Theodore Krupin

A Randomized Trial of Brimonidine Versus Timolol in Preserving Visual Function: Results From the Low-pressure Glaucoma Treatment Study

PURPOSE To compare the alpha2-adrenergic agonist brimonidine tartrate 0.2% to the beta-adrenergic antagonist timolol maleate 0.5% in preserving visual function in low-pressure glaucoma. DESIGN Randomized, double-masked, multicenter clinical trial. METHODS Exclusion criteria included untreated intraocular pressure (IOP) >21 mm Hg, visual field mean deviation worse than -16 decibels, or contraindications to study medications. Both eyes received twice-daily monotherapy randomized in blocks of 7 (4 brimonidine to 3 timolol). Standard automated perimetry and tonometry were performed at 4-month intervals. Main outcome measure was field progression in either eye, defined as the same 3 or more points with a negative slope ≥-1 dB/year at P<5%, on 3 consecutive tests, assessed by pointwise linear regression. Secondary outcome measures were progression based on glaucoma change probability maps (GCPM) of pattern deviation and the 3-omitting method for pointwise linear regression. RESULTS Ninety-nine patients were randomized to brimonidine and 79 to timolol. Mean (± SE) months of follow-up for all patients was 30.0 ± 2. Statistically fewer brimonidine-treated patients (9, 9.1%) had visual field progression by pointwise linear regression than timolol-treated patients (31, 39.2%, log-rank 12.4, P=.001). Mean treated IOP was similar for brimonidine- and timolol-treated patients at all time points. More brimonidine-treated (28, 28.3%) than timolol-treated (9, 11.4%) patients discontinued study participation because of drug-related adverse events (P=.008). Similar differences in progression were observed when analyzed by GCPM and the 3-omitting method. CONCLUSION Low-pressure glaucoma patients treated with brimonidine 0.2% who do not develop ocular allergy are less likely to have field progression than patients treated with timolol 0.5%.

The risk profile of glaucoma filtration surgery.

Glaucoma surgery has evolved over the past 30 years from the full-thickness procedure to the guarded filtration procedure. However, many of the risks and complications attendant with the full-thickness procedure, including endophthalmitis, hypotony, cataract progression, and filtration failure, continue to plague the glaucoma surgeon performing the guarded filtration procedure, although at lower incidences. With proper modification of technique, such as with postoperative bleb titration and use of adjunctive antifibrotic therapy based on prognosticators for failure, the success rates of trabeculectomy reoperations can approach those of primary trabeculectomy. Such risk factors for failure include African-American race, higher preoperative intraocular pressures, previously failed filters, younger age, and uveitic and neovascular glaucomas. In this paper, we review a number of studies that analyze the risks, complications, and long-term results of glaucoma filtration surgery and discuss different surgical recommendations based on risk factors for failure as well as for performing concomitant cataract and glaucoma surgery.

Latanoprost Treatment for Glaucoma: Effects of Treating for 1 Year and of Switching From Timolol

PURPOSE To determine the efficacy and safety of latanoprost treatment for 1 year in glaucoma patients, and to evaluate the effects of switching from timolol to latanoprost therapy. METHODS Latanoprost 0.005% was topically applied once daily without masking for 6 months in 223 patients with elevated intraocular pressure after previous treatment with latanoprost once daily or 0.5% timolol twice daily for 6 months in a multicenter, randomized, double-masked, parallel group study. RESULTS Compared with baseline values before treatment, a significant (P < .0001) diurnal reduction in intraocular pressure of 6 to 8 mm Hg was maintained with minimal fluctuation for the duration of treatment. When treatment was switched from timolol to latanoprost, intraocular pressure was reduced by 1.5 +/- 0.3 mm Hg (mean +/- SEM; 8% change in intraocular pressure; 31% of the intraocular pressure reduction produced by timolol; P < .001) compared with the change in intraocular pressure in patients remaining on latanoprost therapy. Of the patients initially enrolled, 95% successfully completed treatment. There was a slight overall increase in conjunctival hyperemia in patients who switched from timolol to latanoprost, but no change in those who continued latanoprost. The timolol-induced reduction of resting heart rate returned to baseline levels after switching to latanoprost. Of the 247 patients treated with latanoprost during the masked and/or open-label studies, 12 (5%) demonstrated a definite (n = 4) or possible (n = 8) increase in iris pigmentation. CONCLUSIONS Latanoprost is a well-tolerated ocular hypotensive agent that appears to be more effective than timolol in reducing intraocular pressure. The increase in iris pigmentation appears to be harmless but requires further investigation.

