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A randomised crossover study comparing bimatoprost and latanoprost in subjects with primary angle closure glaucoma
  1. A C S How1,
  2. R S Kumar2,
  3. Y-M Chen3,
  4. D H Su1,
  5. H Gao3,
  6. F T Oen1,
  7. C-L Ho1,
  8. S K Seah1,
  9. T Aung1,2,4
  1. 1
    Singapore National Eye Centre, Singapore
  2. 2
    Singapore Eye Research Institute, Singapore
  3. 3
    Clinical Trials and Epidemiology Research Unit, Singapore
  4. 4
    Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  1. Dr T Aung, Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore 168751; tin11{at}pacific.net.sg

Abstract

Background/aims: To compare the intraocular pressure (IOP) lowering efficacy and side effects of latanoprost 0.005% and bimatoprost 0.03% in subjects with chronic primary angle closure glaucoma (PACG).

Methods: This was an observer-masked randomised crossover study of 60 PACG subjects who received either latanoprost or bimatoprost for 6 weeks, after which they were crossed over to the other medication for another 6 weeks. The IOP-reducing effect of the medications was assessed by the reduction in IOP after 6 weeks of treatment compared with baseline.

Results: Fifty-four subjects (80 eyes) completed the study. Latanoprost reduced IOP (mean (SD)) by 8.4 (3.8) mm Hg and bimatoprost by 8.9 (3.9) mm Hg from a baseline of 25.2 (3.6) mm Hg and 25.2 (3.6) mm Hg respectively (p = 0.23). Adverse events were mild in both groups; however there were twice as many reports of an adverse event in the bimatoprost group (81%) compared with the latanoprost group (40%, p<0.01). Ocular irritation was the most frequently reported adverse event in both groups; 22 subjects (37.9%) treated with bimatoprost experienced ocular hyperaemia as compared with 13 subjects (22.4%) treated with latanoprost (p = 0.11).

Conclusions: Bimatoprost once daily was similarly effective in reducing IOP compared with latanoprost once daily in subjects with chronic PACG. Both drugs were well tolerated with mild ocular adverse events.

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Primary angle closure glaucoma (PACG) is a major form of glaucoma in East Asia.1 2 It has been estimated that glaucoma will be the most common cause of irreversible blindness in the world this century with almost 70 million cases of glaucoma worldwide, and Asians account for 87% of those with PACG.3

Latanoprost, a prostaglandin F-analogue, has proven to be an effective ocular hypotensive medication in subjects with primary open-angle glaucoma (POAG) and ocular hypertension.47 Bimatoprost, a prostamide, is another highly efficacious ocular hypotensive agent and has been shown to be superior in its hypotensive effect compared with the other glaucoma medications such as the beta-blockers.810 Studies on POAG and ocular hypertension subjects have reported similar11 and even superior12 13 intraocular pressure (IOP) reduction in bimatoprost-treated subjects compared with latanoprost-treated ones.

The majority of glaucoma research has been focused on populations with a preponderance of POAG, whereas treatment modalities or medication therapies for PACG remain less elucidated. Several studies have shown that latanoprost is superior in lowering IOP compared with beta-blockers in subjects with PACG.1416 The aim of this study was to compare the IOP-lowering efficacy and safety of latanoprost and bimatoprost for the treatment of chronic PACG.

METHODS

This was a randomised observer-masked crossover study comparing the IOP lowering effect of latanoprost 0.005% with bimatoprost 0.03% in subjects with PACG with raised IOP. Written informed consent was obtained from all participants, approval was obtained from the Ethics Committee of the Singapore Eye Research Institute, and the project was conducted in adherence to the tenets of the Declaration of Helsinki.

