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Phacoemulsification versus phacoemulsification with micro-bypass stent implantation in primary open-angle glaucoma

Randomized double-masked clinical trial

Fea, Antonio M. MD

Author Information
Journal of Cataract & Refractive Surgery: March 2010 - Volume 36 - Issue 3 - p 407-412
doi: 10.1016/j.jcrs.2009.10.031
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Abstract

Primary open-angle glaucoma (POAG) is a leading cause of blindness in the world. The disease is characterized by elevated intraocular pressure (IOP), cupping of the optic disc, or a diminished visual field.1–3

Large prospective studies have shown that the risk for glaucomatous progression is significantly reduced when IOP is lowered and that each 1 mm Hg reduction in IOP is associated with an approximate 10% decrease in the risk for progression.4 The Early Manifest Glaucoma Trial Group4 confirmed that the lower the IOP at follow-up, the lower the risk for progression.

Glaucoma medical therapies act by reducing aqueous production or by increasing the outflow of aqueous via the trabecular or uveoscleral pathway. The treatments can, however, be associated with adverse events,5 and some patients may be unable to adequately comply with complex dosing regimens.6–8 Often, when patients are on the maximum tolerated medical therapy and IOP remains uncontrolled, incisional filtering surgery or laser trabeculoplasty are required.

Most resistance to the outflow of aqueous humor is thought to be by the juxtacanalicular connective tissue of the trabecular meshwork, which includes the inner wall of canal of Schlemm.9,10 Traditional surgical therapies lower IOP by redirecting aqueous outflow to the subconjunctival space.11,12

Spiegel and Kobuch13 and Spiegel et al.14 used small tubes to create a direct route from the anterior chamber to canal of Schlemm, bypassing the presumed damaged trabecular meshwork. A further modification of this approach was the development of an L-shaped stent that is approximately 1.0 mm long and is made of lightweight titanium (iStent, Glaukos Corp.) (Figure 1, top).15 The device is implanted with an ab interno approach that bypasses the trabecular meshwork and reroutes aqueous from the anterior chamber directly into canal of Schlemm without disrupting the scleral surface. In human anterior segments in perfused culture, this micro-bypass stent resulted in lower IOP.15 The purpose of this study was to compare the IOP-lowering efficacy of phacoemulsification alone and phacoemulsification and micro-bypass stent implantation in eyes with POAG.

Figure 1
Figure 1:
Top: Photomicrograph of micro-bypass stent. Bottom: Schematic of stent insertion in the eye using the gonioscope.

PATIENTS AND METHODS

This prospective randomized open-label study comprised patients with POAG scheduled to have phacoemulsification with intraocular lens (IOL) implantation alone or phacoemulsification, IOL implantation, and stent insertion. All patients provided written informed consent.

Inclusion criteria included a previous diagnosis of POAG with an IOP above 18 mm Hg at 3 separate visits on 1 or more ocular hypotensive medications, a preoperative corrected distance visual acuity no better than 0.6 (20/80), likely to follow surgeon instructions, and ability to give informed consent. Exclusion criteria were a glaucoma diagnosis other than POAG (ie, Scheie grade <2), peripheral anterior synechias, a cloudy cornea likely to inhibit gonioscopic view of the angle, previous ocular surgery (including glaucoma-filtering surgery), history of trauma or ocular surface disease, preproliferative or proliferative diabetic retinopathy, and age-related macular degeneration with macular scar or large macular atrophy that would inhibit potential visual acuity.

Randomization

Given the investigational nature of the stent used in the study, randomization was weighted to the control group (cataract surgery only) over the investigational group (cataract surgery plus stent implantation). Patient randomization was generated with a 2:1 ratio using Stata data analysis and statistical software (version 10, StataCorp LP).

Patients were masked to their assignment, as were staff members who measured IOP throughout the study.

Surgical Technique

All patients had standard clear corneal phacoemulsification with IOL implantation, with patients in the combined group also having implantation of a micro-bypass iStent. All preoperative peribulbar anesthesia dosing was considered current standard of care.

The stent was implanted using the same small temporal clear corneal incision (approximately 3.0 mm) that had been used for phacoemulsification and IOL placement. The stent was guided into canal of Schlemm by ab interno gonioscopy using a Swan-Jacobs gonioscope (Figure 1, bottom). If no complications occurred during phacoemulsification, acetylcholine was injected into the anterior chamber after IOL implantation to constrict the pupil. The anterior chamber was then filled with an ophthalmic viscosurgical device to reform the anterior chamber and provide more clearance in the angle.

