. In addition, a suture is placed within the canal to tension the inner wall and the associated trabecular meshwork with the intention of restoring natural trabeculocanalicular aqueous outflow. Previously, we reported the 1-year interim results in a multicenter prospective clinical study of canalo- plasty in adults with OAG.24,25The 1-year interim re- sults showed a significant reduction in IOP and glaucoma medication use with few surgical complica- tions. This 2-year interim analysis is intended to ad- dress, in part, the longevity of the treatment’s efficacy and safety, an important consideration in the treatment of OAG. Anterior segment imaging con- tinues tobeacomponentof thestudytorelate postsur- gical anterior segment morphology with IOP efficacy. site by the appropriate institutional review board or ethics committee(IRB/EC),andallpatients(ortheirlegalrepresen- tative) read, signed, and dated an IRB/EC–approved con- sent form before having a screening examination and participating in the study. As a result of the encouraging re- sults in the initial study with a 12-month follow-up, all en- rollees were requested to complete an additional IRB/EC– approved patient consent for extended follow-up at 6-month intervals for up to 5 years. Additional details of the study methods were described with the 1-year interim results.24,25 All enrollees had a single complete baseline ophthalmic examination including history of glaucoma, medication use, IOP, best corrected visual acuity (BCVA), gonioscopy, and slitlamp and fundus evaluation. Postoperative follow- up examinations were at 1 day, 1 week, and 1, 3, 6, 12, 18, and 24 months at minimum. Postoperative evaluations in- cluded IOPmeasurements, BCVA,slitlampexamination, go- nioscopy, ophthalmic medication reporting, and adverse event reporting. The preoperative and postoperative medi- cation regimens were investigator specific and recorded at each follow-up visit. High-resolution ultrasound biomicroscope (UBM) images were obtained using a system designed for intraoperative and office-based anterior segment imaging (iUltrasound, iS- cience Interventional) to characterize anterior angle mor- phology before and after surgery. At least 1 postoperative UBM examination was scheduled for each patient during the follow-up period to evaluate the role of anterior angle morphology on surgical outcome. PATIENTS AND METHODS Design This is a 2-year interim report of an ongoing international multicenter prospective open-label surgical study of canalo- plasty at 14 clinical sites in the United States and Germany, with 16 surgeon investigators. The study was performed in accordance with the principles set forth in the Declaration of Helsinki, the Regulations and Guidelines of the U.S. Food and Drug Administration, International Organization for Standardization ISO 14155-1, and the International Conference on Harmonisation: Good Clinical Practices. The study was designed to evaluate the safety and efficacy of the canaloplasty procedure to reduce IOP in nonpenetrating surgery for OAG. The protocol was approved for each study Patient Inclusion and Exclusion Criteria The study protocol was designed to allow flexibility in pa- tientselectionandtreatmentoptionstoreflecteachinvestiga- tor’s current practice of glaucoma surgery. Specifically, phacoemulsification with posterior chamber intraocular lens (IOL) implantation in combination with canaloplasty and previous surgeries that would not interfere with com- plete circumferential catheterization of Schlemm canal were allowed.Thedataanalysiswassegregatedtoevaluateresults in different subgroups of patients and treatment options. Study monitors verified all patient enrollment and examina- tion case report forms against the patient medical records during the course of the study. Eyes that did not meet enroll- mentcriteriaduringthisverificationwereexcludedfromthis analysisbutwerecontinuedtobeexaminedbytherespective investigators for postoperative complications. All patients were 18 years or older at the time of enroll- ment, able to understand and provide informed consent, and scheduled for glaucoma surgery or combined cataract and glaucoma surgery. Criteria for this study included a glaucoma diagnosis of primary OAG (POAG), pigmentary glaucoma, pseudoexfoliation glaucoma, or POAG mixed with another mechanism; an IOP of 16 mm Hg or higher taken, at most, 60 days before surgery (baseline); and a max- imum historical IOP of 21 mm Hg or higher. With many pa- tients on maximum tolerated medical therapy, the protocol was designed to allow patients to withdraw from medica- tions due to intolerance or poor compliance provided they had an historically recorded maximum IOP of 21 mm Hg or greater. Patients with more than 2 laser trabeculoplasty