Aims: To evaluate the effect of selective laser trabeculoplasty (SLT) on intraocular pressure (IOP) control and diurnal tension curves of patients with open-angle glaucoma (OAG) and ocular hypertension (OHT), and to compare this effect with that of latanoprost.
Methods: Forty patients were randomised to receive either SLT or latanoprost. IOP control was evaluated by comparing pretreatment values with post-treatment measurements on day 3, week 1, month 1 and 4–6 months; success was defined as 20% decrease in IOP. Tension curves were plotted prior to treatment and 4–6 months afterwards; success was 50% reduction in fluctuation.
Results: SLT decreased pressure by 4.7 mm Hg on average (95% CI 3.6 to 5.7 mm Hg; p<0.01). The reduction was similar for latanoprost at all follow-ups except month 1; 75% of SLT patients and 73% of latanoprost patients achieved success in IOP control (p = 0.4). SLT significantly reduced IOP fluctuation, but latanoprost was more effective (3.6 mm Hg, 95% CI 3.2 to 3.9 mm Hg vs 2.5 mm Hg, 95% CI 2.2 to 2.9 mm Hg for SLT; p = 0.04). Success in fluctuation reduction was 50% for SLT and 83% for latanoprost (p = 0.045).
Conclusions: Both SLT and latanoprost had a significant impact on IOP control and fluctuation. While latanoprost may be more likely to reduce IOP fluctuation, SLT has the benefit of being a one-time intervention not requiring ongoing patient compliance.
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Intraocular pressure (IOP) is no longer part of the formal definition of glaucoma but “pressure” still matters. Elevated IOP is the major risk factor for the development and progression of glaucoma, and it is the only modifiable risk factor. We also know that “IOP is a variable variable,” as it fluctuates with time. A single IOP measurement, especially if done in the first hours of the afternoon, is not sufficient to evaluate correctly the IOP-related risk in glaucoma patients.1 Asrani et al found a strong relationship between large diurnal fluctuations of IOP and glaucoma progression, and proposed diurnal intraocular pressure as an independent risk factor for the progression of glaucoma.2 It is still not clear what is more damaging to the retinal ganglion cells and optic nerves—peak IOP, mean IOP or fluctuating IOP—but the aim of management is to achieve a target IOP with minimal diurnal fluctuation. Measuring these fluctuations, however, is a challenging task that must take into account the circadian cycle of IOP, the effect of posture and the varying effects of pharmacological or surgical intervention.
Prostaglandin analogues are known to reduce diurnal IOP fluctuation,3–5 but failure to take medication correctly and missed appointments present major barriers to successful treatment outcomes. Even simple medication regimens may not be complied with, since, until late in the disease, the only symptoms may be the side effects of the medication. Patients are sometimes unaware of poor compliance or they are hindered by physical inability and therefore unable to use eye-drops adequately. Such problems are compounded because the physician often is unable to determine whether and to what extent a patient is not complying with therapy.6
Surgery is an alternative approach for the reduction in IOP and flattening of the diurnal curve. Argon laser trabeculopasty (ALT) and selective laser trabeculopasty (SLT) have both been used in glaucoma management. Medeiros and colleagues observed significantly less IOP fluctuation following trabeculectomy as compared with medical treatment.7 Unlike ALT, SLT facilitates aqueous flow through the trabecular meshwork without causing any significant damage to it.8 Its ability to reduce IOP has been demonstrated.9–11 There has been one previous published investigation showing a decrease in IOP fluctuations following SLT,12 but this was a small pilot study.
The aim of this study was to evaluate the effect of SLT on IOP control and diurnal tension curves of patients with OAG and OHT. This treatment effect was compared with that of the prostaglandin analogue, latanoprost.