Subjects 40 years of age or older with unilateral or bilateral chronic PACG with raised IOP >21 mm Hg were recruited from glaucoma clinics at the Singapore National Eye Centre. PACG was defined as glaucomatous optic neuropathy (defined as a cup:disc ratio of >0.7 or the presence of notching) with a compatible visual-field defect and an anterior chamber angle in which the posterior trabecular meshwork was not visible for at least 180° on static gonioscopy, and evidence of peripheral anterior synechiae (PAS) in any part of the angle. PAS were defined as abnormal adhesions of the iris to the angle that were at least half a clock hour in width and were present to the level of the anterior trabecular meshwork or higher, and were deemed to be present if apposition between the peripheral iris and angle structures could not be broken despite indentation gonioscopy. The extent of PAS was noted in clock hours. A threshold examination of the visual field (program 24-2 SITA-Standard, model 750, Humphrey Instruments, San Leandro, California) showing a glaucoma hemifield test (GHT) “outside normal limits,” and a cluster of three contiguous points on the pattern deviation plot depressed at p<5% level not crossing the horizontal meridian was considered compatible with glaucoma. Subjects had to have performed at least two reliable (fixation loss<20% and false-positive and false negatives<33%) visual fields with reproducible defects.

All subjects were phakic with a patent laser iridotomy and were recruited into the study a minimum of 1 month after the iridotomy. Subjects on previous glaucoma therapy were required to complete a minimum washout period before randomisation: 4 weeks for prostaglandin analogues, 3 weeks for beta-adrenergic antagonists, 2 weeks for adrenergic agonists, 5 days for cholinergic agonists and 5 days for carbonic anhydrase inhibitors. All subjects recruited had IOP>21 mm Hg at prestudy and baseline visits for untreated subjects, or IOP>21 mm Hg at baseline visit after washout of previous glaucoma therapy.

Subjects with previous intraocular surgery or secondary glaucoma such as uveitic, post-trauma or neovascular glaucoma were excluded. Other exclusion criteria were advanced glaucoma (defined as cup:disc ratio >0.9 and/or perimetric evidence of visual-field loss within 10° of macula fixation in one or more quadrants), previous corneal infection or corneal abnormalities, dry eyes, current use of contact lenses, oral drugs known to affect IOP or known allergy to benzalkonium chloride. Also, a history of cerebrovascular, hepatic or metabolic disease (except diabetes mellitus) was considered the reason for exclusion. Pregnant, nursing or women considering pregnancy were excluded, as were subjects with a history of non-compliance or those who participated in another therapeutic drug study within 1 month.

At the prestudy visit, medical and ocular history was taken. Best-corrected Snellen visual acuity, gonioscopy, slit-lamp examination, slit-lamp biomicroscopy with the 78 dioptre lens and measurement of the IOP were performed. The IOP was measured at 09:00 and 17:00 at the baseline, week 6 and week 12 visits, and at 09:00 at week 2 and week 8 visits. The IOP was measured with a Goldmann applanation tonometer, and all IOP measurements were performed by the same observer, who was masked to the treatment the patient was on. Three consecutive measurements were performed in each eye, and the mean of the three measurements was used in the statistical analyses. For subjects in whom both eyes were eligible, the average was based on the measurements made in both eyes. If the patient had only one study eye, the average was based on the measurements made in that eye only.

At baseline, subjects were randomised to receive either latanoprost 0.005% once daily in the evening or bimatoprost 0.03% once daily in the evening for 6 weeks (treatment period I), after which they were crossed over to the other medication for another 6 weeks without any washout period in between (treatment period II). Subjects then underwent exactly the same regimen of examination and clinic visits as in treatment period I. Randomisation was performed through a web randomisation system. During each study period, there were two scheduled visits after the baseline visit, at 2 weeks and at 6 weeks. The IOP-reducing effect of the medications was assessed by the reduction in IOP at week 6 for each treatment compared with baseline. All medications were dispensed with their original labels. Subjects were instructed to instill one drop of the allocated medication at approximately 20:00 each day. Subjects were informed to adhere strictly to the timing and to record the time of administration on a record book.

Adverse events were monitored carefully throughout the study. Subjects were queried at each visit regarding adverse events by standard clinician enquiry, and investigators did not ask specifically about any particular symptom. An adverse event was defined as any undesirable event occurring in a subject regardless if it was considered related to the investigational drug.

STATISTICAL EVALUATION

A sample size of 44 subjects was calculated to detect a difference in IOP between the two treatments of 2.0 mm Hg as determined at week 6 of each treatment period, with a two-sided test size of 5%, power 90% and anticipated standard deviation of the difference in IOP between treatment groups of 4 mm Hg. To compensate for subjects not completing the trial, the sample size was increased to 60 subjects. The primary outcome measures were a change in IOP from the start of each period to the end of the period, and percentage change in IOP during each period. Responders were also classified into subjects who experienced a percentage decrease in IOP of a fixed level (15% to 30%). All statistical tests were conducted using SAS version 9.1 (SAS Institute, Cary, North Carolina).