procedures or a history of chronic angle closure were ex- cluded. Only 1 eye per patient was eligible. Forefficacyanalysisofthecanaloplastyprocedure,thepa- tients were divided into groups: Group 1 included all Submitted: December 5, 2008. Final revision submitted: January 19, 2009. Accepted: January 20, 2009. Fromprivatepractices,Sacramento,California(Lewis),Johnstown, New York (Kearney), Boston, Massachusetts (Shingleton), and Minneapolis, Minnesota (Samuelson), USA; Augen-Tagesklinik Gross Pankow (von Wolff), Gross Pankow, Eye Center Spreebogen and Berlin Eye Research Institute (Tetz), Berlin, and Augen-op- Centrum (Koerber), Koeln, Germany. Drs. Kearney, Lewis, Samuelson, Shingleton, andTetz have consul- tingagreementswithiScienceInterventional.Noauthorhasafinan- cial or proprietary interest in any material or method mentioned. Supported by iScience Interventional. Corresponding author: Richard A. Lewis, MD, Grutzmacher & Lewis, 1515 River Park Drive, Suite 100, Sacramento, California 95815, USA. E-mail: rlewiseyemd@yahoo.com. J CATARACT REFRACT SURG - VOL 35, MAY 2009

  3. 816 CANALOPLASTY FOR OAG Figure 2. Schematic of circumferential tensioning suture (blue) in Schlemm canal. Figure 1. Intraoperative photograph showing the microcatheter be- ing advanced through Schlemm canal. The yellow arrow is pointing at the beacon tip of the microcannula visible through the sclera. tied to the distal tip and the microcatheter withdrawn, pull- ing the suture into the canal. The suture was cut from the mi- crocatheter and then tied in a loop, encircling the inner wall of the canal using a slip knot. The suture loop was tightened to distend the trabecular meshwork inward, placing the tis- sues in tension, after which locking knots were added (Fig- ure 2). A descemetic window was formed just before or immediately after catheterization of the canal. The deep flap was excised and the superficial flap was sutured water- tight to prevent bleb formation. Additional details of the sur- gical procedure have been described.24 patients meeting the inclusion and exclusion criteria. Group 2 included all patients with successful suture implantation during canaloplasty alone. Group 3 included all patients with successful suture implantation during canaloplasty combined with cataract surgery. Analysis was also per- formed on subsets of Group 2 based on UBM examination of the trabecular meshwork distension from the intracanalic- ularsuture.Subgroup2AincludedallGroup2patientswith- outobservedtrabecularmeshworkdistensionandSubgroup 2B, all Group 2 patients with observed trabecular meshwork distension. The primary endpoints included mean IOP and mean number of glaucoma medications at the follow-up visits. The secondary endpoints included surgical and post- surgical complications. Ultrasound Biomicroscopy Imaging High-resolution UBM images of the anterior angle and Schlemm canal were obtained from study eyes preopera- tively, intraoperatively, and postoperatively. Of interest were postoperative images collected of all 4 quadrants of the operative eye to assess viscodilation of Schlemm canal, distension of the trabecular meshwork from the tensioning suture, and the size of the surgically created descemetic window. During the study, evaluation of the acquired UBM images was found to be useful in analyzing for correlation between trabecular meshwork distension and the IOP results. A grad- ingscalewascreatedtorepresentdistensionofthetrabecular meshwork due to the tensioning suture. The distension was measured by estimating the inscribed angle from the trabec- ular meshwork displacement using the protractor function of the ultrasound system on representative anterior chamber angle images (Figure 3). The inscribed angle described by an apex at the scleral spur or the iris insertion was used to mea- sure the distension, with resolution to the nearest 0.5 de- grees. The angle result was used to categorize distension into a grading range of 0 to 3, with 0 equaling no distension and 3 representing maximum distension (Table 1). The values from multiple quadrants were averaged to provide a mean distension grade for each study eye. The evaluation of the images was performed by trained readers who were maskedtopatientfollow-updata.Eachgradingwaschecked Surgical Technique Eachpatientwasenrolledtohavethecanaloplastyprocedure using the microcatheter. The microcatheter had a 200 mm diameter shaft with an atraumatic distal tip approximately 250 mm in diameter. The device incorporated an optical fiber toprovideanilluminatedbeacontiptoassistinsurgicalguid- ance.Theilluminatedtipwasseentranssclerallyduringcath- eterization of Schlemm canal to identify the location of the distaltipofthemicrocatheter.Themicrocatheterhadalumen with a proximal Luer