Intervenciones médicas para el glaucoma de ángulo abierto primario y la hipertensión ocular
Resumen
Antecedentes
El glaucoma primario de ángulo abierto (GPAA) es una neuropatía óptica progresiva con una presión intraocular (PIO) elevada, en la que la cabeza del nervio óptico se excava patológicamente y el campo visual (CV) se altera de forma característica. La hipertensión ocular (HTO) es una afección con PIO elevada pero sin patología discernible de la cabeza del nervio óptico ni del CV. Es un factor de riesgo importante para el desarrollo del GPAA.
Objetivos
Evaluar y comparar la efectividad del tratamiento farmacológico tópico para el GPAA o la HTO para prevenir la progresión o la aparición de la neuropatía óptica glaucomatosa.
Métodos de búsqueda
Se hicieron búsquedas en CENTRAL, MEDLINE y EMBASE en mayo 2007. Se realizaron búsquedas en las bibliografías de los artículos identificados y se estableció contacto con expertos, investigadores y compañías farmacéuticas para obtener estudios adicionales publicados y no publicados.
Criterios de selección
Ensayos controlados aleatorizados que compararon el tratamiento farmacológico tópico con placebo, ningún tratamiento u otro tratamiento para las variables principales de evaluación específicas que incluyeron personas con GAAP o HTO, y con una duración del tratamiento de al menos un año.
Obtención y análisis de los datos
Dos autores de la revisión extrajeron los datos de forma independiente y evaluaron la calidad de los ensayos. Cuando fue apropiado, se resumieron los datos mediante el odds ratio de Peto y la diferencia de medias después de probar la heterogeneidad entre los estudios.
Resultados principales
En esta revisión se incluyeron 26 ensayos que asignaron al azar a 4979 participantes. El metanálisis de diez ensayos demostró claramente una reducción de la aparición de defectos del CV en la HTO tratada (OR 0,62; IC del 95%: 0,47 a 0,81). Ningún fármaco único mostró una protección significativa del CV en comparación con placebo o con los controles no tratados. Se identificó alguna evidencia marginal de una influencia positiva del tratamiento sobre el pronóstico del CV (OR 0,67; IC del 95%: 0,45 a 1,00) para los betabloqueantes.
Conclusiones de los autores
Los resultados de esta revisión apoyan la práctica actual de la disminución de la PIO en el tratamiento de la HTO. Se ha demostrado claramente un efecto protector del campo visual con el tratamiento médico para disminuir la PIO. Se ha mostrado evidencia positiva pero débil de un efecto beneficioso de la clase de los betabloqueantes.
Las comparaciones directas de prostaglandinas o brimonidina con placebo no están disponibles, y la comparación de dorzolamida con placebo no logró demostrar un efecto protector. Sin embargo, la falta de datos o el hecho de que no se demuestre la eficacia no se debe interpretar como evidencia de falta de efecto. La decisión de tratar o no a un paciente, así como la decisión sobre el fármaco con el que empezar el tratamiento, debe seguir siendo individualizada y tener en cuenta la cantidad de daño, el nivel de PIO, la edad y otras características del paciente.
Resumen en términos sencillos
Intervenciones médicas para el glaucoma de ángulo abierto primario y la hipertensión ocular
La hipertensión ocular (HTO) es una afección en la existe presión intraocular (PIO) elevada sin cambios en el campo visual ni patología discernible de la cabeza del nervio óptico. La hipertensión ocular con PIO superior a 21 mmHg sin tratamiento es un factor de riesgo importante para el desarrollo de glaucoma primario de ángulo abierto, que consiste en la pérdida progresiva de fibras nerviosas y el daño del disco óptico, de modo que el campo visual desarrolla defectos característicos. Se administran medicamentos tópicos para reducir la PIO como una forma de prevenir el inicio o la progresión del daño, así como la pérdida de campo visual asociada. Estos fármacos pueden tener efectos secundarios locales y sistémicos que pueden ser suficientemente graves para interrumpir el tratamiento e incluyen irritación local, somnolencia, falta de aliento y efectos secundarios cardiovasculares, particularmente en los pacientes de edad avanzada. Los resultados de esta revisión apoyan la práctica actual de los fármacos tópicos para disminuir la PIO y demuestran claramente un efecto protector del campo visual. Los autores de la revisión identificaron 26 ensayos controlados que asignaron al azar a 4979 personas con HTO o glaucoma de ángulo abierto a recibir fármacos tópicos o placebo, otro fármaco tópico o ningún tratamiento durante al menos un año. El metanálisis de diez ensayos que probaron diferentes fármacos tópicos contra placebo o controles no tratados mostró una menor incidencia de defectos glaucomatosos del campo visual con el tratamiento para los pacientes con HTO. El odds ratio (OR) fue 0,62 (rango 0,5 a 0,8). La clase de los betabloqueantes (incluido el timolol) tuvo evidencia positiva pero débil de un efecto beneficioso en la protección contra los defectos del campo visual (OR 0,7; rango 0,5 a 1,0). Ningún fármaco único mostró una protección significativa del campo visual en la HTO con la evidencia disponible. Los fármacos incluidos fueron los betabloqueantes, la dorzolamida, la brimonidina, la pilocarpina y la epinefrina. A partir de los informes, la mayoría de los ensayos fueron de calidad metodológica baja. Los efectos secundarios locales y sistémicos que dieron lugar a la interrupción del tratamiento a menudo se informaron de forma deficiente y no parecieron diferir entre los grupos de tratamiento. Los abandonos debido a los efectos secundarios ocurrieron con una frecuencia similar en los pacientes tratados con betabloqueantes o placebo y en tres ensayos parecieron ser menores con el timolol en comparación con la brimonidina.
Authors' conclusions
Background
Primary open angle glaucoma (POAG) is a disease in which elevated intraocular pressure (IOP) is combined with a progressive optic neuropathy, resulting in characteristic excavation of the optic nerve head and corresponding visual field defects. Ocular hypertension (OHT) is a condition in which IOP is elevated but there is no discernible glaucomatous damage to the optic nerve head and no detectable visual field changes. The distinction between OHT and POAG remains to some extent arbitrary. Optic nerve head pathology usually precedes the onset of visual field defects. Up to 50% of the optic nerve fibres are lost when the visual field shows the earliest pathologic changes (Quigley 1983). Unfortunately preperimetric damage to the optic nerve head may be missed because of the variable appearance of the normal optic nerve head.
Elevated IOP is an important risk factor for the development of glaucomatous optic neuropathy (Armaly 1980) and between 4% (Kass 2002) and 20% (Ontoso 1997) of people with OHT develop visual field defects within five years. Traditionally people with OHT have been treated with IOP lowering medication. However, the evidence for a protective effect of such treatment is questionable and has led to the recent recommendation by the European Glaucoma Society to refrain from treatment of OHT with IOP below the upper 20 millimetres mercury (mmHg) and no additional risk factor.
