The role of benzalkonium chloride in the occurrence of punctate keratitis: a meta-analysis of randomized, controlled clinical trials.

BACKGROUND: Benzalkonium chloride (BAK), the most commonly used preservative in topical ophthalmic solutions, has undergone considerable criticism in recent years, principally based on in vitro and in vivo studies. Relevance to the clinical setting has not been confirmed. OBJECTIVE: To determine whether administration of twice the amount of BAK was associated with an increased incidence of punctate keratitis in long-term, double-masked trials comparing latanoprost ophthalmic solution and vehicle with timolol ophthalmic solution in patients with glaucoma or ocular hypertension. METHODS: A meta-analysis of the double-masked phases of 7 prospective, controlled clinical trials compared the incidence of punctate keratitis among patients assigned to treatment with latanoprost or timolol. In all studies, the amount of BAK administered daily in the latanoprost arms was approximately twice the amount used in the timolol arms. All reports of punctate keratitis either as a finding or an adverse event were included. A fixed-effect model was used because the heterogeneity was small and not statistically significant. Sensitivity analyses were conducted. Funnel plots were provided to address potential publication bias. RESULTS: Of the 1694 patients enrolled in the double-masked portion of the trials (latanoprost, n = 892; timolol, n = 802), the overall incidence of punctate keratitis was 6.3% (106/1694). The incidence in latanoprost-treated patients was 6.5% and in timolol-treated patients was 6.0%. The risk difference for punctate keratitis of latanoprost versus timolol was 0.005 (95% CI -0.011 to 0.020; p = 0.574), and the risk ratio of latanoprost versus timolol was 1.084 (95% CI 0.739 to 1.589; p = 0.680). CONCLUSIONS: These results indicate that BAK does not produce significant corneal toxicity in the vast majority of patients with glaucoma or ocular hypertension at the concentrations used in these studies.

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.

Commercially available prostaglandin analogs for the reduction of intraocular pressure: similarities and differences.

Over the last 12 years, the pharmacological management of glaucoma and ocular hypertension has significantly changed with the introduction of the prostaglandin analogs, specifically, latanoprost, bimatoprost, and travoprost. Their ability to effectively reduce intraocular pressure with once-per-day dosing, their comparable ocular tolerability with timolol, and their general lack of systemic side effects have made them the mainstay of pharmacological therapy for glaucoma and ocular hypertension in most parts of the world. A review of their pharmacology reveals that they are all prodrugs that are converted to their respective free acids within the eye to activate the prostanoid FP receptor and to reduce intraocular pressure by enhancing the uveoscleral and the trabecular meshwork outflow pathways. A review of numerous prospective, randomized comparative studies indicates that no clinically significant differences exist among these agents regarding their ability to lower intraocular pressure.

Inter-visit intraocular pressure range: an alternative parameter for assessing intraocular pressure control in clinical trials.

PURPOSE: To evaluate whether inter-visit intraocular pressure (IOP) range, which reflects extreme and potentially damaging IOP fluctuations, provides additional information on IOP control compared to mean IOP. DESIGN: Post hoc analysis of Xalatan/Lumigan/Travatan study data, a masked-evaluator, randomized, parallel-group comparison of 12-week efficacy of latanoprost, bimatoprost, and travoprost in open-angle glaucoma/ocular hypertension patients. METHODS: Pretreatment inter-visit IOP range defined as highest IOP minus lowest IOP at screening, safety check, and baseline (six measurements); posttreatment inter-visit IOP range defined as highest IOP minus lowest IOP at weeks two, six, and 12 or early termination (nine measurements). Ranges dichotomized as "high" (>6 mm Hg) vs "low" (< or =6 mm Hg). RESULTS: Included were 410 patients (latanoprost, 136; bimatoprost, 136; travoprost, 138). Each resulted in significant mean IOP range reductions during 12 weeks. Pretreatment inter-visit IOP range was associated with African-American race, male gender, and presence of visual field defect (P < .05 for all). Percentages with high pretreatment inter-visit IOP ranges were comparable across treatments (63% to 64%). High posttreatment inter-visit IOP range was seen in 21% (28/136), 28% (38/136), and 36% (50/138) of latanoprost, bimatoprost, and travoprost groups, respectively (P = .016, overall; P = .005, latanoprost vs travoprost). High posttreatment inter-visit IOP range was associated with African-American race, high pretreatment inter-visit IOP range, and treatment with travoprost vs latanoprost (P < .05 for all). CONCLUSIONS: Given that high inter-visit IOP range is associated with risk factors for glaucomatous damage and that such differences cannot be evaluated using mean IOPs, inter-visit IOP range may be another useful approach to assessing IOP control in clinical trials.