5-Fluorouracil in Initial Trabeculectomy: A Prospective, Randomized, Muldcenter Study

PURPOSE Postoperative subconjunctival 5-fluorouracil (5-FU) injections increase the success of filtration surgery in eyes with prior filtration failure or cataract removal and in eyes with secondary glaucoma. The authors evaluate the safety and benefit of adjunctive 5-FU in eyes undergoing initial trabeculectomy. METHODS Patients with phakic, uncontrolled, open-angle glaucoma who were undergoing initial trabeculectomy were prospectively assigned to the 5-FU group on the first postoperative day. Patients in this group received five 5-mg injections during 2 weeks after surgery. Patients in the control group received no injections. RESULTS Preoperative intraocular pressure (IOP) and number of antiglaucoma medications were similar in the 5-FU (n = 32) and control (n = 30) groups. Transient superficial punctate keratopathy was the only postoperative complication that occurred more frequently (P < 0.05) in the 5-FU (14 eyes) than in the control eyes (3 eyes). Patients were followed for a minimum of 1 year or until a study endpoint was reached: IOP of 21 mmHg or greater with maximum medical therapy (2 5-FU eyes and 8 control eyes; P < 0.03) or cataract removal after filtration (5 treated and 3 control eyes). At last follow-up (mean, > 20 months), IOP and the number of antiglaucoma medications were significantly lower (P < 0.02) in the 5-FU eyes (IOP, 12.0 +/- 1.3 mmHg; medications, 0.2 +/- 0.1) than in the control eyes (IOP, 16.8 +/- 1.3 mmHg; medications, 0.8 +/- 0.2). Intraocular pressure was 20 mmHg or lower in 94% of 5-FU eyes and in 73% of control eyes (P < 0.03) and 16 mmHg or lower in 84% of 5-FU eyes and in 57% of control eyes (P < 0.02). CONCLUSIONS Adjunctive 5-fluorouracil increases the rate of success, decreases the level of postoperative IOP, and reduces the need for postoperative antiglaucoma medication in eyes with open-angle glaucoma undergoing initial trabeculectomy.

Risk Factors for Visual Field Progression in the Low-pressure Glaucoma Treatment Study

PURPOSE To investigate risk factors associated with visual field progression in the Low-pressure Glaucoma Treatment Study, a prospective trial designed to compare the effects of the alpha2-adrenergic agonist brimonidine tartrate 0.2% to the beta-adrenergic antagonist timolol maleate 0.5% on visual function in low-pressure glaucoma. DESIGN Prospective cohort study. METHODS Low-pressure Glaucoma Treatment Study patients with ≥5 visual field tests during follow-up were included. Progression was determined using pointwise linear regression analysis, defined as the same 3 or more visual field locations with a slope more negative than -1.0 dB/year at P < 5%, on 3 consecutive tests. Ocular and systemic risk factors were analyzed using Cox proportional hazards model and further tested for independence in a multivariate model. RESULTS A total of 253 eyes of 127 subjects (mean age, 64.7 ± 10.9 years; mean follow-up, 40.6 ± 12 months) were analyzed. Eyes randomized to timolol progressed faster than those randomized to brimonidine (mean rates of progression, -0.38 ± 0.9 vs 0.02 ± 0.7 dB/y, P < .01). In the final multivariate model adjusting for all tested covariates, older age (hazard ratio [HR] = 1.41/decade older, 95% confidence interval [CI] = 1.05 to 1.90, P = .022), use of systemic antihypertensives (HR = 2.53, 95% CI = 1.32 to 4.87, P = .005), and mean ocular perfusion pressure (HR = 1.21/mm Hg lower, 95% CI = 1.12 to 1.31, P < .001) were associated with progression whereas randomization to brimonidine revealed a protective effect (HR = 0.26, 95% CI = 0.12 to 0.55, P < .001). CONCLUSIONS While randomization to brimonidine 0.2% was protective compared to timolol 0.5%, lower mean ocular perfusion pressure increased the risk for reaching a progression outcome in the Low-pressure Glaucoma Treatment Study. This suggests that the beneficial effect of randomization to the brimonidine arm was independent of possible differences in ocular perfusion pressures between the 2 treatment arms. The current results and large number of drop-outs in the brimonidine 0.2% arm suggest that more research is necessary before altering clinical practice paradigms.