Normal tension glaucoma (NTG) is a clinical entity characterised by similar damage of the optic nerve head and similar visual field defects, but without an elevated IOP. Primary open angle glaucoma, which by definition is characterised by an elevated IOP, is arbitrarily distinguished from NTG using a cut‐off point of IOP of 21 mmHg.
It is widely accepted that the distinction between these two entities remains artificial, because they represent two subsets of patients along a continuum. Nevertheless people suffering from POAG and NTG may show a different clinical course concerning patterns of optic disc damage and quantity and quality of visual field loss (Caprioli 1998). In addition, there is evidence that the mechanism of damage may differ between the two chronic open angle glaucoma populations (Schulzer 1990). A recent Cochrane review resulted in only weak evidence for visual field protection by either medical or surgical treatment of NTG (Sycha 2005).
Primary open angle glaucoma has been treated over the past 100 years with various topically and systemically applied drugs to lower the IOP. The IOP lowering capacity of numerous antiglaucomatous drugs has been thoroughly studied. However, there are no well established guidelines for the treatment of POAG based on evidence of visual fields or optic nerve head protection (Rossetti 1993). Recently published evidence for OHT shows IOP lowering topical antiglaucomatous therapy effectively prevents conversion to glaucoma, defined as onset of visual field defects or morphological change of the appearance of the optic nerve head (Kass 2002). However, since this study did not specify nor restrict the medications to be used, we can neither tell which of the presently available drugs offers a beneficial effect, nor whether this protection will be achieved by all topical IOP lowering treatments.
Objectives
This review aimed to summarise the evidence for the effectiveness of different forms of topical medical treatment of POAG or OHT to prevent the progression or the onset of glaucomatous optic neuropathy. Secondly, this review aimed to answer the question, whether different drugs or classes of drugs differ in their beneficial effect? In addition, this review aimed to summarise the observed local and systemic side effects leading to the cessation of the different forms of topical medical treatment in the retrieved studies.
Methods
Criteria for considering studies for this review
Types of studies
We included all randomised trials with treatment duration of at least one year comparing different forms of topical medical therapy to placebo, no treatment or other medical treatment. We divided studies into short‐term (with a follow‐up time of less than three years) and long‐term (with a follow‐up time of three years or more) trials.
Types of participants
We included trials in which participants were people with POAG or OHT as defined by investigators using the common definitions as mentioned below or using similar definitions. We accepted trials that included people with a mean IOP above 21 mmHg.
There were no age or gender limitations.
At present the following criteria are widely used to define POAG:
(1) A mean untreated IOP above 21 mmHg.
(2) Open drainage angles on gonioscopy without any pathologic changes.
(3) Typical optic disc damage with glaucomatous cupping and loss of neuroretinal rim.
(4) Visual field defect compatible with glaucomatous cupping.
(5) Absence of secondary cause for IOP elevation (e.g. pigment dispersion, uveitis).
Ocular hypertension is commonly defined according to the following criteria:
(1) A mean untreated IOP above 21 mmHg.
(2) Open drainage angles on gonioscopy without any pathologic changes.
(3) Absence of typical optic disc damage with glaucomatous cupping and loss of neuroretinal rim.
(4) Absence of visual field defects.
(5) Absence of secondary cause for IOP elevation (e.g. pigment dispersion, uveitis).
Types of interventions
Interventions included topical ocular administration of pharmacological therapy with the intention to reduce the progression of signs in participants with POAG or OHT. There was no maximum limit of the duration of treatment. Minimum duration of treatment was one year.
Types of outcome measures
Primary outcomes
(1) reduction of onset or progression of visual field loss (proportion of people with visual field loss or visual field loss rate in a specified time period).
Secondary outcomes
(2) improvement of visual field;
(3) reduction of nerve fibre layer loss progression (according to objective measurement);
(4) reduction of optic nerve head cupping progression (according to objective assessment);
(5) local and systemic side effects leading to the cessation of treatment.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, which contains the Cochrane Eyes and Vision Group Trials Register; MEDLINE and EMBASE; and reference lists of identified trial reports. We last searched the databases on 14 May 2007. We placed no language or date restrictions in the searches for trials.
See: Appendices for details of search strategies used for each database.
Searching other resources
We searched the reference lists of identified trial reports and used the Science Citation Index to find reports that cited the identified relevant studies. We contacted experts, investigators and pharmaceutical companies in the field of glaucoma for details of further studies and unpublished studies. We placed no language restriction in the selection of trials.
Data collection and analysis
Selection of trials
Two review authors working independently assessed the titles and abstracts of all reports identified by the electronic searching. The full text copies of possibly and definitely relevant trials were obtained and assessed according to the definitions in the 'Criteria for considering studies for this review'. Only trials meeting these criteria were assessed for methodological quality. There was no restriction concerning publication date or language. The review authors were not masked to any trial detail during the assessment.
Assessment of methodological quality
Trial quality was assessed according to methods set out in section 6 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2006a). We used four components to determine methodological quality: allocation concealment, performance bias, detection bias and attrition bias. Each component was graded A ‐ Adequate, B ‐ Unclear or C ‐ Inadequate as outlined in the Cochrane Eyes and Vision Group Review Development guidelines.
Two review authors working independently assessed trial quality and disagreements were resolved by discussion, additional referees or both. The review authors were unmasked to the report authors and trial results during the assessment. We contacted trial authors for clarification concerning studies that did not report relevant details on the four components mentioned above. We excluded trials scoring C on allocation concealment.
Data collection
Two review authors working independently extracted data onto forms developed by the Cochrane Eyes and Vision Group using Section 7 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2006b). We contacted authors of trials to obtain missing data. We compared the extracted data for differences between review authors and discrepancies were resolved by discussion.
Data synthesis
We summarised data from studies collecting similar outcomes and using similar follow‐up times after testing for heterogeneity between trial results using the I‐square test.
For dichotomous data, we expressed results as odds ratio (OR) estimates or risk ratio (RR) estimates (95% confidence interval (CI)). We also obtained the risk difference or the number needed to treat (95% CI). For continuous data, we obtained the mean and standard deviations. We converted standard errors to standard deviations. We summarised results across studies using mean differences (95% CI).
We conducted sensitivity analyses to determine the effect of excluding trials falling below a quality threshold with the following criteria (one or both of them):
(1) exclusion of trials scoring C on any aspect of methodological trial quality;
(2) exclusion of trials which had assumed that eyes within an individual were independent (fellow eye used as a control group).
Results
Description of studies
Finding the trials
The electronic searches revealed 2236 abstracts of papers. We obtained the full copies of 365 potentially or definitely relevant papers. Checking reference lists revealed a further 19 papers, which were obtained in full text. Contact with the authors of identified trials and with experts and researchers in the field have not identified any further relevant papers.
We screened a total of 384 papers for content and methodological quality according to their full text copies. From these articles we could easily and without any doubt exclude 334 from further assessment, as they either did not involve people with POAG or did not report randomised or controlled trials. This left a total of 50 papers describing 30 trials that addressed topical medical interventions for POAG.