lock connector through which an oph- thalmic viscosurgical device (OVD) was delivered. The mi- crocatheter was packaged with an OVD injector replacing the standard push syringe used to deliver OVDs to allow more precise injection of microliter volumes. Surgeonsfollowedtraditionalviscocanalostomyanddeep sclerectomy methods to perform a 2-flap dissection to the ca- nal. A forceps was used to manipulate the microcatheter and place the tip in alignment with the surgically created ostia of the canal. The microcatheter was advanced 12 clock hours within the canal while the surgeon observed the location of the beacon tip through the sclera and injected the OVD (so- dium hyaluronate 1.4% [Healon GV]) as the tip was ad- vanced (Figure 1). After catheterization of the entire canal lengthwiththe microcatheter andwiththe distaltip exposed at the surgical cutdown, a 10-0 polypropylene suture was J CATARACT REFRACT SURG - VOL 35, MAY 2009

  4. 817 CANALOPLASTY FOR OAG of eyes with more than 1 imaging session between the 1-month and 24-month follow-up were reviewed. The im- ages were placed into groups as follows: 1 to 6 months post- operative, 6 to12 months postoperative, and 12 to 24 months postoperative. The distension grades for these eyes were an- alyzed for decreases in grade of 0.5 units or more over time. Visual Acuity Snellen BCVA was converted to logMAR values for anal- ysis. Visual acuity results in Group 2 were evaluated to as- sess whether there was a potential loss of vision as a result of the canaloplasty-alone procedure. Success The success of the canaloplasty procedure was examined using associative analysis as described in the Advanced Glaucoma Intervention Study (AGIS): 7.1In the AGIS 7 asso- ciative analysis, eyes with 100% of visits with IOP less than 18 mm Hg had nearly zero change to the mean visual field defectscoreatlong-termfollow-up.UsingAGIS7asaguide- line, an associative analysis was prepared for the canalo- plasty data. The number of 6-month interval follow-up visits at which the IOPs were below 18 mm Hg was tallied. Patients missing more than 1 visit during the follow-up pe- riod were excluded from analysis. Eyes were separated intothe4analysisgroupsshowninTable2.Becausetheanal- ysis covered 24 months, only four 6-month periods were included. Figure3.AUBMimageoftheanterioranglewithprotractorusedfor measuring the inscribed angle described by the inward distension of the trabecular meshwork due to the intracanalicular suture. The apexissetatthescleralspur(ortheirisinsertionpoint),andthebase- line (magenta) is drawn along a line approximating the line of Schlemm canal and the inner surface of the corneo–scleral junction. The second arm (green) is placed along the distended trabecular meshwork (AC Z anterior chamber; C Z cornea; CB Z ciliary body; I Z iris; S Z sclera). byasecondreader.Gradingfromthe mostrecentpatient im- aging session available was used in the data analysis. Analysisofthe12-monthinterimresultsindicatedasignif- icant difference in IOP results partitioned by eyes by disten- sion grade. For the 24-month analysis, the results in Group 2 were evaluated using the same criteria for distension grade. The results in the 2 subgroups (Subgroup 2A, mean disten- sion grade !0.5; Subgroup 2B, mean distension grade R0.5) were compared. Serial UBM images were evaluated from a sampling of eyes to determine whether there were significant changes in trabeculardistension over the 2-year study period. Images Statistical Analysis One-way analysis of variance and the Wilcoxon signed rank test were performed for IOP, glaucoma medication, and visual acuity results at all postoperative time points compared with the values at baseline. Comparison of the means for all pairs of follow-up times was performed using the Tukey-Kramer correction adjusted for multiple compar- isons. Individual pair-wise comparison of group means us- ing the Student t test was performed for trabecular distension partitioned results from UBM imaging. RESULTS Demographics The study group consisted of 127 patients who met study inclusion and exclusion criteria with consent for Table 1. Conversion table of angle of trabecular distension to distension grade. Angle (Degrees) Distension Grade 0.0–5.0 5.5–6.5 7.0–8.0 8.5–9.5 10.0–11.0 11.5–12.5 13.0–14.0 14.5–15.5 16.0–17.0 17.5–18.5 19.0–20.0 20.5–21.5 22.0C 0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 2.25 2.50 2.75 3.00 Table 2. Associative analysis groupings. AGIS 7: Visits with IOP !18 mm Hg (%) Canaloplasty: Visits with IOP !18 mm Hg, n (%) AA Group A B C D 100 4 (100) 3 (75) 2 (50) 0 or 1 (!50) 75 to !100 50 to !75 0 to 50 AA Z associative analysis; AGIS Z Advanced Glaucoma Intervention Study; IOP Z intraocular pressure J CATARACT REFRACT SURG - VOL 35, MAY 2009