RESULTS

A total of 60 chronic PACG subjects were recruited. One patient did not fulfil the IOP eligibility criteria and was excluded. Among the remaining 59 subjects, 29 were randomised to bimatoprost in Treatment Period I followed by latanoprost in Treatment Period II, and 30 were randomised to latanoprost followed by bimatoprost in a crossover design. One patient was excluded due to uncontrolled IOP (>36 mm Hg). One patient died of a myocardial infarction during the study. Two other subjects withdrew from the study of their own accord, and another subject was withdrawn by the investigator as the patient had many systemic symptoms such as headache, giddiness and chest and stomach discomfort after one dose of bimatoprost. Fifty-four subjects (80 eyes) completed both treatment periods with data available for evaluation and statistical analysis. The analysis was by “intention to treat.”

Baseline demographic and clinical characteristics of the study group are presented in tables 1, 2. The mean age was 65.7 years (SD 7.2, range 50 to 85 years). There were 41 (69.5%) females, and all subjects were Asian with a predominance of Chinese subjects (88.2%). There were 29 (49.1%) subjects who were newly diagnosed at the time of enrolment and not on any glaucoma therapy. There were 30 (50.9%) subjects who were on previous IOP-lowering therapy and underwent a washout period prior to randomisation, of which 26 subjects (44.1%) were on one medication, and four subjects used two medications. The most frequently used previous medication was a beta-blocker (24 subjects).

Table 1 Demographic characteristics of subjects recruited into the study
Table 2 Clinical characteristics of subjects recruited into the study

From the baseline IOP of 25.2 (3.6) mm Hg, the mean reduction in IOP after treatment with bimatoprost was 8.9 (3.9) mm Hg, while the mean IOP reduction with latanoprost was 8.4 (3.8) mm Hg (p = 0.23, paired t test) (table 3). There were comparable reductions in IOP at both 09:00 (p = 0.67, paired t test) and 17:00 (p = 0.12, paired t test) time points (fig 1). Of the 54 subjects who completed the study, 36 (66.7%) subjects had their IOP reduced more than 30% after treatment with bimatoprost, while 34 (63.0%) subjects had a similar reduction after treatment with latanoprost (p = 0.69, McNemar test). Fifty-one (94.4%) subjects had their IOP reduced by more than 15% after using either bimatoprost or latanoprost (p = 1.0, McNemar test) (table 3).

Figure 1

Mean intraocular pressure (IOP) changes at different time points (mm Hg).

Table 3 Number of subjects who experienced a percentage decrease in intraocular pressure (IOP) (of a fixed level), mean IOP and reduction in IOP among study subjects who completed the trial

Comparison of IOP reduction by extent of PAS

Thirty-two eyes had cumulative PAS greater than 3 clock hours. Eyes with PAS greater than 3 clock hours treated with bimatoprost had a greater IOP reduction compared with latanoprost. The difference in mean IOP reduction was −1.2 (SEM 0.4) mm Hg at week 6 (p<0.01, paired t test). There was no difference in IOP reduction between the two medications for eyes with ⩽3 clock hours of PAS.

Adverse events

The adverse events experienced by the subjects are summarised in table 4. There were few systemic adverse events, and those reported such as headache were mild in nature. The commonest adverse events were ocular irritation and redness. Twenty-two out of 58 subjects (37.9%) treated with bimatoprost experienced ocular hyperaemia as compared with 13 subjects (22.4%) treated with latanoprost (p = 0.11, McNemar test). Comparing the two groups, twice as many eyes receiving bimatoprost (81%) experienced an adverse event as compared with those receiving latanoprost (40%,p<0.01, McNemar test). Of those treated with bimatoprost, there were more subjects who experienced ocular irritation, eye redness and a sensation of blurred vision after administration of the drug as compared with those treated with latanoprost. Among the subjects who complained of blurred vision, there was no actual drop in visual acuity during the follow-up visits.