We did an updated search in May 2007 which yielded a further 685 reports of studies. The Trials Search Co‐ordinator scanned the search results and removed any references which were not relevant to the scope of the review. The authors received abstracts of 80 papers for assessment for potential inclusion in the review. We have identified eight reports of studies which may be added to the review; please see 'Studies awaiting assessment' for further information.
Included/ excluded studies
We excluded four trials (eight papers) (see 'Characteristics of excluded studies' table). We excluded two trials (three papers) because they were carried out in people with POAG or NTG and data were not described separately in the results section (Araie 2003; Vainio 1999). We excluded one trial (one paper) because the protocol allowed topical therapy to be supplemented with acetazolamide, and patients on topical therapy alone were not analysed separately (Holmin 1988). We excluded one trial (four papers) because the treatment also included laser trabeculoplasty (EMGT 1999).
We included a total of 42 papers describing 26 trials in this systematic review. The trials recruited a total of 4979 participants, including 2907 Caucasian, 562 African, 59 Hispanic and 15 Asian people. Sixteen trials did not report on race data. The sample size ranged from 18 to 1636 people. Most trials compared small sample sizes; only six trials included more than 200 participants.
The included trials made three types of comparisons:
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comparisons of a topical antiglaucomatous drug to placebo or no treatment;
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comparisons of different topical antiglaucomatous drugs;
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comparisons with unspecified topical antiglaucomatous drugs with no treatment.
Some trials had more than two arms and made more than one comparison. Twenty‐four trials were parallel arm studies, while two trials compared one treated eye to the untreated or placebo treated fellow eye (Kass 1989; Wishart 1992). See 'Characteristics of included studies'.
Sample characteristics
Inclusion and/or exclusion criteria were not uniform and not always well defined. Nine trials included only people with POAG (Collignon‐Brach 1992; Drance 1998; Fama 1996; Flammer 1992; Kaiser 1994; Sponsel 1987; Tsai 2005; Vogel 1992; Watson 2001). Eleven trials restricted entry to participants with OHT (Epstein 1989; Heijl 2000; Kamal 2003; Kass 1989; Kass 2002; Kitazawa 1990; EGPS 2005; Ravalico 1994; Schulzer 1991; Schwartz 1995; Wishart 1992). Six trials accepted both POAG and OHT participants (Alexander 1988; Collignon‐Brach 1994; Geyer 1988; Leblanc 1998; Novack 1989; Schuman 1997).
Most trials either evaluated data from one eye per patient or considered the patient as basis of evaluation. Two trials made an intra‐individual comparison of both eyes (Kass 1989; Wishart 1992).
Interventions
Eleven trials (16 papers) made comparisons to placebo (six trials) or an untreated control group (five trials). Fourteen trials made comparisons between two or three drugs, and one trial compared free topical antiglaucomatous therapy versus an untreated control group.
The following comparisons were made:
(1) comparisons versus placebo or untreated controls.
(a) beta‐blockers versus placebo or untreated controls:
(i) timolol versus placebo (Heijl 2000; Kass 1989; Kitazawa 1990; Schwartz 1995) or untreated controls (Epstein 1989; Schulzer 1991; Wishart 1992);
(ii) levobunolol versus untreated controls (Ravalico 1994);
(iii) betaxolol versus placebo (Kamal 2003);
(iv) all beta‐blockers versus placebo or untreated controls;
(b) dorzolamide versus placebo (EGPS 2005):
(c) unspecified topical treatment versus untreated control (Kass 2002).
(2) comparisons of different topical treatments.
(a) comparison of one beta‐blocker versus another:
(i) timolol versus carteolol (Fama 1996; Flammer 1992; Watson 2001);
(ii) timolol versus levobunolol (Geyer 1988; Novack 1989);
(iii) timolol versus betaxolol (Collignon‐Brach 1992; Collignon‐Brach 1994; Drance 1998; Fama 1996; Kaiser 1994; Watson 2001);
(iv) carteolol versus betaxolol (Fama 1996; Watson 2001);
(b) comparison of one beta‐blocker versus other topical medication:
(i) timolol versus brimonidine (Leblanc 1998; Schuman 1997; Tsai 2005);
(ii) timolol versus pilocarpine (Drance 1998; Sponsel 1987; Vogel 1992);
(iii) timolol versus epinephrine (Alexander 1988);
(iv) betaxolol versus pilocarpine (Drance 1998).
Two studies also compared different doses of levobunolol (Geyer 1988; Novack 1989). Since it was not the goal of this review to compare different dosages of the same drug, we did not further analyse this comparison.
Outcome measures
The lack of similarity in outcome measures limited the possibility for combining data from individual trials.
(1) The primary outcome of interest in this systematic review was the reduction of onset or progression of visual field loss. There was, however, limited agreement between the trials in the presentation of visual field data. Seven trials reported on the incidences of visual field deterioration (Alexander 1988; EGPS 2005; Epstein 1989; Flammer 1992; Geyer 1988; Heijl 2000; Kamal 2003; Kass 1989; Kass 2002; Kitazawa 1990; Leblanc 1998; Novack 1989; Schwartz 1995; Schulzer 1991; Schuman 1997; Watson 2001; Wishart 1992). Nine trials reported on changes in mean sensitivity or in mean defect of visual fields. Most of the latter did not present any measure of variation for this change (Fama 1996; Kaiser 1994; Ravalico 1994; Vogel 1992; Watson 2001), while only four mentioned the standard error of change (Collignon‐Brach 1992; Collignon‐Brach 1994; Drance 1998; Sponsel 1987).
(2) Improvement of visual field: No study was focused on measuring improvement and only two trials reported cases with visual field improvement (Flammer 1992; Leblanc 1998).
(3) Reduction of nerve fibre layer loss progression (according to objective measurement): Two trials reported changes in retinal nerve fibre loss progression according to photogrammetric measurement (Schwartz 1995) or scanning laser polarimetry (Tsai 2005).
(4) Reduction of optic nerve head cupping progression (according to objective assessment): One trial reported changes in optic nerve head progression according to photogrammetric measurement (Schwartz 1995).
(5) Local and systemic side effects leading to the cessation of treatment: Not all trials presented detailed data about the reasons for drop‐outs. Some papers did not report on drop‐outs (Collignon‐Brach 1992; Wishart 1992), and some authors did not separately report numbers of patients exiting the studies due to local and systemic adverse events in the different treatment groups (Drance 1998; EGPS 2005; Geyer 1988; Heijl 2000; Kass 2002; Leblanc 1998; Ravalico 1994; Schulzer 1991; Sponsel 1987; Vogel 1992).
Risk of bias in included studies
Most studies did not describe the method of allocation concealment in detail. A double‐masked design should adequately conceal the group allocation, although this cannot be guaranteed. For the purpose of this review, we coded the five trials that stated a double‐masked design as having adequate allocation concealment (Geyer 1988; Kaiser 1994; Kitazawa 1990; Leblanc 1998; Novack 1989). In 10 trials, allocation concealment was unclear (Collignon‐Brach 1992; Collignon‐Brach 1994; Drance 1998; Fama 1996; Ravalico 1994; Schulzer 1991; Sponsel 1987; Tsai 2005; Vogel 1992; Wishart 1992).