MATERIALS AND METHODS
The study was designed as a prospective, randomised, masked trial. It was conducted at the Clayton Eye Centre, Wakefield, West Yorkshire, UK, and Medical Ethics Committee approval was obtained. Fifty-three consecutive patients with newly diagnosed OHT or primary OAG were assessed. Of these, 13 were excluded, as they did not meet the inclusion/exclusion criteria (table 1); 40 patients did meet the criteria and were recruited. Before entry into the study, informed consent was obtained. Patients underwent a detailed examination including a full ocular and medical history, visual-field assessment (Humphrey 24–2 perimetry), slit-lamp biomicroscopy, gonioscopy, pachymetry, mydriatic funduscopy and Goldmann tonometry at different time points throughout the day. A diurnal tension curve was plotted using IOPs recorded at 08:00, 11:00, 14:00 and 18:00. The difference between the peak and trough IOP recorded in the diurnal curve was noted as the diurnal fluctuation.
Following this examination, patients were randomised into one of the two treatment groups: SLT or latanoprost. Randomisation was performed using a sealed, shuffled envelope system. Cards were placed into identical sealed envelopes, which were shuffled several times and sequentially numbered. No patient identifiers were used and none of the individuals involved in generating the randomisation took any further part in the study. The envelopes were kept in a locked drawer, which was accessed just prior to treatment when the next numbered envelope was opened and the patient allocated to the group according to the modality written on the card. If indicated, both eyes of each patient received identical treatments on the basis of randomisation. However, only one eye of each patient was entered into the study. It was not possible to mask the treating ophthalmologist (MN) or the patient due to the nature of interventions, but the two observers responsible for follow-up, data collection and analysis (NS and EL) were masked to the patients’ group allocation.
SLT treatment group
The laser used was the Ellex Tango ophthalmic laser system (Ellex, Adelaide, Australia), a frequency doubled, q-switched Nd:YAG laser emitting at 532 nm, with a pulse duration of 3 ns, a spot size of 400 mm and pulse energies ranging from 0.2 to 1.4 mJ, coupled to a slit-lamp delivery system with a He–Ne aiming system. One surgeon (MN) performed the laser procedures. Immediately prior to treatment, an application of amethocaine 1% was instilled into the eye. The patient was seated at the slit lamp, a single mirror goniolens was used, and the laser was focused on the trabecular meshwork. Using a 400 mm spot the entire width of the trabecular meshwork was irradiated with each pulse. The laser energy was initially set at 0.8 mJ, and a single pulse was delivered at the 12 o’clock position. If cavitation bubbles appeared, the energy was reduced by 0.1 mJ increments until no bubble formation or fine champagne bubbles were observed and treatment continued at this energy level. If no cavitation bubbles occurred, the energy was increased by increments of 0.1 mJ until bubble formation and then decreased as described above. The entire meshwork was treated with 100 (SD 5) non-overlapping spots. The total number of pulses and the energy delivered were recorded. Postoperatively, non-steroidal anti-inflammatory drops (ketorolac tromethamine), were prescribed four times a day for 5 days.
Latanoprost treatment group
Patients allocated to this group were instructed to instil one drop of latanoprost 0.005% into the eye every night. Compliance was stressed, and any questions that the patients had were addressed during the teaching session.
All patients in both treatment groups were evaluated by one of the two masked observers at day 3, week 1, month 1 and at final follow-up which occurred between months 4 and 6. IOP control was evaluated by comparing the baseline measurement with the value obtained at each follow-up. On each occasion, this measurement was taken in the morning within the same 2 h period. The observers were instructed not to ask questions regarding mode of treatment, and patients were advised not to discuss their treatment with these doctors. Instead, patients were provided with the chief investigator’s (MN) contact details, and if there were any questions or concerns, these were dealt with separately to the study follow-ups.
At the final follow-up visit (between 4 and 6 months’ postintervention) Goldmann tonometry was performed to assess IOP control, and the measurement was repeated at 08:00, 11:00, 14:00 and 18:00 to create a diurnal tension curve. Treatment success for IOP control was defined as at least a 20% reduction from baseline measurement. For IOP fluctuation, success was defined as at least a 50% reduction in the fluctuation. At the end of the study, eyes that had not achieved adequate IOP control were treated with laser or latanoprost at the discretion of the chief investigator.