Krupin Eye Valve with Disk for Filtration Surgery

PURPOSE The authors evaluate a long posterior tube shunt device with a pressure sensitive valve for filtration surgery in eyes with recalcitrant glaucoma. METHODS The device consisted of an anterior chamber tube connected to an oval (13 x 18 mm) episcleral explant. The explant was designed to maximize the area of surrounding encapsulation while still allowing implantation within one quadrant. A pressure-sensitive and unidirectional slit valve in the tube provided resistance to aqueous humor flow. One-stage implantation without the use of restrictive sutures was performed in 50 eyes with various types of glaucoma unresponsive to prior glaucoma surgery. RESULTS Mean (+/- standard error of the mean) preoperative intraocular pressure (IOP) of 36.4 +/- 1.6 mmHg was reduced significantly (P < 0.001) to 8.3 +/- 1.3 mmHg on the first postoperative day. Mean anterior chamber depth (scale, 0-4+) was 3.4 +/- 0.1. Mean IOP 1 month after surgery was 14.1 +/- 1.3 mmHg. The implant was removed from four eyes due to IOP failure (1 eye), external erosion (2 eyes), or endophthalmitis (1 eye). A suprachoroidal hemorrhage occurred in one eye on the first postoperative day. Diplopia developed in one eye after surgery. Mean IOP at last follow-up examination (mean, 25.4 +/- 2.4 months; range, 16-36 months) was 13.1 +/- 1.3 mmHg. Intraocular pressure was 19 mmHg or lower in 80% of the eyes, 59% of which were without adjunctive antiglaucoma medications. CONCLUSIONS Design features of the Krupin Eye Valve with Disk result in a large area of encapsulation in a single ocular quadrant which functions as an external reservoir for passage of aqueous humor. The valve portion facilitates maintenance of anterior chamber depth during the early postoperative interval. This new therapeutic device can be effective in the long-term control of IOP in glaucomatous eyes not responsive to prior filtration surgery with adjunctive antimetabolite therapy.

Combination of systemic acetazolamide and topical dorzolamide in reducing intraocular pressure and aqueous humor formation

OBJECTIVE The study aimed to determine whether topical dorzolamide and systemic acetazolamide have an additive effect on intraocular pressure (IOP) and aqueous humor formation (AHF). DESIGN This was a prospective, open-label, two-protocol clinical study. PARTICIPANTS Sixteen patients with ocular hypertension or with primary open-angle glaucoma were studied. INTERVENTION Baseline AHF was measured by computerized fluorophotometry and IOP by pneumatonometry without antiglaucoma therapy. In the first protocol, dorzolamide was randomized to one eye (N = 10) and IOP and AHF measurements were repeated. One week later, having used dorzolamide in one eye three times daily, patients had measurements performed before and after the single administration of oral acetazolamide 250 mg. In the second protocol, having used acetazolamide 250 mg four times daily for 4 to 7 days (N = 6), patients had measurements performed before and after a single drop of dorzolamide was instilled randomly into one eye. The patient continued acetazolamide and unilateral dorzolamide for 4 to 7 more days and returned for IOP and AHF measurements. MAIN OUTCOME MEASURES Intraocular pressure and AHF were measured in treated and contralateral control eyes. RESULTS In the first protocol, IOP (mmHg +/- standard deviation) was significantly (P = 0.02) lower in the dorzolamide (16.3 +/- 2.6) than in the contralateral control (19.9 +/- 2.9) eyes. Aqueous humor formation (microliter/minute +/- standard deviation) also was lower (P = 0.02) in dorzolamide eyes (1.79 +/- 0.4 vs. 2.33 +/- 0.5). After oral acetazolamide 250 mg, IOP was unchanged in dorzolamide eyes (17.6 +/- 2.0 preacetazolamide vs. 17.9 +/- 2.0 postacetazolamide), whereas it was reduced (P = 0.003) in control eyes (20.5 +/- 2.2 preacetazolamide vs. 16.9 +/- 2.3 postacetazolamide). Aqueous humor formation was reduced in control eyes (2.31 +/- 0.8 preacetazolamide vs. 1.73 +/- 0.6 postacetazolamide; P = 0.005) but not in dorzolamide-treated eyes (1.56 +/- 0.45 preacetazolamide vs. 1.77 +/- 0.39 postacetazolamide). In the second protocol, acetazolamide 250 mg four times daily symmetrically reduced IOP and AHF in both eyes. After single-drop dorzolamide in one eye, IOP and AHF did not change significantly. After 4 to 7 days of acetazolamide and unilateral dorzolamide, IOP and AHF remained reduced to a similar level in dorzolamide and control eyes not receiving topical therapy. CONCLUSION Topical dorzolamide and oral acetazolamide, in the concentrations and doses used in this study, are not additive. Either drug alone results in maximum reduction in IOP and AHF. Concomitant glaucoma therapy of a topical and systemic carbonic anhydrase inhibitor is not warranted.