Additional Table 1 summarises the quality aspects of the trials. Of the studies with low methodological quality, 14 had scored C in at least one category of quality assessment, and two assumed two eyes of participants to be independent. There was no relationship between low methodological quality and earlier date of publication in logistic regression analysis.
| Criteria | Number of trials |
| Allocation concealment adequate | 16 / 26 |
| Baseline comparability stated | 19 / 26 |
| Analysis: intention‐to‐treat | 9 / 26 |
| Withdrawals adequately reported | 17 / 26 |
| Drop‐out rate below 10% | 1 / 26 |
| Low methodological quality | 16 / 26 |
Effects of interventions
1. Comparisons versus placebo or untreated controls
(a) Beta‐blocker versus placebo or untreated controls
(i) Timolol versus placebo or untreated controls
We retrieved four trials comparing timolol to placebo (Heijl 2000; Kass 1989; Kitazawa 1990; Schwartz 1995) and three trials that included an untreated control group (Epstein 1989; Schulzer 1991; Wishart 1992). All of these trials included only patients with OHT, and two of them compared one treated eye to the untreated fellow eye (Kass 1989; Wishart 1992). Five trials were long‐term studies (Epstein 1989; Heijl 2000; Kass 1989; Schulzer 1991; Wishart 1992), including 430 participants with a median follow‐up time of 63 months.
* Primary outcome measure (Analysis 1.1;Analysis 1.3)
All seven trials report data on the incidence of glaucomatous visual field defects. Meta‐analysis failed to achieve clear statistical evidence for visual field protection by timolol (OR 0.66, 95% CI 0.41 to 1.05). In a sensitivity analysis there was still no significant difference (OR 0.54, 95% CI 0.19 to 1.54).
* Secondary outcome measures (Analysis 1.2)
Schwartz 1995 analysed the morphological change of the optic nerve head and the retinal nerve fibre layer (RNFL), using a quantifying method based on fundus photographs (Takamoto 1985). In an analysis with multiple comparisons, a significant difference between groups was detected for change over time for several optic disc parameters. Considering the borderline statistical significance for most of the parameters, it remains unclear whether the significances are in part the result of multiple testing without correcting for this. However, for nearly all the significantly changed parameters, the timolol group showed an improvement, whereas the placebo group on average deteriorated. Similarly the authors observed a significant protection of the RNFL by two years of timolol treatment. On average, for both eyes there was a RNFL decrease of 0.22 μm in the placebo and an increase of 0.23 μm in the timolol group.
Regarding local and systemic side effects leading to the cessation of treatment, only the placebo controlled studies with interindividual comparison were included in the meta‐analysis (Heijl 2000; Kitazawa 1990; Schwartz 1995). One of these studies (Heijl 2000) did not specify the side‐effect‐related drop‐outs in local and systemic adverse events. Due to the small numbers, we did not perform separate analyses regarding the local and systemic side effects. There was no statistically significant difference between groups (OR 2.48, 95% CI 0.61 to 10.10).
(ii) Levobunolol versus untreated controls
Only one study compared levobunolol to an untreated control group (Ravalico 1994) in OHT patients.
* Primary outcome measure
The visual field results were presented as mean deviation. At 18 months of treatment, the mean deviations of the levobunolol and the no treatment groups improved by 1.71 dB and 1.69 dB. The difference between groups was not statistically significant.
* Secondary outcome measures
The authors did not detail the reasons for drop‐out of patients.
(iii) Betaxolol versus placebo
We included only one placebo‐controlled trial (Kamal 2003) studying OHT patients. Follow‐up time was 60 months.
* Primary outcome measure (Analysis 1.1)
Incidence of visual field loss was noted in 12/182 (7.8%) in the betaxolol group, and in 16/174 (9.2%) in the placebo group. This difference was not statistically significant (RR 0.70, 95% CI 0.32 to 1.51).
* Secondary outcome measures (Analysis 1.2)
Drop‐outs occurred at a very similar rate in the betaxolol and the placebo groups (OR 0.95, 95% CI 0.40 to 2.26). In the betaxolol group, eight patients had to stop treatment as a consequence of local, and three patients due to systemic adverse effects. For the placebo group, these figures were seven (local) and four (systemic).
(iv) All beta‐blockers versus placebo or untreated controls
We analysed the seven trials (Epstein 1989; Heijl 2000; Kass 1989; Kitazawa 1990; Schulzer 1991; Schwartz 1995; Wishart 1992) comparing timolol to placebo or untreated control with Kamal 2003, which compared betaxolol to placebo.
* Primary outcome measure (Analysis 1.1; Analysis 1.3; Analysis 1.4)
Incidence of visual field loss was registered in 45/469 (9.6%) in the beta‐blocker group, and in 64/466 (13.7%) in the placebo/untreated group. There was some borderline evidence for a positive influence of treatment on visual field prognosis (OR 0.67, 95% CI 0.45 to 1.00). In a sensitivity analysis (excluding trials scoring C or assuming both eyes are independent) which included Heijl 2000, Kitazawa 1990 and Schwartz 1995, this difference was no longer statistically significant (OR 0.64, 95% CI 0.34 to 1.19).
We performed a separate analysis which included only the long‐term studies, with a follow‐up of at least three years (Epstein 1989; Heijl 2000; Kamal 2003; Kass 1989; Schulzer 1991; Wishart 1992). This analysis failed statistical significance but again demonstrated the same trend as above (OR 0.67, 95% CI 0.45 to 1.01).
* Secondary outcome measures (Analysis 1.2)
Drop‐outs due to drug‐related side effects occurred with similar frequency in beta‐blocker treated and in placebo treated groups (OR 1.24, 95% CI 0.59 to 2.58).
(b) Dorzolamide versus placebo
EGPS 2005 reported on this comparison. Mean follow up was 55.3 months.
* Primary outcome measure (Analysis 6.1)
In participants with OHT, 26/536, 4.9% dorzolamide treated and 38/541, 7.0% placebo treated developed reproducible visual field defects. Despite this trend, the difference was not statistically significant (OR 0.68, 95% CI 0.41 to 1.12). The study also failed to demonstrate a significant difference between groups when its primary endpoint (visual field defect or glaucomatous change of optic disc) was analysed (OR 0.86, 95% CI 0.58 to 1.26).
* Secondary outcome measures (Analysis 6.2)
During the 55 months of follow‐up, 116/536 dorzolamide and 51/541 placebo treated patients had to discontinue therapy because of side effects. The nature of these side effects was not reported. Significantly more patients under dorzolamide had to discontinue due to side effects compared to placebo (OR 2.54, 95% CI 1.83 to 3.53).
