Eye (2009) 23, 810–818 & 2009 Macmillan Publishers Limited All rights reserved 0950-222X/09 $32.00 www.nature.com/eye CLINICAL STUDY Bimatoprost/timolol A Martinez and M Sanchez fixed combination vs latanoprost/timolol fixed combination in open-angle glaucoma patients Abstract Eye (2009) 23, 810–818; doi:10.1038/eye.2008.148; published online 6 June 2008 Objective To evaluate bimatoprost/timolol fixed combination (BTFC) vs latanoprost/ Keywords: open-angle glaucoma; bimatoprost/ timolol fixed combination (LTFC) given each timolol fixed combination; latanoprost/timolol evening over the 12-h intraocular pressure fixed combination; pseudoexfoliative glaucoma; (IOP) diurnal curve. intraocular pressure; diurnal curve Methods A total of 54 eyes of 54 patients (24 with primary open-angle glaucoma (POAG) and 30 with pseudoexfoliative glaucoma (PXG)) were included in this prospective, Introduction randomized, evaluator-masked single centre crossover study. Patients with an IOP of Lowering intraocular pressure (IOP) reduces the X19 mmHg, under treatment with risk of visual field loss in patients with Instituto Gallego de prostaglandin analogues, were randomized to glaucoma and ocular hypertension.1–3 ´ ´ Oftalmologıa, C/Ramon BTFC or LTFC for a 12-week treatment period Whenever possible, it is preferable to control Baltar Sn, Santiago de after a 6-week run-in period on timolol Compostela, La Corun˜ a, IOP with a single drug rather than multiple Spain maleate 0.5% (one drop in each eye twice each drugs, because every drug added to the regime day). Patients were then switched to the has side effects, and each added drug increases Correspondence: opposite treatment for the second period. Six the costs and may reduce patient compliance. A Martı´nez, 12-h IOP curves were recorded for each patient When a single medication does not Instituto Gallego de at baseline (under treatment with timolol adequately reduce IOP, additional hypotensive Oftalmologı´a, maleate 0.5% BID), week 6 and 12 for each C/Ramo´ n Baltar Sn, agents are added to the therapeutic regime. In Santiago de Compostela, treatment period. this setting, a fixed combination preparation La Corun˜ a 15706, Results The 12-h IOP (mean (SD)) values may improve both the compliance and the Spain were 22.0 (1.0) mmHg at baseline, 17.7 (0.8) quality of life.4 Tel: þ 34 646 17 81 04; mmHg on BTFC, and 18.5 (0.8) mmHg on LTFC The fixed combination of latanoprost and Fax: þ 34 981 83 59 99. ( 0.001). At individual time points, there s E-mail: tontxu_1999@ Po timolol (LTFC; Xalacom , Pharmacia, yahoo.com was a significant difference between groups at Kalamazoo, MI, and Pfizer, New York, NY) was 0800, 0100, 1200, 1800, and 2000 hours with the first prostaglandin analogue/beta-blocker Received: 15 January 2008 BTFC having greater ocular hypotensive effect, fixed combination available in the market. Accepted in revised form: Po0.001. The most frequently reported Several papers have shown the IOP-lowering 17 April 2008 adverse event in the study was conjunctival effect of the LTFC.5–13 Published online: 6 June hyperaemia. Average hyperaemia scores were 2008 The fixed combination bimatoprost/timolol slightly but significantly lower in the LTFC (BTFC; Ganforts, Allergan, Irvine, CA) is a new treatment period (P ¼ 0.04). fixed combination antiglaucoma therapy that Antonio Martı´nez has Conclusion This study suggests that the combines bimatoprost 0.03% and timolol 0.5%. received honoraria from evening-dosed BTFC provides better IOP BTFC has been shown to be as effective as the lectures and reimbursement control than that of LTFC over 12 h. However, 14 for attending symposia from association of its individual components. Allergan the IOP difference was small and may not be We recently published the results of an Financial interest: None clinically meaningful. evaluator-masked, randomized parallel study Fixed combination therapies in OAG A Martinez and M Sanchez 811 comparing BTFC administered once daily in the evening To provide baseline comparison data, all patients were vs once-daily evening LTFC in patients with open-angle placed on timolol maleate 0.5% (one drop in each eye glaucoma (OAG).15 twice each day) for a period of 6 weeks. Our study found that BTFC demonstrated a superior To be eligible for randomization, a mean diurnal IOP IOP-lowering effect than LTFC in OAG patients over a X19 mmHg, under treatment with timolol 0.5% BID, was period of 4 weeks. required at baseline. The purpose of this study was to evaluate the 12-h Study visits occurred at baseline and after 6 and 12 pressure curve of BTFC vs LTFC, both administered in weeks of therapy. The masked investigator performed the evening in patients with OAG. three IOP measurements in each eye, alternating between To the best of our knowledge (after a Medline search, eyes, and starting with the right eye at 0800, 1000, 1200, update December 2007), this is the first crossover study 1400, 1600, 1800, and 2000 hours. The mean of these three to compare 12-h diurnal IOP reduction with these two measurements at each time