effect of previous argon laser trabeculoplasty

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1 Graefe s Arch Clin Exp Ophthalmol (2006) 244: CLINICAL INVESTIGATION DOI /s x Esther Arranz-Marquez Miguel A. Teus Effect of previous argon laser trabeculoplasty on the ocular hypotensive action of latanoprost Received: 18 June 2005 Revised: 1 October 2005 Accepted: 29 November 2005 Published online: 14 January 2006 # Springer-Verlag 2006 E. Arranz-Marquez (*). M. A. Teus Vissum Hospital Oftalmológico Madrid, e.arranzmarquez@gmail.com Tel.: Fax: E. Arranz-Marquez. M. A. Teus Hospital Universitario Príncipe de Asturias, M. A. Teus Universidad de Alcalá, Abstract Purpose: To study the effect of previous argon laser trabeculoplasty (ALT) on the hypotensive activity of latanoprost in primary open-angle glaucoma (POAG). Methods: This was a prospective, observer-masked study. We measured the intraocular pressure (IOP) before andafter3monthsofmonotherapy with latanoprost in 43 eyes that had undergone a previous ALT, and in a control group (not treated with ALT) of 43 IOP-matched eyes with POAG. Results: Latanoprost induced a 17.4± 16.6% IOP decrease in the study group (ALT-treated eyes) and a 25.8±17.2% IOP reduction in the control eyes (P=0.02, unpaired Student s t-test). Conclusions: Latanoprost is less effective in ALT-treated eyes than in eyes with POAG not treated with ALT. Keywords Primary open-angle glaucoma. Latanoprost. Intraocular pressure. Argon laser trabeculoplasty Introduction Despite the extensive use of argon laser trabeculoplasty (ALT) in the treatment of glaucoma, the exact mechanism of its hypotensive action remains unclear. When Krasnov first proposed laser treatment to the trabecular meshwork to decrease intraocular pressure (IOP), the rationale was that the laser treatment produced holes in the structure, thus reducing the aqueous humor outflow resistance [5]. Wise and Witter later proposed that the mechanism of ALT was probably thermal retraction and not hole formation. Based on this hypothesis, the laser-induced trabecular heat retracts the meshwork lamellae, thus improving trabecular outflow [16]. Other investigators suggested that ALT modifies the trabecular cells, inducing cellular activation [14] capable of eliminating trabecular detritus and generating matrix metalloproteinases (MMPs), which are enzymes that can degrade the extracellular matrix, and therefore inducing consecutive trabecular meshwork remodeling with reduced conventional outflow resistance [8]. On the other hand, a new class of antiglaucomatous drugs, the prostaglandin analogues, is now available for clinical use. Latanoprost, a prostaglandin analogue, is a potent ocular hypotensive drug [15], and it is considered a first-line treatment for glaucoma [1]. However, its mechanism of action is peculiar, in that it induces increased turnover and remodeling of the extracellular matrix adjacent to ciliary muscle cells, due to an FP-receptormediated production of MMPs [6]. Such changes may contribute to the enhanced uveoscleral outflow of aqueous humor, which accounts for most of the hypotensive effect of latanoprost [13]. We studied the ocular hypotensive effect of latanoprost in ALT-treated eyes for two reasons. Considering that

2 1074 latanoprost is used worldwide, we think it would be of interest to determine the effect of adding this medical therapy to ALT-treated eyes. In addition, knowledge of the degree of additivity of two different treatments can provide some information regarding the mechanism of action, because two treatments with a common mechanism of action will provide minimal added effect [11]. Materials and methods This was a prospective, observer-masked study in which we included consecutive patients who fulfilled all the inclusion criteria and agreed to participate. The nature and purpose of the study were explained in detail to all participants, who provided informed consent before entering the study. To be eligible for the study, patients had to have a diagnosis of primary open-angle glaucoma (POAG) and a normal anterior segment. The study population was comprised partly of newly diagnosed patients who needed hypotensive therapy and partly of patients who had been treated previously with antiglaucoma therapy that was considered ineffective or was not well tolerated, and were thus candidates for latanoprost therapy. No patient had been treated with any prostaglandin analogue before entering the study. Patients with a history of ocular surgery, angle closure, inflammation, ocular infection, or previous ocular prostanoid treatment were excluded. When both eyes of the same patient met the inclusion criteria, one eye was randomly chosen for the study. The study group was comprised of eyes in which ALT had been performed in our institution a minimum of 1 year previously by the same, experienced glaucoma specialist in all cases. In contrast, controls had not undergone previous ocular laser therapy and were matched with study eyes for basal IOP. The baseline IOP was measured on the first visit. The recorded basal IOP was the untreated IOP in the case of newly diagnosed patients; if the patients were already being treated for glaucoma, a 3-week washout period was required before the basal IOP was determined. In the study eyes, ALT had been performed using an Aesculap argon laser (Meditec CLU-07) using blue green radiation, a 50-μm spot, and a 100-ms exposure time, over the anterior portion of the trabecular meshwork, with variable power intensities in each patient. ALT was applied to the inferior half of the angle (180 deg). Treatment was started and maintained with latanoprost 0.005%, once daily as monotherapy, during the study in all cases. In all cases, the same masked observer checked the IOP 1 and 3 months after commencement of latanoprost therapy, and the same calibrated applanation tonometer was used. In every case, IOP was measured between 10 a.m. and 12 a.m., and the recorded IOP was the average of two consecutive readings. Statistical analysis was performed using Statview SE + Graphics software (Abacus Concepts, Berkeley, CA) on a Macintosh PowerBook 1,400 cs/117 personal computer (Apple Computer, Cupertino, CA). The data are expressed as the average ± standard deviation. The unpaired two-tailed Student s t-test and the chisquare test were used for comparisons between groups when appropriate. The exact p value is expressed for each comparison. P values <0.05 were considered significant. Results A total of 86 eyes, from 86 different patients, fulfilled the inclusion criteria and were included in the study. Fortythree patients with POAG had undergone ALT previously (study group) and 43 controls with POAG had not undergone previous ocular laser therapy. Fig. 1 Mean IOP values (±SE) at baseline and at 1 and 3 months after latanoprost therapy in eyes previously treated with ALT (study group) and in eyes that had not undergone previous ocular laser therapy (control group)