  5. 818 CANALOPLASTY FOR OAG Table 3. Study group demographics. Table 4. Postoperative interventions. Parameter Value Intervention Number (%) Enrollees, n Eyes, n Age (y) Mean G SD Range Sex, n (%) Female Male Unrecorded Race, n (%) White African American or African descent Hispanic Asian Pseudophakic at baseline, n (%) Diagnosis, n (%) POAG PXF Mixed (POAG and PXF) Mixed (POAG and acute angle closure) Pigmentary dispersion glaucoma Previous ocular surgery, n (%) Laser trabeculoplasty Peripheral laser iridotomy Nd:YAG capsulotomy Successful placement of intracanalicular suture, n (%) Combined procedure (phacocanaloplasty), n (%) 127 127 Cataract surgery Laser goniopuncture Conjunctival suture replacement Nd:YAG capsulotomy Peripheral laser iridotomy Cyclophotocoagulation Iridoplasty Paracentesis Selective laser trabeculoplasty Wound revision Nd:YAG laser to reduce synechias 11 (8.6) 6 (4.7) 5 (3.9) 5 (3.9) 2 (1.6) 1 (0.8) 1 (0.8) 1 (0.8) 1 (0.8) 1 (0.8) 1 (0.8) 67 G 11 37–88 63 (49.6) 63 (49.6) 1 (0.8) 114 (89.8) 8 (6.3) 4 (3.1) 1 (0.8) 16 (12.6) Nd:YAG Z neodymium:YAG Ninety-seven eyes (76%) had canaloplasty alone (Group 2). Thirty eyes (24%) had visually significant cataract and had canaloplasty combined with phaco- emulsification and IOL implantation (phacocanalo- plasty) (Group 3). 113 (89.0) 8 (6.3) 2 (1.6) 2 (1.6) 2 (1.6) 21 (16.5) 7 (5.5) 1 (0.8) 108 (85) Postoperative Interventions Table 4 shows the interventions in the 24-month postoperative period. The most frequent intervention was cataract surgery, followed by laser goniopuncture and replacement of a conjunctival suture for surgical site leakage 30 (24) Nd:YAG Z neodymium:YAG; POAG Z primary open-angle glaucoma; PXF Z pseudoexfoliation glaucoma Procedure Efficacy Table 5A and Figure 4 show the efficacy results in Group 1. At baseline, 28 (22.0%) eyes were on 3 or more medications at baseline and 6 eyes (4.7%) were not on any medication. At 24 months, 65 eyes (61.3%) were not on medication and 3 eyes (2.8%) were on 3 or more medications. At 24 months, the de- crease in the mean IOP from baseline was 32% and the mean reduction in medication use, 74%. All time-point IOP and medication-use results were statistically sig- nificant versus baseline values (P!.001). Table 5B and Figure 5 show the efficacy results in Group 2. At baseline, 17 eyes (20.2%) were on 3 or more medications and 2 eyes (2.4%) were not on any medication. At 24 months, 40 eyes (55.5%) were not on any medication and 2 eyes (2.7%) were on 3 or more medications. At 24 months, the decrease in the mean IOP from baseline was 30% and the mean reduc- tion in medication use, 70%. All time-point IOP and medication-use results were statistically significant versus baseline values (P!.001). Table 5C and Figure 6 show the efficacy results in Group 3. At baseline, 6 eyes (25.0%) were on 3 or long-term follow-up. Group 1 (all included patients) consisted of 127 eyes in 127 patients at baseline and 106 eyes in 106 patients (85%) at 24 months. Of the 21patients(16.5%)notrepresentedinthe24-monthco- hort, 6 (4.7%) had confirmed missed visits at 24 months, 4 (3.1%) had early terminations; the 24 month-data for 11 patients (8.7%) had not been col- lected at the time of manuscript preparation. The 4 early terminations included 1 patient (0.8%) converted to trabeculectomy and 1 patient (0.8%) converted to tube shunt 6 months and 18 months postoperatively, respectively, because of poor IOP control. One patient (0.8%) died after 18 months, and 1 patient (0.8%) with- drew after 18 months for personal reasons. Table 3 shows the demographics of all patients. The reasons for not achieving successful suture placement in 19 eyes were primarily device and anatomical fac- tors, such as the microcatheter tip entering a collector channel ostium, or other factors that prevented full catheterization of Schlemm canal. No significant ad- verse events resulting from failure to catheterize the canal were recorded. J CATARACT REFRACT SURG - VOL 35, MAY 2009

  6. 819 CANALOPLASTY FOR OAG Table 5A. Results in Group 1 (all included eyes). Table 5B. Results in Group 2 (canaloplasty alone). Mean IOP (mm Hg) G SD (Range) Mean Medications (n) G SD (Range) Mean IOP (mm Hg) G SD (Range) Mean Medications (n) G SD (Range) Exam n Exam n Baseline Postoperative 3 mo 6 mo 12 mo 18 mo 24 mo 127 23.6 G 4.8 (16–38) 1.9 G 0.8 (0–4) Baseline Postoperative 3 mo 6 mo 12 mo 18 mo 24 mo 84 23.2 G 4.0 (16–38) 2.0 G 0.8 (0–4) 88 83 15.7 G 5.3 (7–46) 15.6 G 4.0 (8–28) 15.4 G 4.2 (8–30) 16.1 G 4.1 (7–27) 16.0 G 4.2 (7–35) 0.3 G 0.6 (0–3) 0.3 G 0.5 (0–2) 0.4 G 0.7 (0–3) 0.4 G 0.6 (0–2) 0.5 G 0.8 (0–3) 60 53 67 68 72 16.5 G 5.3 (10–46) 16.5 G 3.9 (8–28) 15.7 G 3.9 (10–29) 16.2 G 4.2 (7–27) 16.3 G 3.7 (8–28) 0.4 G 0.7 (0–3) 0.4 G 0.6 (0–2) 0.5 G 0.8 (0–3) 0.5 G 0.6 (0–2) 0.6 G 0.8 (0–3) 101 100 106 more medications and 2 eyes (8.3%) were not on any medication. At 24 months, 17 eyes (85.0%) were not on any medication and no eye was on more than 1 medication. At 24 months, the decrease in the mean IOP from baseline was 42% and the mean reduction in medication use, 88%. All time-point IOP and medi- cation-use results were statistically significant versus baseline values (P!.001). but the difference in medication use was not (P Z .266, Student t test) (Figure 7, bottom). Of the 106 patients in which serial UBM images were evaluated, 24 (23%) had more than 1 graded im- aging session during the 24-month follow-up period. Two eyes (8.3%) had a decrease in distension grade of greater than 0.5 units. The eyes were not associated with an elevation in IOP after observation of the de- creased distension. Effect of Suture Tension Ultrasound images for measurement scoring of the distension grade were obtained in 102 (80%) of 127 pa- tients. Twenty-five patients (20%) did not have an im- aging session beyond 1 day postoperatively or had images that were not of sufficient quality to obtain an accurate measurement. Table 6 shows the IOP and medication results in Subgroup 2A (no discernible tension on UBM) and Subgroup 2B (observed tension on UBM). At baseline, the 2 subgroups had nearly identical IOP and medica- tion use. At 24 months in Subgroup 2A, the decreasein the mean IOP from baseline was 20% and the mean reduction in medication use, 60%. The decreases in Subgroup 2B were 31% and 75%, respectively. At 24 months, the difference in mean IOP between Sub- group 2A and Subgroup 2B means was statistically significant (P Z .018, Student t test) (Figure 7, top), Visual Acuity Table 7 shows the visual acuity results in Group 2. The mean BCVA in this group at 24 months was not significantly different from that at baseline. At 24 months, 3 (3%) of 127 eyes in Group 1 had lost 3 or more lines (0.3 logMAR) of BCVA. Of the 3 eyes, 1 (0.8%) had posterior capsule opacification and 1 had a dense nuclear sclerotic cataract; the reason for the vi- sual acuity decrease in the remaining eye was not specified. Success Table 8 and Figure 8 show the associative analysis results by group. Twenty (15.7%) of 127 patients did not meet the analysis criteria because of missed visits. Figure 4. Group 1 efficacy (all included patients) showing mean IOP (GSD)andmeanmedications.Thedashedlineindicatesthebaseline IOP of 23.6 mm Hg (IOP Z intraocular pressure). Figure 5. Group 2 efficacy (canaloplasty alone) showing mean IOP (GSD)andmeanmedications.Thedashedlineindicatesthebaseline IOP of 23.2 mm Hg (IOP Z intraocular pressure). J CATARACT REFRACT SURG - VOL 35, MAY 2009

  7. 820 CANALOPLASTY FOR OAG Table 5C. Results in Group 3 (phacocanaloplasty). Table 6. Distension-grade partitioned results in Group 2 (canal- oplasty alone). Mean IOP (mm Hg) G SD (Range) Mean Medications (n) G SD (Range) Exam n Mean IOP (mm Hg) G SD (Range) Mean Medications (n) G SD (Range) Distension Grade n Baseline Postoperative 3 mo 6 mo 12 mo 18 mo 24 mo 24 23.1 G 5.5 (16–38) 1.7 G 1.0 (0–3) Less than 0.5 Baseline Postoperative 3 mo 6 mo 12 mo 18 mo 24 mo 0.5 or greater Baseline Postoperative 3 mo 6 mo 12 mo 18 mo 24 mo 27 22.9 G 3.6 (16–34) 2.0 G 0.8 (0–3) 18 18 20 15 20 13.2 G 3.7 (7–22) 12.8 G 2.5 (9–20) 13.2 G 4.0 (8–20) 15.3 G 4.2 (10–25) 13.4 G 4.0 (7–22) 0.0 0.1 G 0.2 (0–1) 0.1 G 0.3 (0–1) 0.1 G 0.4 (0–1) 0.2 G 0.4 (0–1) 17 18.3 G 3.7 (13–27) 18 18.6 G 3.8 (10–28) 21 17.7 G 4.6 (10–29) 21 17.8 G 4.6 (7–25) 21 18.3 G 4.2 (8–28) 0.4 G 0.7 (0–2) 0.6 G 0.7 (0–2) 1.0 G 1.0 (0–3) 0.7 G 0.7 (0–2) 0.8 G 0.8 (0–3) 52 22.9 G 3.6 (16–38) 2.0 G 0.8 (1–4) Surgical and Postsurgical Complications Overall, the frequency of serious postsurgical com- plications was low, with 13 adverse events reported in 10 eyes. Table 9 shows all ocular-related surgical and postoperative complications that were reported regardless of severity. During surgery, there were 3 reported adverse events. The adverse events were classified as mild in severity and probably related to the surgical proce- dure. One suture extrusion (0.8%) through a partial segment of the trabecular meshwork was reported. A temporary decrease in the BCVA of 0.6 logMAR occurred in 1 eye at the 1-day follow-up; BCVA re- turned to the baseline value by the 1-month follow- up visit. The second eye had a reduction in BCVA of 0.22 logMAR at 1 day; BCVA returned to baseline value by the 1-week follow-up visit. Intheearly3-monthpostoperativeperiod,hyphema was observed in 10 of 127 eyes (7.9%). Cases of gross hyphema reported at the 1-day follow-up resolved at 1 week and 2 weeks postoperatively. Hyphema of 1.0 mm or greater was observed in 8 (6.3%) of 127 eyes at 