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Editors Selection IGR 15-3

Medical Treatment: Combination Therapy Switch

Comment by Fotis Topouzis on:

61329 Effects of Switching from Timolol to Brimonidine in Prostaglandin Analog and Timolol Combination Therapy, Aihara M; Adachi M; Hamada N et al., Journal of Ocular Pharmacology and Therapeutics, 2015; 31: 482-486

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Currently prostaglandin analogues (PGAs) are used as first line treatment for lowering intraocular pressure (IOP). Alternative choices exist as second-line drugs in addition to PGA. Additional IOP lowering effects and safety profile of the second-line drugs when used in combination of PGA is of clinical interest.

Aihara et al., conducted a prospective, open-label multi-center study, examining the efficacy and safety of switching from Timolol 0.5% to Brimonidine 0.1% in Japanese patients with glaucoma or ocular hypertension treated with a PGA and Timolol combination. After switching, patients were followed for 12 weeks (visits at 4 and 12 weeks). The main outcome measure was the change in IOP from baseline. Safety evaluations included hyperemia formation, conjunctival follicles, superficial punctate keratopathy (SPK), blood pressure (BP) and heart rate (HR). One hundred and seven patients participated while 103 patients completed the study. IOP was significantly reduced at 4 and 12 weeks (14.3 ± 2.8 and 14.0 ± 2.8 mmHg, respectively) compared to baseline (15.7 ± 2.7 mmHg) (p < 0.001). However, investigators concluded that switching from Timolol 0.5% to Brimonidine 0.1% may not change the reduction of IOP in the combination use of Timolol 0.5% and a PGA. It is clear that this conclusion does not rely on actual data from the study but on highlighting limitations of the study in discussion and on assumptions arising from those limitations driving the authors' interpretation of the results. Indeed, the open-label design has inherent limitations. In addition, the study included only one arm and one-way switching design. A double-masked two-arm cross-over study design would have been more informative. In addition, there is a well-known tachyphylaxis effect associated with long-term use of Timolol, and the study does not provide any information on the timelength of Timolol use by study participants. Another important limitation is that patients were not washed-out from Timolol and therefore no information on baseline IOP under PGA only is provided. This limits the ability of the study to provide information on the additional IOP of lowering effects of Timolol and Brimonodine when used in combination with a PGA. Also, interpreting the results, one should keep in mind that this study included Japanese patients with well controlled IOP at baseline (15.7 ± 2.7 mmHg) and therefore generalizability of the results may be limited. Statistically significant differences in SPK, BP and HR were found after switching but they were qualified as not clinically significant. A double-masked, two-arm, crossover study and with longer follow up under each treatment regimen would be needed to answer the research questions of this study.

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