(c) Unspecified topical medication versus untreated control
The OHTS evaluated the effect of any topical medical therapy on the prevention of onset of visual field defects in OHT (Kass 2002). For meta‐analysis we included all trials comparing any topical IOP lowering medication to placebo or untreated controls (EGPS 2005; Epstein 1989; Heijl 2000; Kamal 2003; Kass 1989; Kitazawa 1990; Schulzer 1991; Schwartz 1995; Wishart 1992). With the exception of two trials (Kitazawa 1990; Schwartz 1995), all other trials were long‐term studies including 3503 participants with a follow up of 63 months.
* Primary outcome measure (Analysis 6.1; Analysis 6.2; Analysis 6.3)
The OHTS (Kass 2002) found a significant reduction in the incidence of visual field defects in treated participants compared to the untreated control group (18/817, 2.2% versus 38/819, 4.6%; OR 0.48, 95% CI 0.28 to 0.82).
Meta‐analysis of all available trials comparing any topical medical treatment to placebo or untreated controls similarly provided clear evidence of a positive treatment effect on visual field protection (OR 0.62, 95% CI 0.47 to 0.81). Sensitivity analysis (Analysis 6.2) ‐ excluding all trials scoring C on any aspect of trial quality and trials using the fellow eye as control ‐ did not change this significant protective effect of IOP lowering treatment (OR 0.58, 95% CI 0.42 to 0.81). Additional sensitivity analysis (Analysis 6.3), including only studies with an inclusion criterion of 22 mmHg (as opposed to the 24 mmHg of the OHTS) was still significant (OR 0.66, 95% CI 0.44 to 0.98).
* Secondary outcome measures
A comparison of drop‐outs due to unspecified topical therapy to those under placebo does not provide useful information and was thus not performed.
2. Comparisons of different topical treatments
(a) Comparison of one beta‐blocker versus another
(i) Timolol versus carteolol
We identified three trials comparing timolol to carteolol that had patients with POAG (Fama 1996; Flammer 1992; Watson 2001).
* Primary outcome measure (Analysis 2.1)
Two trials reported data on the progression of glaucomatous visual field defects in POAG (Flammer 1992; Watson 2001). For Flammer 1992, we extracted incidences of progression or improvement from Analysis 2.1, arbitrarily counting a slope of mean defect of plus or minus 0.3 dB or more as progression or improvement. There were fewer POAG patients with progressing visual field defects amongst those using timolol compared to carteolol treated patients (1/88, 3.4% timolol group, 9/83, 9.6% carteolol group, OR 0.18, 95% CI 0.05 to 0.62). It has to be emphasised that statistically significant heterogeneity was observed in this comparison. While the open label three‐year study of Watson 2001 described a striking difference between groups (12.5% progression with carteolol and no progression with timolol), Flammer 1992 reported in his one‐year study a much lower and more similar rate of visual field progression in both groups (1/37, 2.7% timolol group, 3/35, 8.1% carteolol group). Additionally, in the latter study, a similar proportion of patients showed improvement of visual field indices (3/37 timolol group and 2/35 carteolol group). It should be noted that this study excluded 22% of the patients after completion of the study as a result of some protocol violation or unreliable visual field exams. Together with the drop‐outs, this added to an attrition of 40%.
Two papers provided data concerning the change of visual field mean sensitivity, and data could be extracted from a figure of the third paper (Analysis 2.1) (Flammer 1992). None of the papers presented variances, which prevented a meta‐analysis. Combining the weighted means of the three studies resulted in no change of mean sensitivity for the timolol group (+0.10 dB) and an improvement of 1.44 dB for the carteolol group. This difference between groups disappeared after exclusion of the open‐label study of Watson 2001 (+0.05 dB versus +0.03 dB).
* Secondary outcome measures
Only Flammer 1992 reported in detail the causes of drop‐outs. In the timolol group, seven patients had to stop treatment as a consequence of local and three patients due to systemic adverse effects, whereas in the carteolol group six patients had to discontinue due to systemic side effects.
(ii) Timolol versus levobunolol
We included two trials (Geyer 1988; Novack 1989), both with a follow‐up time of four years. We included only the commercially available dose of 0.5% levobunolol in the analysis.
* Primary outcome measure (Analysis 3.1)
Study sizes and incidence rates of progression were very inhomogeneous. The small study of Geyer 1988 included 50 POAG and one OHT patient, whereas the larger study of Novack 1989 (391 participants) comprised 60% OHT patients. This may in part explain why the study of Geyer 1988 reports visual field progression in 59% and 35% of the timolol and the levobunolol groups, whereas Novack 1989 detected only 18% and 9%. However, the difference between groups was similar in both studies. In a meta‐analysis there were significantly more patients with new or progressing visual field defects amongst those using timolol compared to levobunolol treated patients (32/141, 22.7% timolol group, 18/149, 12.1% levobunolol 0.5% group, OR 2.20, 95% CI 1.17 to 4.14).
* Secondary outcome measures (Analysis 3.2)
There was no significant difference between treatments in the incidence of side effects leading to cessation of therapy (OR 0.80, 95% CI 0.34 to 1.87). Detailed information for drop‐outs was given only by Novack 1989. In the levobunolol group, six patients had to stop treatment as a consequence of local and four patients due to systemic adverse effects, whereas in the timolol group three patients discontinued due to local and seven patients due to systemic side effects.
(iii) Timolol versus betaxolol
Six trials were included comparing timolol and betaxolol (Collignon‐Brach 1992; Collignon‐Brach 1994; Drance 1998; Fama 1996; Kaiser 1994; Watson 2001). All trials had small samples (19 to 105 participants). Primarily OHT patients were included in Collignon‐Brach 1994, whereas the other trials comprised POAG patients only. Three trials were long‐term studies (Collignon‐Brach 1994; Kaiser 1994; Watson 2001) including 216 people with a median follow‐up time of 39 months.
* Primary outcome measure (Analysis 4.1)
Watson 2001provided data on incidences of visual field progression. In this study 5/54, 9.3% betaxolol and 0/51 timolol patients developed visual field progression.
All six trials reported data on the change of visual field mean sensitivity or mean defect (Analysis 4.1). The results of the six equivalent studies show highly variable effects, the mean differences of pre‐post changes of the primary outcome variable between the two treatments being 0.07 dB favouring timolol (CI ‐0.43 to +0.57).
A crude average of these effects (not accounting for the different sample sizes between studies) is 0.2 dB, with a standard deviation of 1.23. The standard deviations of the pre‐post differences are not available for three of the studies (Fama 1996; Kaiser 1994; Watson 2001). However, it is obvious that there are large differences in the standard deviations. In such a situation a meta‐analysis of the equivalent trials is considered not to be useful, particularly because the previous meta‐analysis of studies comparing beta‐blocker treatments with a control does not provide clear evidence for a positive treatment effect.