With the stent on the tip of the applicator, the anterior chamber was traversed with the applicator and the trabecular meshwork located. The leading edge of the stent was gently slid through the trabecular meshwork and into canal of Schlemm at the nasal position (3 to 4 o'clock in right eye; 9 to 8 o'clock in left eye) with the tip of the stent directed inferiorly. If there was difficulty with insertion at the primary location, a location of approximately 0.5 clock hour inferiorly was attempted and the surgeon continued to move inferiorly as needed for subsequent attempts. Next, the stent was released by pushing the button on the applicator. After the position of the stent was verified, the applicator was withdrawn.

Postoperative Protocol

The patients were instructed to discontinue all glaucoma medications after surgery. A standard post cataract surgery antibiotic and antiinflammatory drug regimen was prescribed. Before the study, the primary referring ophthalmologist set the target IOP in each eye based on visual field and optic nerve examinations and age and risk factors in accordance with European guidelines.16 Any patient with a postoperative IOP (measured between 8:00 am and 10:00 am) that was more than 2 mm Hg over the target IOP was instructed to return twice in the following 3 days to have repeat IOP remeasurements. If the patient's IOP remained more than 2 mm Hg over the target pressure on 2 visits during those 3 days, ocular hypotensive agents were added using a preset schedule based on Italian government reimbursement policy as follows: β-adrenoceptor antagonists first, carbonic anhydrase inhibitors second, and prostaglandins third. If the patient's postoperative IOP returned to within 2 mm Hg of target, he or she returned to the normal visit schedule. Investigators were masked to treatment assignment when measuring IOP and when determining when or whether to add medications.

Follow-up visits were at 24 hours, 1 week, and 1, 2, 3, 6, 9, 12, and 15 months. Examinations at 6 months and 12 months included gonioscopy by an operator unaware of the treatment assignment. At 15 months, patients discontinued all ocular hypotensive agents and returned for a final unmedicated study evaluation 1 month later. This washout of ocular hypotensive agents was performed to evaluate the efficacy of the stent and to ensure the study masking was effective.

Statistical Analysis

Patients who did not complete the entire study were excluded from efficacy analyses. The primary outcome measure was IOP by Goldmann applanation tonometry. The secondary outcome measures were the number and type of glaucoma medications preoperatively and postoperatively. For continuous variables, 2-sample t tests were used to evaluate between-group differences and paired sample t tests to evaluate within-group differences. Fisher exact tests were used to evaluate nominal between-group differences. An a priori 2-tailed α level of 0.05 was considered statistically significant. StatView software (SAS Institute, Inc.) was used for all analyses. No correction for multiple comparisons was made. The sample size was selected based on safety considerations for a pilot study of an investigational implant. An a priori power calculation for this pilot study showed at least an 80% power to detect a difference in IOP of approximately 3 mm Hg.

RESULTS

Patient Demographics

There were 36 patients in this study, 24 (15 women; 12 right eyes) in the control group and 12 (8 women; 4 right eyes) in the combined group. The mean age was 64.9 years ± 3.1 (SD) (range 59 to 71 years) and 64.5 ± 3.4 years (range 60 to 70 years), respectively.

Three patients, all in the control group, were lost to follow-up. One patient had a capsule rupture, 1 did not present for the 6-month scheduled visit, and 1 died. The patient who died had broken her ankle and was unable to attend the 2-month follow-up visit; she subsequently died from complications from the ankle surgery. After exclusion of patients lost to follow-up, 33 patients were analyzed.

Ocular Hypotensive Efficacy

Figure 2 shows the mean IOP at each visit from baseline to 15 months (before medication washout). At baseline, the mean IOP was 17.9 ± 2.6 mm Hg in the combined group and 17.3 ± 3.0 mm Hg in the control group; the difference between groups was not statistically significant (P = .512). At 15 months, the mean IOP in the combined group was 14.8 ± 1.2 mm Hg, which was statistically significantly lower than the mean of 15.7 ± 1.1 mm Hg in the control group (P = .031). The mean decrease from baseline was numerically greater in the combination group than in the control group (3.2 ± 3.0 mm Hg versus 1.6 ± 3.2 mm Hg) (P = .177). Moreover, after washout of ocular hypotensive agents 16 months after surgery, the mean IOP in the combined group was 16.6 ± 3.1 mm Hg, which was statistically significantly lower than the mean of 19.2 ± 3.5 mm Hg in the control group (P = .042).

Figure 2
Figure 2:
Mean IOP ± SD (mm Hg). Asterisks indicates a statistically significant difference. The IOP at 16 months is 1 month after cessation of ocular hypotensive medications (H = hour; IOP = intraocular pressure; M = month; W = week).