1 day, 1 (0.9%) of 110 eyes at 1 week, and no 39 15.9 G 5.8 (10–46) 31 15.5 G 2.8 (8–20) 44 14.9 G 3.2 (10–21) 44 15.4 G 3.7 (10–27) 47 15.7 G 3.1 (9–24) 0.4 G 0.7 (0–3) 0.3 G 0.5 (0–1) 0.3 G 0.6 (0–2) 0.4 G 0.6 (0–2) 0.5 G 0.8 (0–3) IOP Z intraocular pressure eye at 1 month. Microhyphema (circulating red blood cells without layered blood in the anterior chamber) was noted in 11 eyes at 1 day, 4 eyes at 1 week, and no eye at 1 month. Figure 7. Top: Comparison of mean IOP (G SD) between Subgroup 2A and Subgroup 2B. The dashed line indicates the baseline IOP of 22.9 mm Hg (both groups). Bottom: Comparison of mean medica- tions (G SD) between Subgroup 2A and Subgroup 2B. The dashed line indicates the baseline medication of 2.0 (both groups) (DG Z distension grade; IOP Z intraocular pressure). Figure 6. Group 3 efficacy (phacocanaloplasty eyes) showing mean IOP (GSD) and mean medications. The dashed line indicates the baseline IOP of 23.1 mm Hg (IOP Z intraocular pressure). J CATARACT REFRACT SURG - VOL 35, MAY 2009

  8. 821 CANALOPLASTY FOR OAG procedureorthedevice.Theeventsincluded2incidents ofchestpain,1deathforunrelatedmedicalreasons,and single incidents of dizziness, dry and numb mouth, hip pain, indigestion, stomach pain, and tinnitus. Table 7. Visual acuity results in Group 2 (canaloplasty alone). Exam n Mean LogMAR BCVA G SD P Value* Baseline Postoperative 3 months 6 months 12 months 18 months 24 months 84 0.23 G 0.39 d 60 53 67 68 72 0.24 G 0.56 0.24 G 0.50 0.24 G 0.50 0.21 G 0.52 0.22 G 0.44 .935 .971 .896 .686 .860 DISCUSSION The canaloplasty procedure intends to increase the flow of aqueous humor from the anterior chamber, through the trabecular meshwork and the descemetic window, into and around Schlemm canal, and out through the collector channels, thereby reducing IOP. In the 1-year interim clinical study reports,24,25 the mean IOP was 16.2 G 3.5 mm Hg in eyes having canaloplasty alone and 13.7 G 4.4 mm Hg in eyes hav- ing canaloplasty combined with cataract surgery. Medication use dropped to a mean of 0.6 G 0.9 and 0.2G0.4,respectively,at12months.The2-yearresults shownearlyequivalentIOPandmedicationuseforca- naloplasty alone and canaloplasty combined with cat- aract surgery. After 2 years, the data indicate continued IOP control. Although it is difficult to compare results in studies with different patient populations and study methods, the canaloplasty efficacy results are comparable to published reports of trabeculectomy 2 years postoper- atively. In general, the Collaborative Initial Glaucoma Treatment Study2found IOP in the range of 14 to 15 mm Hg over the 4 to 5 years of follow-up. Other comparative studies of trabeculectomy6,26–31report a mean IOP after 2 years in the range of 10.1 to 16.9 mm Hg and mean medication use in the range of 0.1 to 1.2 medications. The lowest IOP and medication results were usually associated with the use of adjunc- tive antimetabolites and careful postoperative man- agement of the eye.6,11,14The associative analysis of the 2-year results indicate that 36% of eyes with canal- oplasty alone and 50% of canaloplasty alone eyes with observed trabecular meshwork distension met the cri- teria for AGIS associative analysis Group A (no mean BCVA Z best corrected visual acuity *Student t test In the early postoperative period, all cases of IOP el- evation (R30 mm Hg) were transient and resolved by the next required study follow-up except in 1 eye. The eye was subsequently treated with glaucoma medica- tions through the 24-month postoperative examina- tion. The wound hemorrhages were located in the corneal incision, subconjunctival space, or trabeculo– descemetic window and were not associated with ele- vated IOP. In the eye with hypotony secondary to a break in the trabeculo-descemetic window during surgery, the hypotony resolved by 1 week; peripheral anterior synechias were noted on the window near the suture location. Of the eyes with elevated IOP in the late postopera- tive period, 1 had an IOP of 35 mm Hg at 24 months and was treated with additional medication. One eye with an IOP of 27 mm Hg at 578 days was treated with medications until conversion to trabeculectomy at 651 days. One eye with an IOP of 28 mm Hg at 539 days was treated with medications and revision of the surgicalsite. The caseof suture erosion at the de- scemetic window after 1 year was not associated with IOP rise and did not require treatment. Nonocular-related surgical and postsurgical compli- cations included 9 reported events. These adverse events were not considered to be related to the Table 8. Associative analysis results at 24 months. Number (%) A B C D IOP for 4 Visits !18 mm Hg IOP for 3 Visits !18 mm Hg IOP for 2 Visits !18 mm Hg IOP for !2 Visits !18 mm Hg Group in Present Study n 1: All included eyes 2: Canaloplasty alone 3: Phacocanaloplasty 2A: Canaloplasty, DG !0.5 2B: Canaloplasty, DG R0.5 107 73 19 23 46 38 (36) 26 (36) 9 (47) 2 (9) 23 (50) 26 (24) 14 (19) 6 (32) 4 (17) 8 (17) 23 (21) 18 (25) 2 (11) 10 (43) 8 (17) 20 (19) 15 (21) 2 (11) 7 (30) 7 (15) DG Z distension grade; IOP Z intraocular pressure J CATARACT REFRACT SURG - VOL 35, MAY 2009