Combining the weighed mean differences of all six studies resulted in an improvement mean sensitivity for both groups (betaxolol group +1.43 dB, timolol group +1.11 dB). The lack of variances hindered statistically comparing the two treatments. Only three of the trials (Collignon‐Brach 1992; Collignon‐Brach 1994; Drance 1998) provided the standard error of the change. When including only these trials, mean change over time was slightly negative in both groups (betaxolol group ‐0.68 dB, timolol group ‐0.78 dB). This difference between groups was statistically not significant (WMD 0.07, 95% CI ‐0.43 to 0.57). The treatment effects showed statistically significant heterogeneity between studies.
In a sensitivity analysis, only two trials might have been included (Fama 1996; Kaiser 1994). Both did not report variances or standard errors of mean change, which prevented a meta‐analysis. The mean improvement of visual field sensitivity was 0.59 dB in the betaxolol group and 1.55 dB in the timolol group.
* Secondary outcome measures (Analysis 4.2)
Collignon‐Brach 1992 did not report drop‐outs. The other five trials reported a total number of drop‐outs of 17/117 patients in the timolol group (eight local, four systemic and five unspecified side effects) and 8/121 patients in the betaxolol group (one local, five systemic and two unspecified side effects). The OR for side‐effect related drop‐out was 2.4 in favour of betaxolol (95% CI 1.04 to 5.53). In the sensitivity analysis, only two trials were includable (Fama 1996; Kaiser 1994) but only one (Fama 1996) reported a complete follow‐up of all 24 patients. Meta‐analysis was not performed on the one remaining trial.
(iv) Carteolol versus betaxolol
This comparison was made by two trials (Fama 1996; Watson 2001).
* Primary outcome measure
Watson 2001 reported that 6/48, 12.5% carteolol and 5/54, 9.3% betaxolol patients developed a visual field progression over three years. Patients under carteolol (+1.6 dB) or betaxolol (+1.2 dB) therapy displayed a similar change in visual field mean sensitivity over one year (Fama 1996). Meta‐analysis could not be performed due to the small number of studies and different outcome reporting.
* Secondary outcome measures
In both trials, drop‐out rates due to systemic side effects were similar (no local side effect, 6/60, 10% carteolol patients and 5/66, 7.6% betaxolol patients). A statistical analysis was not possible due to the small number of trials and their heterogeneity.
(b) Comparison of one beta‐blocker versus other topical medication
(i) Timolol versus brimonidine
We identified and included three trials. Leblanc 1998 and Schuman 1997 reported visual field progression and included slightly more than 50% POAG patients, the rest being OHT. Tsai 2005 included only POAG patients. This latter study did not include visual field endpoint data, but reported only on change in RNFL according to scanning laser polarimetry with fixed corneal compensation.
* Primary outcome measure (Analysis 5.1)
The incidences of new visual field defects (OHT) or visual field progression (POAG) within one year (Leblanc 1998; Schuman 1997) were similar between groups (29/302, 9.6% timolol group, 22/369, 6.0% brimonidine group, OR 1.11, 95% CI 0.60 to 2.04). For Leblanc 1998, data of a three‐year extension have been published. This study comprised only 46 and 48 patients in the timolol and brimonidine groups. Compared to baseline, two patients in each group displayed a worsening of visual field, while one versus two patients appeared to improve in visual field.
Tsai 2005 included 44 patients, 39 completing the one‐year follow up. No visual field data were reported. The authors reported a significant reduction of RNFL thickness (ellipse average, superior average, temporal average, inferior average and nasal average) in the timolol group, but no change was detected in the brimonidine group. In group comparison the timolol group displayed significantly more reduction in RNFL thickness regarding the ellipse average, temporal average and inferior average.
* Secondary outcome measures (Analysis 5.2)
Meta‐analysis of drop‐outs due to drug‐related adverse events showed clear evidence of better tolerance of timolol compared to brimonidine (OR 0.21, 95% CI 0.14 to 0.31).
(ii) Timolol versus pilocarpine
We included three trials comparing timolol versus pilocarpine (Drance 1998; Sponsel 1987; Vogel 1992). All were short‐term studies with a weighted mean follow up of 32 months.
* Primary outcome measure
The change in mean sensitivity of visual field was ‐0.01 dB for the timolol group and ‐1.07 dB for the pilocarpine group (Drance 1998; Vogel 1992). Both studies were lacking the standard deviation. Sponsel 1987 analysed the progression rate of visual field score based on both Goldmann kinetic and Friedmann static suprathreshold perimetry. Patients receiving timolol lost visual field at a mean rate of 0.46 units per month (SE 0.05) and those receiving pilocarpine lost 0.92 units per month (SE 0.11). All three trials were open label and additionally it was difficult to rule out an effect of miosis on the visual field performance. A meta‐analysis was not possible for this comparison.
* Secondary outcome measures
Only Drance 1998 presented the rate of participants being withdrawn due to drug‐related side effects (five timolol group, all due to unspecified side effects; six pilocarpine group, three due to local and three due to unspecified side effects).
(iii) Timolol versus epinephrine
* Primary outcome measure
In Alexander 1988, 0/24 timolol and 1/23 epinephrine treated OHT patients developed a visual field defect over 33 months.
* Secondary outcome measures
Five patients on timolol and six patients on epinephrine were withdrawn due to adverse events. The authors did not specify the types of adverse events.
(iv) Betaxolol versus pilocarpine
Data for this comparison were provided from one open label trial (Drance 1998).
* Primary outcome measure
The mean change of mean sensitivity of visual fields amounted to 0.98 dB in betaxolol and 0.83 dB in pilocarpine treated patients.
* Secondary outcome measures
One patient on betaxolol and six patients on epinephrine were withdrawn due to adverse events. For three of these patients on pilocarpine, the reason for withdrawal was local adverse events; for all other patients the reasons were not specified.
See: Table 2 for additional information.
| Comparison | POAG | OHT | POAG & OHT | Drop‐out due to AE |
| Beta‐blockers vs. placebo or untreated | 0.67 (0.45 to 1.00; n=935) | 1.24 (0.59 to 2.58; n=503) | ||
| Longterm trials | 0.67 (0.45 to 1.01; n=882) | |||
| Sensitivity analysis | 0.64 (0.34 to 1.19; n=499) | |||
| Timolol vs. placebo or untreated | 0.66 (0.41 to 1.05; n=579) | 2.48 (0.61 to 10.10; n=147) | ||
| Timolo vs. carteolol | 0.18 (0.05 to 0.62; n=171) + | |||
| Timolol vs. levobunolol | 2.20 (1.17 to 4.14; n=290) # | 0.80 (0.34 to 1.87; n=290) | ||
| Timolol vs. betaxolol | 0.07dB (‐0.43dB to 0.57dB; n=158) $ | 2.40 (1.04 to 5.53; n=238) § | ||
| Timolol vs. brimonidine | 1.11 (0.60 to 2.04; n=671) | 0.21 (0.14 to 0.31; n=957) ++ | ||
| All treatment vs. placebo or untreated | 0.62 (0.47 to 0.81; n=3648) | |||
| Sensitivity analysis | 0.58 (0.42 to 0.81; n=3212) | |||
| Sensitivity analysis without OHTS | 0.66 (0.44 to 0.98; n=1576) | |||
| + favours timolol; # favours levobunolol; | $ 14 participants with OHT included | § favours betaxolol | ++ favours timolol |
Discussion
The large therapeutic trials published during the past few years have helped with establishing evidence of the principle for the visual field protection in OHT and POAG by lowering IOP (EMGT 1999; Kass 2002). This represents an advance in knowledge since 1993, when Rossetti had concluded that IOP reduction had not been proven to prevent development of glaucoma (Rossetti 1993). The newer studies, however, did not support any deduction as to which (or whether possibly all) of the drugs ‐ or possibly laser treatment ‐ can be attributed to this beneficial effect. Due to its study design, the EMGT 1999 even left the question open, whether betaxolol or laser trabeculoplasty or both were responsible for the protective effect, while the OHTS (Kass 2002) did not allow any conclusion for a specific drug or class of drugs.