A power analysis statement was calculated by the statistician based on 0.9 power to detect a significant difference in fluctuation of IOP between the groups (p = 0.05, two-sided), and assuming an SD of 2 mm Hg, it was estimated that 16 eyes were required for each study group. We deemed this number suitable for a feasibility study. If both eyes were treated, only one eye was chosen for analysis using a random number generator. Independent-samples t tests were used to compare the two treatment groups at baseline and to compare those with partial versus complete follow-up. The difference between IOP prior to treatment and at each follow-up visit was calculated. These difference scores were analysed with linear mixed models to determine whether there were any differences in IOP control between treatment groups at each follow-up. Logistic regression was used to evaluate whether there were any differences in success of IOP control between treatment groups. All models were adjusted for baseline IOP to reduce the influence of regression to the mean effects. The statistical analyses included baseline IOP or baseline IOP fluctuation as covariates in the models. IOP fluctuation was defined as the maximum minus the minimum of the diurnal tension curves. The difference in IOP fluctuation (peak minus trough) between the baseline tension curve and the post-treatment tension curve was calculated, and an analysis of covariance was used to determine whether the IOP fluctuation difference varied with treatment. Logistic regression was used to assess the difference in successful control of IOP fluctuation between treatment groups. All IOP fluctuation analyses were adjusted for baseline fluctuation. Statistical analyses were performed with SAS JMP (V7.01, SAS Institute, Cary, North Carolina).
Of the 40 patients, 21 (52%) were male, 19 (48%) female, and all were Caucasians (100%). The mean age was 66.4 years (range 43 to 88). Seventeen patients (43%) had the diagnosis OAG, and 23 (57%) were OHT.
Twenty patients were randomised to the latanoprost treatment group and 20 patients to the SLT group. There were no significant differences between the two treatment groups in terms of age, sex, race, aetiology of raised IOP or follow-up. However, there was a difference between the groups for baseline IOP (p = 0.017). Of the 40 patients, 30 attended all appointments. Analysis of those with complete (n = 30) versus incomplete (n = 10) follow-up showed there to be no significant difference in age, sex, treatment assigned or baseline IOP (all p>0.4). Incomplete follow-up occurred mainly because of the short interval between the standard clinic appointment and the study appointment to monitor diurnal fluctuation.
For the SLT group, the mean IOP prior to treatment was 26.1 (4.0) mm Hg. In the latanoprost group, the mean baseline IOP was significantly lower at 22.8 (4.5) mm Hg (p = 0.017). SLT lowered the IOP significantly (mean reduction across all follow-up visits 4.7 mm Hg; 95% CI 3.6 to 5.7; p<0.01), and the treatment effect was similar for both groups at all follow-ups except the 1-month assessment. At this appointment, there was a greater treatment effect with the latanoprost group, that is, a mean reduction of 7.0 mm Hg versus 3.2 mm Hg (p<0.05). However, in the longer term, at the 4–6-month follow-up, the treatment effect was not significantly different: the absolute reduction was 6.2 mm Hg with SLT as compared with a 7.8 mm Hg reduction in the latanoprost group. The treatment effects at each follow-up visit are given in table 2 and illustrated in fig 1.
In terms of success in IOP control, the percentage of patients in the treatment groups achieving control at each follow-up is shown in table 3. The odds of success were the same for the two treatments except the month 1 follow-up when latanoprost provided a greater success (odds ratio 6.25; CI 1.72 to 51.10; p = 0.003). At the final follow-up, 75% of patients in the SLT group and 73% in the latanoprost group achieved success in IOP control (p = 0.4).