Number of Glaucoma Medications

At baseline, the mean number of ocular hypotensive medications used was 1.9 ± 0.7 in the control group and 2.0 ± 0.9 in the combined group (Figure 3). Consistent with the protocol, ocular medication use decreased postoperatively to zero. Medication use increased over time in both treatment groups. By 15 months, the mean number of ocular medications was 1.3 ± 1.0 in the control group and 0.4 ± 0.7 in the combined group (P = .007). As required by the protocol, all patients used 1 or more ocular medications at study entry. At 15 months, 5 patients (24%) in the control group and 8 patients (67%) in the combined group did not require ocular hypotensive medication (P = .027).

Figure 3
Figure 3:
Mean number of medications ± SD. Asterisks indicates a statistically significant difference (H = hour; IOP = intraocular pressure; M = month; W = week).

DISCUSSION

In this study, implantation of the micro-bypass stent combined with cataract extraction resulted in significantly lower IOP and a significant reduction in the use of ocular hypotensive medications 15 months postoperatively compared with cataract surgery alone. Every 1 mm Hg decrease in IOP results in an exponential decrease in the likelihood of disease progression.17 Therefore, even small decreases in IOP are clinically relevant if the goal is to slow or halt disease progression. In this study, the mean decrease in the combined surgery group was 3.2 mm Hg compared with 1.6 mm Hg in the control group. Other studies18,19 report a similar decrease in IOP with phacoemulsification alone in patients with POAG.

The micro-bypass stent used in our study successfully reduced the mean number of medications needed to control IOP throughout the study, with noticeable differences between the combined group and control group beginning at 1 month. At the final follow-up at 15 months, 67% of those in the combined group were medication-free compared with 24% in the control group. Our results are similar to those in other studies that monitored glaucoma medication use after cataract surgery.17 One strength of our study design is that the addition of ocular hypotensive medications was in a prescribed order and based on explicit IOP criteria, eliminating medication selection bias.

Regarding safety, there were no reported adverse events related to stent implantation. One patient in the control group had a ruptured capsule and was excluded from the results. Two stents were malpositioned; 1 appeared to be functioning based on the lower IOP. The other patient required additional medications to control IOP. In the first patient, baseline IOP was 20 mm Hg on 1 medication (carteolol); at the 15-month follow-up, IOP was 13 mm Hg. This patient remained medication free at the 15-month follow-up. In the second patient, baseline IOP was 21 mm Hg on 2 medications (dorzolamide and timolol). At the 15-month follow-up, the patient had to use 1 medication to maintain target IOP.

Patient compliance is an ongoing concern for most ophthalmologists; therefore, a main goal is to keep the patient as free as possible from medications postoperatively. The reduction in topical medications, as in our study, is also likely to improve patients' ocular surface integrity because chronic use of glaucoma medications can result in corneal damage and inflammation.20 Moreover, chronic use of topical ocular hypotensive agents has been shown to reduce the probability of successful future trabeculectomy.21,22

Our results agree with those in numerous studies that show cataract surgery alone reduces IOP in patients who also have glaucoma; most prospective and retrospective studies show an approximate IOP reduction of 2 mm Hg.18,19,23,24 In this study, there were also a few cases of a slight postoperative IOP increase, which has also been reported after cataract surgery.25,26

This study is not without limitations. The number of patients was small, and extrapolating these results to a larger group may not be possible. Nevertheless, significantly more patients in the combined surgery group than in the control group remained medication free throughout the study. This study followed patients through 15 months, and the inclusion of a terminal washout 1 month after the final study visit provided unbiased evidence that the stent delivered effective IOP lowering beyond that generated by cataract surgery alone. This is not to say that the results to date would continue in a longer term study. Finally, endothelial cell counts (ECCs) were not tracked. Earlier studies found that ECCs were lower in patients with glaucoma than in those without.27 In other nonfiltering procedures, no clinically significant cell loss was found.28,29 I would expect ECC results similar to those after other nonfiltering procedures but cannot confirm that. I plan to continue following these patients and recommend a larger cohort trial with longer follow-up.

In conclusion, most patients having a combined cataract surgery and micro-bypass stent implantation maintained IOP target levels without medication through 15 months postoperatively. Conversely, the majority of patients having only cataract surgery reached the target IOP only with the addition of medications. Therefore, the stent reduced the need for medications postoperatively by restoring the aqueous outflow through a patent bypass in the trabecular meshwork.

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