The fact that over 95% of all therapeutic trials dealing with glaucoma use the surrogate endpoint IOP instead of visual field progression reflects two assumptions: 1) the necessary study duration and cost of an IOP‐related trial are very much lower compared to a trial targeting progression; and 2) reduction of IOP as the main risk factor for glaucoma will uniformly reduce the risk, regardless of the specific drug used. While the first assumption is evidently correct, the second assumption should be subjected to scientific investigation. In other fields of medicine, a treatment mainly based on a surrogate parameter probably would not be widely accepted. With treatment of systemic arterial hypertension, for example, the primary outcomes of relevant trials are mortality and morbidity. A recent Cochrane review of arterial hypertension (Wiysonge 2006) has clearly demonstrated that different classes of blood pressure lowering drugs have different protective effects regarding overall mortality, as well as stroke and coronary heart disease morbidity. In this meta‐analysis, beta‐blockers had no effect on overall mortality compared to placebo, but a significant positive effect on stroke morbidity. On the other hand, calcium‐channel blockers (CCB) significantly reduced total mortality and also had a significantly stronger effect reducing cardiovascular morbidity compared to beta‐blockers, when used as treatment for arterial hypertension.
Regarding glaucoma, the basic assumption that IOP lowering of any kind will result in a similar protection of the optic nerve has never been proven. Theoretically there might be a difference in optic nerve head protection or other ocular or systemic morbidity between different classes of drugs, despite similar reduction of IOP. Our systematic review addresses three main questions: firstly, whether there is scientific evidence of visual field protection by unspecified topical medical therapy in OHT (this is in fact already known) and POAG; secondly, whether there is such evidence for any of the currently used topical IOP lowering drugs or classes of drugs; and thirdly, whether different drugs or classes of drugs differ in their beneficial effect.
The meta‐analysis of all trials testing against placebo or untreated controls ‐ irrespective of the substances used ‐ confirmed the finding of the OHTS that IOP lowering reduces the incidence of glaucomatous visual field defects in OHT. The OR was 0.62 with a 95% CI of 0.47 to 0.81, being highly significant. This result, however, is of limited practical value, due to pooling of different therapies. Of the treated participants of this meta‐analysis, 26% had received beta‐blockers (16% timolol), 29% dorzolamide and 55% unspecified therapy (including all commercially available drugs). All trials comparing medical therapy with an untreated or placebo treated control group exclusively included OHT participants. Our results also confirmed those of a recent meta‐analysis (Maier 2005), that reported a hazard ratio of 0.56 (95% CI 0.39 to 0.81) for unspecified medical therapy in OHT participants. One result of that meta‐analysis was that this effect lost significance after excluding the OHTS (Kass 2002). As a consequence of this, the authors stated that the overall beneficial effect could only be safely assumed in patients with an IOP of 24 mmHg or more, which was an inclusion criterion of the OHTS. Our meta‐analysis provides some additional evidence in remaining significant, even after exclusion of the OHTS (OR 0.66, 95% CI 0.44 to 0.98). We may thus now safely assume a protective effect in patients with an IOP of 22 mmHg or more instead of 24 mmHg or more.
There are some differences between this review and the meta‐analysis by Maier 2005. Unlike Maier 2005, we included comparative trials and had the goal of not only evaluating whether IOP lowering effectively protects from progression, but also to look for evidence that currently available drugs might be different in this respect. On the other hand, we concentrated our efforts on POAG with a baseline IOP above 21 mmHg and on topical medical therapy. There is another difference in the endpoints that have been evaluated. While Maier 2005 compared the effectiveness in prevention of visual field loss or deterioration of optic disc, we evaluated visual field loss but not change of the appearance of the optic disc. The basis of this decision has been that only loss of visual field is directly relevant to the patient, while morphologic change of the optic disc has to be deemed a (well‐accepted) surrogate parameter. We were interested in the visual field protective effect of IOP lowering treatment, which to our knowledge has never been evaluated in a meta‐analysis before. On the other hand, we included the reduction of nerve fibre loss or progressive damage to the optic disc according to objective measurement as additional outcome parameters for separate analyses. The reason for this decision was that these quantitative parameters theoretically allow for valid statistical conclusions in a shorter time with fewer participants. When designing this review, we had hoped that these advantages might have stimulated smaller placebo or active controlled trials.
For the first time, this systematic review provides at least weak evidence of visual field protection for one class of substances. At borderline significance, the class of beta‐blockers reduced the onset of glaucoma in OHT, when compared to placebo or untreated controls (OR 0.67, 95% CI 0.45 to 1.00). This evidence is based on patients on timolol (61%) or betaxolol. It should, however, be noted that in a sensitivity analysis (after exclusion of studies with questionable trial quality) the effect of beta‐blockers lost statistical significance (OR 0.64, 95% CI 0.34 to 1.19). Furthermore, we want to emphasize that the fact that this is the only class of drugs for which this evidence is available does not mean that they are more effective than the others.
We were unable to provide evidence for any single antiglaucomatous drug to prevent the onset of glaucoma in OHT. Timolol, the most frequently tested drug in this review, was lacking a significant effect (OR 0.66, 95% CI 0.41 to 1.05) although the trend was very similar to that of the whole class of beta‐blockers. While dorzolamide and betaxolol clearly failed to demonstrate evidence of a protective effect, both drugs exhibited a very similar trend. No trial comparing any of the other drugs to placebo or untreated controls could be identified. Regarding the trial investigating the effect of dorzolamide (EGPS 2005), there has been extensive discussions about possible reasons for the failure of this trial, which had shown an unusually pronounced placebo effect (Quigley 2005). This failure might have been caused in part by the commitment to dorzolamide therapy regardless of IOP lowering effect, a major regression to the mean, and selective loss to follow up of persons with higher IOP. The counter arguments in this discussion, however, should not be ignored, namely that regression to the mean would have exerted a similar IOP lowering effect on both study arms and the fact that the EGPS data show a trend of 10% risk reduction per 1 mmHg IOP lowering which is in line with other published data. It has to be emphasised that these failures to prove effectiveness should not be interpreted as proof of absence of any effect, but may as well have been a consequence of biologic variability, together with lacking power of the included trials to detect small differences.