Diurnal tension curves measured prior to treatment and at final follow-up showed that SLT had a significant impact on IOP fluctuation. The mean IOP fluctuation (peak minus trough) for this treatment group was 5.5 (2.7) mm Hg and a reduction of 2.3 (2.4) mm Hg, that is, 41% reduction in IOP fluctuation was achieved after treatment (p = 0.0007). In comparison, the latanoprost group had a mean IOP fluctuation of 5.7 (2.1) mm Hg, which decreased by 3.7 (2.8) mm Hg (p<0.0001), that is, 64% reduction in IOP fluctuation was achieved after treatment. After adjustment for baseline IOP fluctuation, there was a significant difference between treatments, with the latanoprost group having a greater reduction in fluctuation (3.6 vs 2.5 mm Hg; p = 0.0444). The mean IOP fluctuation is shown before and after treatment for both SLT and latanoprost in fig 2.
Treatment with SLT was successful in lowering IOP fluctuation in 50% of patients, whereas latanoprost showed success in 83% of cases. After adjustment for baseline IOP fluctuation, success was more likely for latanoprost than for SLT (odds ratio 2.25; CI 1.01 to 5.67; p = 0.049).
The importance of IOP fluctuation was identified by the pointwise, linear regression analysis of the AGIS patients reported by Nouri-Mahdavi et al.13 IOP fluctuation remained a significant predictor of visual field (VF) worsening despite inclusion of mean IOP and the number of glaucoma interventions as an independent covariate in the regression models. When multivariate logistic regression was repeated, excluding IOP fluctuation, the mean IOP reached statistical significance (p = 0.045) along with age, number of surgical interventions and male gender. The low correlation between IOP fluctuation and mean IOP during follow-up and the less significant p value for the latter after exclusion of IOP fluctuation from the multivariate analysis suggest that IOP fluctuation is an independent and stronger predictor than mean IOP for VF progression. It was also found that each 1 mm Hg increase in IOP fluctuation equated to an approximately 30% increase in the risk of VF progression. In summary, the two parameters in AGIS consistently associated with VF progression were greater IOP fluctuation and older age at first glaucoma intervention. In our study, both treatment modalities had a significant impact on IOP fluctuation, with SLT successfully lowering IOP fluctuation in 50% of patients and latanoprost in 83% of patients. The response rate and IOP reduction in this present study were comparable with those reported in published literature in which the success rate varies from 64% to 89%.14–16
The crossover study of Orzalesi et al comparing three prostaglandin analogues found no significant difference between these agents in their ability to lower IOP during the 24 h circadian cycle.4 Other studies have reported conflicting findings, however.17 18 Although it is unclear if one of the prostaglandin analogues is superior to others in its ability to damp IOP fluctuation, the prostaglandin analogues, as a class, appear to provide significant IOP reduction throughout the 24 h circadian cycle. Our study clearly supports the concept that latanoprost damps IOP fluctuation, and it demonstrates the ability of SLT to have a significant effect, too. This study has also confirmed the well-established benefit of SLT in controlling the mean IOP, which was comparable with that of the prostaglandin analogues.19 However, SLT has the advantage of not being dependent on patient compliance. This fact alone may influence long-term success in some patients.
We recognise that our study is limited by the number of patients and the difference between the treatment groups’ baseline IOPs. A study with increased patient recruitment and, ideally, 24 h IOP monitoring would be helpful. Higher peak pressures can occur during sleep at night, but these are difficult to diagnose. Such elevated night-time pressures might be at least a partial explanation why seemingly well-controlled patients show glaucomatous progression.20–23
An observation worthy of comment was the presence of some slow/late responders in the SLT group. In a large number of instances, the response was predominantly immediate (IOP reduction noted on week 1), but there were a few late responders (10–15%) who showed an IOP reduction between 4 and 12 weeks post-treatment, hence the difference in IOP reduction at months 1 and 4 (table 2).
More research is needed to determine the best treatment indications and stepwise therapies, particularly in relation to long-term compliance by the patient. SLT is a realistic first-option choice in some cases, even in those with significant IOP fluctuation, although further research will help to establish the optimum role for SLT.
Competing interests: None.
Ethics approval: Ethics approval was provided by the Research and Ethics Committee, Pinderfields & Pontefract NHS trust.
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