John W. Grunden

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.

Using diurnal intraocular pressure fluctuation to assess the efficacy of fixed-combination latanoprost/timolol versus latanoprost or timolol monotherapy

Aim: To evaluate differences in diurnal intraocular pressure (IOP) fluctuation in glaucoma/ocular hypertension patients treated with once-daily fixed-combination latanoprost/timolol, once-daily latanoprost or twice-daily timolol. Methods: In two 6-month, double-masked, parallel-group studies, patients received run-in timolol (2–4 weeks) and randomised (1:1:1) to therapy. IOP was measured three times/day at baseline and weeks 2, 13 and 26. In posthoc analyses, diurnal IOP fluctuation = highest daily IOP–lowest daily IOP at baseline and week 26. Fluctuation also was dichotomised: high (>6 mm Hg), low (⩽6 mm Hg). Results: 854 patients were randomised (fixed combination = 278; latanoprost = 287; timolol = 289). Diurnal fluctuation was significantly reduced from baseline to week 26 with the fixed combination (p = 0.002) but not with latanoprost or timolol monotherapy (p = 0.601; p = 0.097). Relative to baseline, the percentage with high diurnal IOP fluctuation at week 26 was reduced by 48% with fixed combination but increased 13% with latanoprost and 48% with timolol. Changes in IOP fluctuation and in mean IOP were significantly correlated for the monotherapies but not the fixed combination. Conclusions: Fixed-combination latanoprost/timolol results in lower diurnal IOP fluctuation and significantly fewer patients with a high fluctuation than treatment with latanoprost or timolol monotherapy. The fixed combination may have an independent effect on reducing IOP fluctuation in addition to lowering IOP.

Assessing the Importance of IOP Variables in Glaucoma Using a Modified Delphi Process.

PurposeTo assess the degree of consensus among glaucoma experts on the measurement, characterization, and potential implications of intraocular pressure (IOP) and its fluctuation for glaucoma treatment. MethodsA multinational panel of 9 glaucoma experts used a modified Delphi process to rate the level of agreement with 72 statements characterizing methods of measuring IOP, the importance of IOP reduction, and clinical implications of changes in IOP over time. After receiving a literature review, panelists rated each statement on a 9-point Likert scale. A panel meeting was held to discuss the ratings followed by a second round of independent ratings. Consensus and nonconsensus regarding the panels agreement with each statement were determined using a binomially distributed statistical definition. ResultsThe panel found consensus in 46% of 81 statements, nonconsensus in 6%, and indeterminate status in 48%. Categories having the highest proportion of statements with consensus were importance of IOP reduction (4/4 statements), importance of long-term IOP fluctuation and reduction (6/9), and impact of medication on short-term and long-term IOP fluctuation (6/10 for each). Indeterminate statements were distributed unevenly with 74% of statements related to IOP measurement rated indeterminate compared with 38% related to the clinical implications of short-term and long-term IOP fluctuation. ConclusionsA modified Delphi process was useful in identifying areas of consensus regarding IOP measurement and importance of IOP fluctuation among glaucoma experts. Concurrently, the need for additional investigations assessing the role of IOP changes in glaucoma management is highlighted by the indeterminate and nonconsensus ratings.

Assessing the Efficacy of Latanoprost vs Timolol Using an Alternate Efficacy Parameter: The Intervisit Intraocular Pressure Range

PURPOSE To compare latanoprost and timolol with regard to changes in the intervisit intraocular pressure (IOP) range, a measure of long-term IOP fluctuation. DESIGN Post hoc analysis of three 6-month, multicenter, randomized (1:1), double-masked registration trials of latanoprost (n = 313) vs timolol (n = 318). METHODS Analyses included patients with glaucoma or ocular hypertension who instilled latanoprost once daily in the evening and vehicle in the morning and those instilling timolol twice daily. Pretreatment intervisit IOP range: highest IOP minus lowest IOP of 4 measurements obtained at screening and baseline. Posttreatment intervisit IOP range: highest IOP minus lowest IOP of 4 measurements obtained at weeks 18 and 26. Ranges were dichotomized to high (> 6 mm Hg) and low (< or = 6 mm Hg). RESULTS Both treatments resulted in significant reductions in mean intervisit IOP range during 26 weeks. Pretreatment, comparable proportions of patients treated with latanoprost and timolol had high intervisit IOP ranges (22% [70/313] and 23% [72/318], respectively; P = .934). After treatment, 6% (19/313) and 11% (35/318) of patients in the latanoprost and timolol groups, respectively, had high intervisit IOP ranges (P = .026). Significant risk factors for high posttreatment intervisit range (multivariate logistic regression) were high pretreatment intervisit IOP range, treatment with timolol, Black race, longer time since diagnosis, and higher mean pretreatment IOP. CONCLUSIONS Compared with timolol, treatment with latanoprost results in significantly fewer patients with a high IOP fluctuation. The impact of reducing high IOP fluctuation on progressive glaucomatous damage deserves further investigation in prospective studies.

Five-year, multicenter safety study of fixed-combination latanoprost/timolol (Xalacom) for open-angle glaucoma and ocular hypertension.

PurposeTo evaluate the safety of fixed-combination latanoprost/timolol (Xalacom) in patients requiring additional intraocular pressure (IOP) reduction over 5 years. MethodsThis phase 3b, open-label, multicenter study included prostaglandin-naive participants with open-angle glaucoma or ocular hypertension insufficiently responsive to &bgr;-blockers and requiring additional IOP reduction. Participants were evaluated at eleven 6-month visits. A masked assessor evaluated iris/eyelash changes at baseline and 12, 36, and 60 months. Increased iris pigmentation incidence was compared with a historic control from a similarly designed study evaluating latanoprost. Ocular and systemic adverse events were recorded. ResultsAmong 828/974 treated participants with assessable iris photographs, 233 (28.1%) developed increased iris pigmentation versus 127/380 (33.4%) in the historic controls. Participants with mixed eye colors exhibited greater susceptibility to overall increased iris pigmentation (85.8% in both studies). In this study, most participants (80.3%) with increased iris pigmentation developed only a weak increase. Eyelash changes were seen in 58.1% of participants and darkening of the eyelids in 5-6%; 14.1% experienced a serious adverse event. Adverse events resulted in treatment withdrawal in 133 (13.7%) participants. Most were nonserious ocular adverse events, about half of them ocular irritation. Only 3 of 13 serious systemic adverse events were considered to be drug related by the investigator. Mean IOP reductions were stable over 5 years. ConclusionsAfter 5 years, more than 70% of participants treated with fixed-combination latanoprost/timolol had no increased iris pigmentation. The fixed combination is safe and well tolerated for long-term treatment in patients with open-angle glaucoma or ocular hypertension.