  9. 822 CANALOPLASTY FOR OAG Table9. Ocular-relatedandpostoperativesurgicalcomplications. Complication n (%) Microhyphema (!1.0 mm layered blood) Early elevated IOP (0–3 mo postop) Hyphema (R1.0 mm layered blood) Blebs at 24 months Late elevated IOP (O3 mo postop) Wound hemorrhage Descemet membrane detachment Gross hyphema Suture extrusion through trabecular meshwork Hypotony 10 (7.9) 10 (7.9) 8 (6.3) 4 (3.8) 3 (2.4) 3 (2.4) 2 (1.6) 2 (1.6) 2 (1.6) 1 (0.8) Figure 8. Associative analysis results. Percentage of eyes in Groups 1, 2, 3 and Subgroups 2A and 2B and having a postoperative IOP of less than 18 mm Hg at all visits from 6 months onward (A), at 3 of 4 visits (B), at 2 of 4 visits (C), and at fewer than 2 visits (D) (DG Z dis- tension grade). IOP Z intraocular pressure progression of visual field loss). Although reporting on a different study population, AGIS1found that 24% of patients met Group A criteria 2 years postoperatively. The safety profile of canaloplasty continues to be favorable over that of penetrating surgery such as trabeculectomy. The acute complications 1 year post- operatively24comparefavorablytothoseoftrabeculec- tomy. The incidence of hypotony after trabeculectomy is reported to be between 4% and 42%.6–8,20,28,30 Hyphema as a postoperative complication in trabecu- lectomy is reported in 8% to 42% of cases.5–8,20,28,30 Choroidal detachment has been reported in the range of 1% to 29%.20,28,30In reexamining the adverse event reporting in the study eyes in the acute postoperative period, the complications compare very favorably, with a 0.8% incidence of hypotony, 7.9% incidence of hyphema, and 0% incidence of choroidal detachment andcornealedema.However,10eyes(7.9%)hadatran- sient IOP spike of 30 mm Hg or greater during the im- mediate postoperative period, which in all but 1 case resolvedbythenextpostoperativevisit.Also,microhy- phema was observed in 11 eyes (8.7%) 1-day postoper- atively, most of which resolved by 1 week and in almost all cases, resolved by 1 month. Althoughcanaloplastyisdesignedasableblessproce- dure, it was uncertain whether there would be other forms of late postoperative complications. To date, the late complications have been infrequent and include 1 case of suture erosion (0.8%) and 3 cases (2.4%) of tran- sient IOP rise. This is in contrast to trabeculectomy, in which late hypotony, bleb encapsulation with loss of IOPcontrol,andendophthalmitisareconstantconcerns. The early surgical cases for the investigators were often without observed trabecular meshwork disten- sion on UBM. Suture tensioning and observed disten- sion improved for most investigators with a greater number of enrolled eyes. trabecular meshwork distension from suture tension had a lower mean IOP than eyes without distension 1 year postoperatively and continued to show a statis- tically significantly lower IOP and medication use at 2 years.Whetherthebeneficialeffectisderivedfromapi- locarpine-like effect on the trabecular meshwork,32,33 stenting of Schlemm canal,34or a combination is not clear. However the difference in postoperative IOP be- tween eyes with a tensioning suture and at least some observable trabecular meshwork distension (grade R0.5) and eyes with no or little observable tension (grade !0.5) supports a beneficial role of trabecular tension. One year postoperatively, eyes having combined ca- naloplasty and posterior chamber IOL implantation had significantly lower IOP and medication use than eyeshavingcanaloplastyalone,24,25indicatinganaddi- tional effect, possibly due to the IOP-lowering effect of cataractsurgery.35–39Theefficacyresultsat2yearswere nearly identical, with a mean IOP of 13.4 mm Hg and 85% of eyes on no medications. Reviewofthe2-yearpostoperativedatacontinuesto showatrendofgreatersuccessincatheterizationofthe canal and the placement of the tensioning suture at siteswithagreaternumber ofenrolledeyes.The learn- ing curve effect may have had a role in the outcomes; thus, the study results are indicative of a blend of sur- geons, many of whom had no experience with nonpe- netrating glaucoma surgery before the study. The findingsofthis2-yearinterimanalysisindicatethatcir- cumferentialdilation andtensioningofSchlemmcanal is a safe and effective technique to reduce IOP. The studydesignincludesadditionalfollow-upandreport- ingwithmoreextensivesubgroupanalysisanticipated during the continuing study. Inconclusion, canaloplastyisaformofnonpenetrat- ing glaucoma surgery that attempts to restore the nat- ural outflow process of the eye without the use of Eyes with observed J CATARACT REFRACT SURG - VOL 35, MAY 2009