3 1075 The mean age of the patients of the study group was 72.6±8 years and that of the control group was 66.4±15 years (p=0.02). Of the 43 patients treated with ALT, 19 were men (44.19%) and 24 were women (55.81%); the control group was comprised of 21 men (48.84%) and 22 women (51.16%). The gender distributions were similar in the two groups (p=0.8). In the study group, ALT was performed an average of 45±26 months before latanoprost therapy was instituted, i.e., before the patients entered the study. The basal IOP was matched between groups; the mean IOP values were 22.4±3 mmhg in the ALT-treated eyes and 22.4±3 mmhg in the controls (p=0.8) (Fig. 1). After 1 month of latanoprost therapy, the IOP values had decreased to 18.3±4 mmhg and 16.1±3 mmhg in the study and control groups, respectively, yielding a mean decrease of 17.4±16% in the study eyes and 25.8±17% in the control eyes (p=0.01) (Fig. 1). At the 3-month follow-up visit, the IOP values were 17.6±4 mmhg and mmhg in the study eyes and the control eyes, respectively. The average decrease in the control eyes (29.0±12%) was significantly greater than that in the ALT-treated eyes (19.6±19%) after 3 months of latanoprost therapy (p=0.03) (Fig. 1). Discussion In the control eyes latanoprost induced a greater hypotensive effect than in the eyes treated previously with ALT, after 1 and 3 months of therapy. This may indicate that ALT-treated eyes are less sensitive to latanoprost than those that have not been treated with ALT. There was a statistically significant difference between our study and control groups regarding patient age, which was higher in the study patients. This probably did not affect our results, since age has not been shown to have any effect on the IOP-lowering effect of latanoprost [2]. We are unaware of any previous reports that specifically evaluated the efficacy of latanoprost in ALT-treated eyes and could find no such study in a search of the Medline database. To the best of our knowledge, there has been only one study of the hypotensive effects of latanoprost that included patients who had undergone a previous ALT [10]. However, those investigators studied latanoprost as adjunctive therapy in patients receiving maximal tolerated medical therapy, including ALT. They concluded that there was no association between previously performed ALT and the hypotensive effect of latanoprost. However, we think that patients receiving maximal tolerated therapy are not the best candidates to test the effect of a single drug. Endogenous prostaglandin E2 (PGE2) and F2α (PGF2α) have been shown to regulate aqueous humor dynamics in the human trabecular meshwork (h-tm), and functional activation of the h-tm cell FP receptors may play a role in the prostaglandin-mediated regulation of IOP by promoting conventional outflow. A recent study reported that latanoprost and its free acid bind to and activate FP prostaglandin receptors in the h-tm cells to induce second-messenger functional responses [12]. On the other hand, ALT has been reported to increase the production of endogenous prostaglandins [3], which leads to reduced outflow resistance. The extracellular matrix turnover is regulated by enzymes, including the MMP families [17]. ALT is thought to induce an increase of these enzymes, which may lead to remodeling of the juxtacanalicular extracellular matrix, thus explaining the effect of ALT on IOP [9]. In addition, PGE2 levels increase after ALT therapy; and inhibitors of the arachidonic acid cascade prevent this event [3], partially reducing the hypotensive effectiveness of ALT [4]. Thus, it seems that prostaglandins may play a role in the complex mode of action of ALT. Considering this, a possible explanation of our results is that ALT and prostanoid drugs share, in part, the same mechanism of action, thus accounting for the lower efficacy of latanoprost in ALT-treated eyes. An alternative explanation is that irreversible changes in the anterior chamber angle and ciliary body surface after ALT preclude the IOP-lowering effect of latanoprost, at least to some extent. For instance, some authors observed proliferation of cells apparently from the corneal endothelium, at the level of Schwalbe s line, extending over the trabecular meshwork several weeks after ALT treatment. This membrane could be a cause of ALT failure [7]. The decreased efficacy of latanoprost in lowering IOP in eyes previously treated with ALT should be taken into account when selecting the best hypotensive drug to prescribe in a particular case. More studies are needed to assess the course of this difference over a longer follow-up period, as well as to determine the factors that affect the variability of the hypotensive response to prostaglandin analogues. References 1. Camras CB (1996) Comparison of Latanoprost and timolol in patients with ocular hypertension and glaucoma. A six month, masked, multicenter trial in the United States. Ophthalmology 103: Camras CB, Alm A, Watson P, Stjernschantz J (1996) The Latanoprost study group. Latanoprost, a prostaglandin analog, for glaucoma therapy. Efficacy and safety after one year of treatment in 198 patients. 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