Charles S. Tressler

Fixed combination of latanoprost and timolol vs individual components for primary open-angle glaucoma or ocular hypertension: a randomized, double-masked study.

OBJECTIVE To assess the efficacy and safety of fixed-combination latanoprost-timolol (FCLT) vs latanoprost or timolol monotherapy. METHODS This 12-week, randomized, double-masked, parallel-group study included patients with open-angle glaucoma or ocular hypertension treated with a beta-blocker and with baseline intraocular pressure (IOP) of 26 through 36 mm Hg. Following washout, eligible patients were randomized to once-daily FCLT in the evening, latanoprost in the evening, or timolol in the morning. MAIN OUTCOME MEASURES Postbaseline IOP assessments at 8 am, 10 am, and 4 pm at weeks 2, 6, and 12; statistical superiority of FCLT for the 18 pairwise comparisons between FCLT and the 2 monotherapies, using analysis of variance. RESULTS All therapies resulted in significant IOP reductions from baseline. Pairwise comparisons favored FCLT at all time points. When the 18 comparisons were tested simultaneously, FCLT was statistically superior to latanoprost at 7 of 9 time points and at all 9 time points when compared with timolol. In addition, FCLT was associated with greater percentage reductions in diurnal IOP levels and a greater likelihood of achieving lower mean diurnal IOP levels. Diurnal IOP reductions of 30% or more from baseline to week 12 were achieved by 73.5%, 57.5%, and 32.8% of those treated with FCLT, latanoprost, and timolol, respectively (P = .007 for FCLT vs timolol; P < .001 for FCLT vs latanoprost). All therapies were well tolerated. CONCLUSIONS Fixed-combination latanoprost-timolol therapy is as safe and effective in lowering IOP in patients with either ocular hypertension or glaucoma as monotherapy with latanoprost or timolol. Combination therapy can be used to treat patients for whom monotherapy does not provide sufficient IOP reduction. APPLICATION TO CLINICAL PRACTICE The simplicity, efficacy, and tolerability of FCLT contribute to its utility in clinical practice. TRIAL REGISTRATION clinicaltrials.gov Identifier NCT00277498.

Preservative Use in Topical Glaucoma Medications

Benzalkonium chloride (BAK) is the principal preservative employed in topical ocular hypotensive medications, although alternative compounds recently have begun to be employed or examined. Individual clinical trials have shown that exposure to BAK concentrations contained in ophthalmic solutions does not produce adverse sequelae in the majority of glaucoma patients, but concerns continue with regard to its long-term use. These concerns have resulted from an extensive research effort, including preclinical studies with in vitro and in vivo models, as well as recent clinical investigations dedicated specifically to this issue. The aim of this systematic literature review of both preclinical and clinical data was to determine the relevance of these findings to clinical practice. Most preclinical studies reported negative effects of BAK exposure, but with few exceptions, BAK concentrations and exposure times greatly exceeded those likely to be experienced by patients, given the normal physiological dilution by the tear film. In addition, consistent evidence of BAK-related toxicity did not emerge from our review of dedicated clinical investigations. Thus, taken together, current evidence supports the safety of BAK for most glaucoma patients, although subpopulations with abnormal tearing may benefit from alternative preservative compounds or preservative-free formulations. Further studies to identify these populations are needed.

A 12-week, randomized, double-masked study of fixed combination latanoprost/timolol versus latanoprost or timolol monotherapy.

Purpose. To evaluate the efficacy and safety of fixed combination latanoprost/timolol versus latanoprost or timolol monotherapy. Methods. This 12-week, randomized, double-masked study was designed to overcome potential shortcomings of previous trials. We enrolled 788 subjects with open-angle glaucoma or ocular hypertension treated with a beta-blocker for ≥4 weeks before screening. After washout, 500 subjects with a baseline mean intraocular pressure (IOP) ≥26 and <37 mmHg were randomized to fixed combination latanoprost-timolol in the evening (n=170), latanoprost monotherapy in the evening (n=165), or timolol monotherapy in the morning (n=165). At weeks 2, 6, and 12, each subjects IOP level was measured in triplicate at 8 AM (predose), 10 AM, and 4 PM in each eye. Adverse events were monitored throughout. The statistical superiority of the fixed combination for the 18 pairwise comparisons with the 2 monotherapies was evaluated (analysis of variance). Results. The statistical superiority of the fixed combination was demonstrated at 7/9 time points versus latanoprost and 9/9 time points versus timolol. Mean diurnal IOP levels were similar at baseline but significantly lower with the fixed combination than with either monotherapy at weeks 6 and 12 (each p<0.05). Patients treated with the fixed combination were significantly more likely than those treated with either monotherapy to reach prespecified percent IOP reductions at the upper thresholds and to achieve very low target diurnal IOP levels. All therapies were well tolerated. Conclusions. Fixed combination latanoprost/timolol safely reduces IOP levels in patients with glaucoma or ocular hypertension, though only slightly more than does latanoprost monotherapy.

Lack of evidence for a link between latanoprost use and malignant melanoma: an analysis of safety databases and a review of the literature.