point was used in the fixed combinations. statistical analyses. Table 1 summarizes the main inclusion and exclusion criteria. Material and methods Study design Methods This was a prospective, single centre, evaluator-masked The methods of this study were similar to those crossover study. described previously by our group.17 At the screening The study was evaluator masked because differences visit (visit 0), each patient underwent a standard in patient adverse events were likely to reveal treatment ophthalmic examination, including a review of the assignments. Unmasked personnel were responsible for medical history, best-corrected visual acuity (EDTRS study medication distribution and collection, whereas scale), slit-lamp examination of the anterior segment masked personnel performed all study-related with dilated pupils, IOP measurement at 0900 and 1100 examinations. hours using Goldmann applanation tonometry, Patients and unmasked personnel were recommended gonioscopy, dilated funduscopic examination using a 78 not to reveal the study assignment to the masked evaluator. dioptre lens, stereoscopic optic disc photography, central corneal thickness (CCT), and an automated perimetry using the 24-2, full threshold strategy on the Humphrey Patients visual field analyzer (Carl Zeiss Meditec, Dublin, CA, Enrolled patients were men or women of at least 40 years USA). CCT was measured using an ultrasonic with a clinical diagnosis of OAG, with or without pachymeter (Corneo-gage plus 2, Sonogage, Cleveland, exfoliation syndrome. OH). The study was conducted on consecutive patients, Patients potentially eligible started a 6-week run-in referred or recruited, attending the outpatient service of period under timolol maleate 0.5% (one drop in each eye the Glaucoma Unit, Instituto Galego de Oftalmoloxia, twice each day). After completion of the timolol run-in Santiago de Compostela, Spain, from November 2006 to period, patients reported to the clinic for baseline March 2007 who met the inclusion and exclusion criteria. measurements (visit 1). All patients signed a written informed consent form in Baseline visit included medical and ophthalmic history accordance with the tenets of the Declaration of Helsinki and a complete ophthalmic examination including best- and with local ethical approval. corrected visual acuity (EDTRS scale), slit-lamp We included patients of either gender, older than 40 examination of the anterior segment, and diurnal 12-h years, who had an IOP of X19 mmHg, under treatment IOP measurement using Goldmann applanation with prostaglandin analogues, at 0900 and 1100 hours. tonometry and conjunctival hyperaemia by means of a For entry into the study, the IOP-lowering effect of digital camera MVC CD 400 (Sony Corporation, Tokyo, prostaglandin analogues must be higher than 20%. Japan). Glaucoma was defined on the basis of at least two To record the diurnal tonometric curves, the patients reliable achromatic automated perimetry using the 24-2 arrived in the morning (at 0745 hours) and stayed for the Swedish Interactive Threshold Algorithm (SITA) following 12 h. The same investigator (AM) measured the (Humphrey visual field analyzer, Carl Zeiss Meditec Inc., IOP using the same calibrated instrument (Goldmann Dublin, CA) with a Glaucoma Hemifield Test outside of applanation tonometer) to perform 12-h diurnal curves of normal limits in the presence of a typical glaucomatous IOP. The IOP measurements were recorded at 0800, 0100, disc and an open chamber angle. 1200, 1400, 1600, 1800, and 2000 hours. Eye Fixed combination therapies in OAG A Martinez and M Sanchez 812 Table 1 Inclusion/exclusion criteria Inclusion criteria Exclusion criteria X40 years of age. Presence of any form of glaucoma other than OAG. Clinical diagnosis of OAG in at least one eye with Any concurrent infectious/noninfectious conjunctivitis, keratitis or uveitis in or without pseudoexfoliation. either eye. Early or moderate glaucomatous visual field Any abnormality preventing reliable applanation tonometry in study eye(s). defect.16 An IOP-lowering effect higher than 20% under Patients previously treated with argon laser trabeculoplasty and/or ocular treatment with prostaglandin analogues. filtering surgical intervention. The 0900 and 1100 hours IOP must be X19 mmHg Progressive retinal or optic nerve disease due to any cause other than under treatment with prostaglandin analogues. glaucoma. The mean diurnal IOP must be X19 mmHg under Asthma or other obstructive pulmonary disease. treatment with timolol maleate 0.5%, twice daily. Spherical refractive error between þ 3.00 and Cardiogenic shock, 2 or 3 degree atrioventricular block, sinus bradycardia, or À6.00 dioptres. heart failure. Diabetes with any sign of retinopathy (haemorrhages, hard and/or soft exudates, macular oedema. Systemic medications that affect IOP or systemic blood pressure were ineligible unless the patients’ medication dosages were stable X6 months before the screening visit. Pregnant or nursing women. Abreviattions: OAG, open-angle glaucoma; IOP, intraocular pressure.