  10. 823 CANALOPLASTY FOR OAG a subconjunctival bleb. Interim analysis of a prospec- tive clinical study indicated that the surgical proce- dure appears to effectively lower IOP with few postsurgical complications, with continued control of IOP in patients followed to 2 years. Late complications have been infrequent compared with the incidence with trabeculectomy, which uses a bleb for subcon- junctival filtration. The use of a microcatheter in the procedure to access the entire circumference of Schlemm canal facilitates treatment of the trabeculoca- nalicular outflow system. 8. Edmunds B, Thompson JR, Salmon JF, Wormald RP. The Na- tional Survey of Trabeculectomy. III. Early and late complica- tions. Eye 2002; 16:297–303 9. Mac I, Soltau JB. Glaucoma-filtering bleb infections. Curr Opin Ophthalmol 2003; 14:91–94 10. Ophir A. Encapsulated filtering bleb; a selective review–new deductions. Eye 1992; 6:348–352 11. 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Microsurgery of Schlemm’s canal and the human aqueous outflow system. Am J Ophthalmol 1973; 76:906–917 17. Stegmann R, Pienaar A, Miller D. Viscocanalostomy for open- angle glaucoma in black African patients. J Cataract Refract Surg 1999; 25:316–322 18. O’Brart DPS, Shiew M, Edmunds B. A randomised prospective study comparing trabeculectomy with viscocanalostomy with adjunctiveantimetaboliteusageforthemanagementofopenan- gle glaucoma uncontrolled by medical therapy. Br J Ophthalmol 2004; 88:1012–1017 19. Yalvac IS, Sahin M, Eksioglu U, Midillioglu IK, Aslan BS, Duman S. Primary viscocanalostomy versus trabeculectomy for primary open-angle glaucoma; three-year prospective ran- domized clinical trial. J Cataract Refract Surg 2004; 30:2050– 2057 20. Carassa RG, Bettin P, Fiori M, Brancato R. Viscocanalostomy versus trabeculectomy in white adults affected by open-angle glaucoma; a 2-year randomized, controlledtrial. Ophthalmology 2003; 110:882–887 21. Kobayashi H, Kobayashi K, Okinami S. A comparison of the intraocular pressure-lowering effect and safety of viscocanalos- tomy and trabeculectomy with mitomycin C in bilateral open- angle glaucoma. Graefes Arch Clin Exp Ophthalmol 2003; 241:359–366 22. Lu ¨keC,DietleinTS,JacobiPC,KonenW,KrieglsteinGK.Apro- spective randomized trial of viscocanalostomy versus trabecu- lectomy in open-angle glaucoma: a 1-year follow-up study. J Glaucoma 2002; 11:294–299 23. Cameron B, Field M, Ball S, Kearney J. Circumferential viscodi- lation of Schlemm’s canal with a flexible microcannula during non-penetrating glaucoma surgery. Digit J Ophthalmol 2006; 12(1). Available at: http://www.djo.harvard.edu/site.php?urlZ /physicians/oa/929. Accessed February 5, 2009 24. Lewis RA, von Wolff K, Tetz M, Koerber N, Kearney JR, ShingletonB,SamuelsonTW.Canaloplasty:circumferentialvis- codilationandtensioningofSchlemm’scanalusingaflexiblemi- crocatheter for the treatment of open-angle glaucoma in adults: interim clinical study analysis. J Cataract Refract Surg 2007; 33:1217–1226 APPENDIX Canaloplasty Clinical Investigators and Centers Germany:NorbertKoerber,MD,Koeln;Kurt-DietrichvonWolff,MD, Holger Bull, MD, Augen-Tagesklinik Gross Pankow, Gross Pankow; Manfred Tetz, MD, Eye Center Spreebogen and Berlin Eye Research Institute (BERI), Berlin. United States: Michael Field, MD, Bruce Cameron, MD, Northwest Eye Surgeons, Seattle, Wash- ington; Richard Lehrer, MD, Alliance, Ohio; John R. Kearney, MD, Cataract Care Center, Johnstown, New York; Thomas W. Samuel- son, MD, Minnesota Eye Consultants, Minneapolis, Minnesota; Garry Condon, MD, Allegheny-Singer Research Institute, Pitts- burgh, Pennsylvania; Richard A. Lewis, MD, Grutzmacher & Lewis, Sacramento,California;MarleneMoster,MD,RickWilson,MD,Wills Eye Hospital, Philadelphia, Pennsylvania; Bradford Shingleton, MD, Ophthalmic Consultants of Boston, Boston, Massachusetts; Ronald Fellman, MD, Glaucoma Associates of Texas, Dallas, Texas; Howard Weiss, MD, Washington Eye Physicians and Surgeons, Chevy Chase, Maryland; Alan L. Robin, MD, Johns Hopkins University, Baltimore, Maryland REFERENCES 1. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol 2000; 130:429–440 2. Feiner L, Piltz-Seymour JR. Collaborative Initial Glaucoma Treatment Study: a summary of results to date. Curr Opin Oph- thalmol 2003; 14:106–111 3. Jones E, Clarke J, Khaw PT. Recent advances in trabeculec- tomy technique. Curr Opin Ophthalmol 2005; 16:107–113 4. Borisuth NSC, Phillips B, Krupin T. The risk profile of glaucoma filtration surgery. 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