Table 4 Number of subjects with ocular or system adverse events reported (at least once) during the study

DISCUSSION

Previous studies conducted in Asia in subjects with PACG have demonstrated the efficacy of latanoprost in reducing IOP with mean IOP reduction, with latanoprost being about −8 mm Hg.1416 The results of our current study show that after 6 weeks of treatment, both latanoprost and bimatoprost have a similar IOP-lowering efficacy in subjects with chronic PACG. In the latanoprost-treated group, the IOP reduction was 8.4 (3.8) mm Hg, while it was 8.9 (3.9) mm Hg for bimatoprost-treated subjects (p = 0.23, paired t test). A recent study conducted in Taiwan also showed no difference between bimatoprost and latanoprost in the treatment of PACG.17 However, the reduction in IOP (5.2 mm Hg) of either medication was less than what our study found. This could be explained by the fact that the baseline IOP was lower than that in our study, and the IOP-lowering effect of prostaglandins may be less at lower IOP levels. The results of our study are also consistent with the results of meta-analyses and review articles comparing the efficacy of these two medications in the treatment of POAG and ocular hypertension.18 19 In a recent review, bimatoprost was found to be marginally better in its IOP-lowering effect as compared with latanoprost in some studies, although this difference was not statistically significant all the time.19 With regards to IOP lowering for daytime pressures, our study found that the IOP-lowering effect of both medications was almost similar at both 09:00 and 17:00 IOP measurements. Interestingly, Stewart et al found that the mean reduction in IOP at night was statistically lower than that of daytime points for latanoprost (p = 0.031) but not for bimatoprost (p = 0.057).20

A previous study found that the IOP-lowering effect of latanoprost in subjects with PACG was not affected by the degree of angle closure or the extent of PAS present.21 We found that subjects with PAS greater than 3 clock hours treated with bimatoprost had greater IOP reduction of 1.2 mm Hg (SEM 0.4) compared with latanoprost. We speculate that this could be explained by different routes of absorption for the two drugs. The sclera is the preferred route of accession of bimatoprost to the eye, whereas latanoprost is absorbed primarily through the cornea,22 and it is possible that corneal absorption may impact IOP reduction due to the reduced access to uveoscleral outflow caused by PAS. Another possibility could be due to an upregulation of FP receptors in subjects with a greater extent of PAS, since bimatoprost has been known to stimulate FP receptors directly.23 24

Although twice as many eyes receiving bimatoprost (81%) experienced an adverse event compared with those receiving latanoprost (40%) (p<0.01), the nature of these ocular side effects was relatively mild such as ocular irritation and eye redness. These side effects were well tolerated, and none of the patients had to be taken off the drug or given lubricants due to the intolerability.

The strengths of this study include a randomised crossover design and observer-masking to reduce bias. Potential limitations include the relatively short treatment periods of 6 weeks, a moderate sample size and the drugs dispensed as open-label. As study subjects were not masked, this could have affected the reporting of adverse events by subjects. A previous study has shown that IOP returned to near pretreatment levels 14 days after cessation of latanoprost,25 so the assessment of IOP was only determined after 6 weeks of treatment. This was to allow the effect of the the first prostaglandin to be completely washed out. However, the possibility of a prolonged residual IOP lowering effect from the first medication during the second treatment period cannot be excluded. As the study population was predominantly Asian, it is not known if these results could be applied to PACG subjects in Western countries.

In conclusion, this study has found that in subjects with chronic PACG, the prostaglandin analogues, latanoprost and bimatoprost were similarly effective in IOP lowering, with a good safety profile and relatively mild side effects. Bimatoprost has a slightly greater IOP-lowering effect in subjects with >3 clock hours of PAS and may be preferable in eyes with advanced synechial closure. However, the higher frequency of ocular side effects of bimatoprost, though well tolerated, may be a consideration in a physician’s choice of a prostaglandin analogue.

REFERENCES

Footnotes

  • Competing interests: TA has received research funding, travel support and honoraria from Allergan and has been a consultant and received travel support and honoraria from Pfizer.

  • Funding: This research was funded by an unrestricted grant from Allergan.

  • Ethics approval: Ethics approval was provided by the Ethics Committee of the Singapore Eye Research Institute.

  • Patient consent: Obtained.

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