5-Fluorouracil After Primary Combined Filtration Surgery

We examined the safety and efficacy of 5-fluorouracil in eyes with open-angle glaucoma undergoing combined cataract removal and filtration surgery. We randomly assigned one eye each of 24 patients to receive 5-fluorouracil (five injections of 5 mg during two weeks after surgery) and one eye each of 20 patients to comprise the control group. Preoperatively, the two groups had similar mean intraocular pressure (P = .8) and number of medications (P = .2). The mean intraocular pressure of the 5-fluorouracil group was 18.6 +/- 1.1 mm Hg, with 2.5 +/- 0.3 medications; that of the control group was 18.2 +/- 1.2 mm Hg, with 2.2 +/- 0.2 medications. One year postoperatively, intraocular pressure and the number of medications were significantly reduced by a similar amount in both groups of patients (5-fluorouracil, 14.2 +/- 0.7 mm Hg, 0.8 +/- 0.2 medications; controls, 14.3 +/- 0.6 mm Hg, 1.0 +/- 0.2 medications). Transient superficial punctate keratopathy occurred more frequently (P = .04) in the 5-fluorouracil group (16 of 24 eyes, 67%) than in the control group (seven of 20 eyes, 35%). In our randomized and prospective study, the adjunctive use of 5-fluorouracil did not result in improved control of intraocular pressure one year after combined surgery in eyes with open-angle glaucoma.

Apraclonidine and Argon Laser Trabeculoplasty

Sixty patients with medically uncontrolled open-angle glaucoma (intraocular pressure greater than 21 mm Hg) were randomly assigned to one of two treatment regimens with apraclonidine before undergoing 360-degree argon laser trabeculoplasty. One drop of apraclonidine 1% was instilled one hour before and immediately after laser treatment in 30 eyes or apraclonidine was delivered only after trabeculoplasty in 30 eyes. Intraocular pressure before laser treatment, number of antiglaucoma medications, and the laser treatment settings were comparable between the two groups. The mean and percent change in intraocular pressures were similar in both treatment groups one and two hours after trabeculoplasty. One drop of apraclonidine 1% instilled immediately after argon laser trabeculoplasty prevented intraocular pressure increase one hour and two hours postoperatively as effectively as its instillation both one hour before and immediately after laser treatment.

Apraclonidine and Anterior Segment Laser Surgery: Comparison of 0.5% versus 1.0% Apraclonidine for Prevention of Postoperative Intraocular Pressure Rise

PURPOSE To compare the efficacy of 0.5% and 1.0% apraclonidine in preventing laser-induced intraocular pressure (IOP) elevation after trabeculoplasty, neodymium: YAG (Nd: YAG) iridotomy, and capsulotomy. METHODS This is a prospective, masked, and randomized study of 83 patients undergoing trabeculoplasty, 62 patients undergoing iridotomy, and 57 patients undergoing capsulotomy. Surgical eyes received one drop of 0.5% or 1.0% apraclonidine immediately after surgery. RESULTS Intraocular pressure reduced 2 hours after trabeculoplasty in the 0.5% (P = 0.028) and 1.0% (P = 0.004) groups. Intraocular pressure was higher than baseline in a greater number of eyes treated with 0.5% (12 of 39 eyes, 31%) compared with 1.0% apraclonidine (5 of 44 eyes, 11%) (P = 0.032). Intraocular pressure in eyes with a narrow chamber angle was reduced in 16 (85%) of 19 eyes treated with 0.5% and in 10 (84%) of 12 eyes treated with 1.0% apraclonidine after iridotomy. Of patients with chronic angle-closure glaucoma, IOP was similar to prelaser values in 11 (69%) of 16 eyes treated with 0.5% (P > 0.7) and 12 (80%) of 15 eyes treated with 1.0% apraclonidine (P > 0.3). In patients undergoing capsulotomy, pressure was significantly lowered in the 0.5% group (P = 0.04) but not in the 1.0% apraclonidine group. After capsulotomy, both treatment groups had similar (P > 0.3) numbers of eyes with an IOP less than baseline (83% for 0.5% apraclonidine and 81% for 1.0% apraclonidine). CONCLUSION The single postoperative administration of 0.5% apraclonidine is as effective as the 1.0% concentration in preventing IOP elevation immediately after trabeculoplasty, iridotomy, or capsulotomy.