Aim To determine if there is an association between the use of latanoprost ophthalmic solution and malignant melanoma and to assess the evidence of a plausible biological mechanism. Methods Two safety databases were reviewed: one representing all latanoprost (n=24) and fixed-combination latanoprost/timolol (n=16) clinical trials conducted from November 1992 through November 2007 and a global safety database of all spontaneous non-trial-related clinical reports spanning 13 and 9 years for latanoprost and for latanoprost/timolol, respectively. A systematic PubMed search for studies evaluating potential mechanisms was conducted. Results Amongst 12 880 latanoprost-treated subjects in clinical trials, no reported cases of ocular melanoma and three cases of cutaneous melanoma were identified. Of 19 940 cases recorded in the global safety database, 22 reports of ocular/cutaneous neoplasms were identified. Of these neoplasms, 11 were ocular and six were cutaneous melanomas. Possible association with latanoprost use could not be excluded in three ocular and one periorbital report. In vitro and in vivo data were consistent with a mechanism whereby the increased iris pigmentation results from stimulation of melanin synthesis by induction of tyrosinase transcription without increasing mitotic activity. Conclusion There is no evidence at present that establishes a link between latanoprost use and either ocular or cutaneous melanoma.

Treating early choroidal neovascularisation with pegaptanib sodium in patients with neovascular age-related macular degeneration: Findings of the PERSPECTIVES study

Based on the success of intravitreal therapies targeting vascular endothelial growth factor,1–3 some of which suggested efficacy independent of lesion subtype,3 we investigated the benefit and safety of pegaptanib sodium in patients with early neovascular age-related macular degeneration (NV-AMD) versus those with established lesions.4 PERSPECTIVES (NCT00327470) was a 102-week, open-label trial. Participants aged ≥50 years with evidence of NV-AMD in at least one eye, clear ocular media and a visual acuity >25 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters, and a lesion <12 disc areas were eligible (see supplemental data, figure 1). Using an algorithm reflecting function and morphology, we characterised lesions as early when (a) the baseline visual acuity was ≥54 ETDRS letters and (b) on angiography with neovascularisation classified as occult with no classic or occult with classic consisting of <50% of lesion area, with no retinal haemorrhage, lipid exudation, or retinal pigment epithelial (RPE) detachment. Lesions were classified as established when classic neovascularisation comprised ≥50% of lesion area or if retinal haemorrhage, lipid exudation, or RPE detachment were present even if classic constituted <50% of lesion area. Figure 1 Participant disposition. MITT, modified intent-to-treat. *Two participants withdrew …

Practice patterns of ophthalmologists administering intravitreal injections in Europe: a longitudinal survey

Purpose This study was performed to understand the practice patterns of ophthalmologists administering intravitreal (IVT) injections in Europe after the procedure became routine. Methods As part of a prospective, multinational, non-interventional cohort study in 13 countries in Europe between 2006 and 2012, ophthalmologists completed the Baseline Questionnaire and the Follow-up Questionnaire 1 year after baseline. Results and discussion Of the 125 ophthalmologists who participated in the study, 113 (90.4%) completed the Baseline Questionnaire. Most of these ophthalmologists were medical retina specialists (43.0%). The median number of IVT injections that the ophthalmologists performed per month during the year prior to completing the Baseline Questionnaire was 20.0. The majority of the ophthalmologists had performed their last IVT injection prior to completing the questionnaire in an operating room or theater (68.4%). When performing IVT injections, a majority of the ophthalmologists reported applying povidone–iodine (90.4%) before IVT injections and topical antibiotics right after IVT injections (89.5%). In addition, 81.6% of the ophthalmologists reported using a sterile adhesive eye drape and 80.7% reported using an eyelid speculum. In all, 95 ophthalmologists (76%) completed the Follow-up Questionnaire. The median number of IVT injections performed per month during the year prior to completing the Follow-up Questionnaire by these ophthalmologists was increased to 35. The results of the Follow-up Questionnaire on administering IVT injections were similar to those of the Baseline Questionnaire. A majority of the ophthalmologists reported applying povidone–iodine (87.4%) before IVT injections, topical antibiotics right after IVT injections (89.5%), and an eyelid speculum (85.3%). Conclusion The results of this study indicated a good adherence to all aspects of the guidelines on IVT injections. It seemed that ophthalmologists were more experienced in IVT injections after they became a routine treatment procedure.

Ocular Safety of Intravitreal Injections of Age-Related Macular Degeneration Treatments in a Prospective Observational Cohort Study in Europe

Purpose:Estimate the incidence of pertinent ocular adverse events (POAEs) related to intravitreal (IVT)injections for age-related macular degeneration (AMD) treatments in Europe. Methods:Ophthalmologists prospectively followed patients, who received IVT injection treatment for AMD including Macugen ® , Lucentis ® , and Avastin ® at ophthalmic clinical centers in Europe, and determined outcomes of interest as clinically appropriate up to two years. Main outcomesincluded endophthalmitis, retinal detachment, vitreous hemorrhage, retinal tear, traumatic cataract, and increased intraocular pressure (IOP). Results: 501 patients from 69 sites in 13 countries were enrolled.The mean age was 73.6 years. Most patients received monotherapy (80.4%), were white (97.4%), and never smoked (65.3%).The total number of IVT injections for AMD treatment was 3,754 among those patients. The incidence of POAEs was low overall (0 to 1.28% per injection, 0 to 6.6% per patient).Increased IOP was the most frequently reported POAE. There was a positive association between the incidence of increased IOP and the number of injections received.Endophthalmitis was not reported. Conclusions: The incidence of POAEs related to IVT injections in this study was low and similar to that reported in the literature.