It is noteworthy that this evidence completely arises from studies investigating OHT patients. None of the studies continued to follow the patients under their original treatment once the first visual field defects had occurred. At present there is no evidence that topical medical IOP lowering therapy reduces progression of POAG after the onset of the first visual field defects. While it may be assumed that a drug being able to avoid or postpone the onset of a disease would offer advantages for the treatment following that onset, this might not necessarily be true. The clinical impression that treatment might be more effective in the early stages has often been expressed. This is supported by some trials not the subject of this review, which indicate that IOP lowering therapy reduces progression of visual fields and optic disc appearance in patients with established POAG and NTG (CNTGS 1998; EMGT 1999).
Some drugs of other classes have been compared to timolol, such as brimonidine, pilocarpine and epinephrine. The fact that all of these comparisons failed to prove superiority in visual field protection of any of the tested substances should, however, not be interpreted as evidence of equivalence. None of these studies had been adequately powered for testing equivalence of visual field protection. Only one study indicated superiority of brimonidine over timolol (Tsai 2005) in protection from progressive RNFL damage. While this study was well conducted, it only included 39 participants in both arms and study duration was only 12 months. Study size and duration might, however, be adequate for this type of quantitative comparison of objectively measured parameters, instead of evaluating differences in incidences. A direct comparison of brimonidine to placebo or untreated controls is missing.
A number of trials have compared the different beta‐blockers timolol, levobunolol, carteolol and betaxolol. Considering the failure for each of these drugs to clearly demonstrate evidence of a positive treatment effect, these comparisons are questionable. Nevertheless levobunolol appeared to demonstrate some evidence for better visual field protection than timolol (Geyer 1988; Novack 1989). This result should be interpreted with caution, since it is based on only two trials; one being rather small (17 participants in each treatment group), it should also be noted that a direct evaluation of the treatment effect of levobunolol compared to untreated control resulted in similar change in visual field mean deviation (Ravalico 1994). Carteolol on the other hand, when compared to timolol, resulted in a significantly worse visual field outcome. Again this was the result of only two small studies, one having an open‐label design.
In the past, other studies not included in this review have provided evidence of potential harmfulness of topically applied beta‐blockers. Elderly people undergoing treatment with beta‐blockers may experience respiratory and cardiovascular side effects (Diggory 1998). In this study five of 20 patients on timolol 0.5% had to change to betaxolol because of impaired spirometry, three of them being symptomatic. Also three of 20 patients on betaxolol had to change treatment due to symptomatic decrease in respiratory function. Similarly Waldock 2000 reported a 15% reduction in spirometric parameters in five of 33 patients treated with timolol, although only one of these patients had an increase in shortness of breath. In this latter study, seven of 34 patients on brimonidine complained about drowsiness. Compared to these figures, no patient on latanoprost reported any systemic side effect. A weakness of this study is that both the observers and the participants were unmasked, and the latter were aware of the accompanying manufacturers' leaflet outlining the potential side effects associated with their treatment. Although Diggory 1998 was randomised and double masked, this avoids only a bias in the comparison between the two treatment arms: timolol and betaxolol (which was negative). The study design, with the patients aware that the medication has a potential negative effect on breathing, may still have influenced reporting of symptoms and performance in spirometry in both groups. Another unmasked study with a laser treated control group has concluded that beta‐blocker‐ induced increase in bronchial reactivity may be partially irreversible (Gandolfi 2005).
These reports contrast the relatively few reported systemic side effects out of the placebo‐controlled trials included in this review. Only one small study comparing timolol to placebo did explicitly mention the number of systemic side effects leading to cessation of therapy (2/17 versus 1/20) (Schwartz 1995). Another larger study did not find evidence for increased systemic side effects leading to cessation of therapy for betaxolol (3/182) compared to placebo (4/174) (Kamal 2003). Due to limited data reporting of most trials, a meta‐analysis of systemic side effects was not performed.
The comparisons of drop‐outs due to adverse events have to be interpreted with caution, since the primary goal of this review has been treatment efficacy. Studies not reporting data regarding treatment efficacy or with a duration below one year have not been included. As a result of this, safety data in this review represent only a smaller part of the potentially available body of evidence. Nonetheless, within the group of beta‐blockers, the frequency of side‐effect related drop‐outs was significantly larger for timolol compared to betaxolol. This was, however, mainly caused by the increased frequency of local side effects in one of three included studies (Watson 2001), while a second study did not divide the side effects into local and systemic ones (Drance 1998). Contrary to this finding, when compared to brimonidine, patients under timolol had a significantly lower risk of adverse events, necessitating cessation of treatment. This latter comparison was highly significant, with an OR of 0.21 (95% CI 0.14 to 0.31). Only one of the three studies included in this analysis divided the side effects into local and systemic (Schuman 1997). This study reported five times more systemic side effects with brimonidine compared to timolol (10 versus two).
Comparison 1 Beta‐blockers versus placebo or untreated, Outcome 1 Incidence of visual field defect progression.
Comparison 1 Beta‐blockers versus placebo or untreated, Outcome 2 Drop‐out due to drug‐related adverse events.
Comparison 1 Beta‐blockers versus placebo or untreated, Outcome 3 Sensitivity analysis concerning the incidence of visual field defect progression.
Comparison 1 Beta‐blockers versus placebo or untreated, Outcome 4 Long‐term studies concerning the incidence of visual field progression.
Comparison 2 Comparison of timolol and carteolol, Outcome 1 Incidence of visual field defect progression.
Comparison 3 Comparison of timolol and levobunolol, Outcome 1 Incidence of visual field defect progression.
Comparison 3 Comparison of timolol and levobunolol, Outcome 2 Drop‐out due to drug‐related adverse events.
Comparison 4 Comparisons of timolol and betaxolol, Outcome 1 Change of visual field mean sensitivity.
Comparison 4 Comparisons of timolol and betaxolol, Outcome 2 Drop‐out due to drug‐related adverse events.
Comparison 5 Comparison of timolol and brimonidine, Outcome 1 Incidence of visual field defect progression.
Comparison 5 Comparison of timolol and brimonidine, Outcome 2 Drop‐out due to drug‐related adverse events.
Comparison 6 All treatments versus placebo or untreated, Outcome 1 Incidence of visual field defect progression.
Comparison 6 All treatments versus placebo or untreated, Outcome 2 Sensitivity analysis concerning the incidence of visual field progression.
Comparison 6 All treatments versus placebo or untreated, Outcome 3 Sensitivity analysis concerning the incidence of visual field progression; without OHTS study.
| Criteria | Number of trials |
| Allocation concealment adequate | 16 / 26 |
| Baseline comparability stated | 19 / 26 |
| Analysis: intention‐to‐treat | 9 / 26 |
| Withdrawals adequately reported | 17 / 26 |
| Drop‐out rate below 10% | 1 / 26 |
| Low methodological quality | 16 / 26 |
| Comparison | POAG | OHT | POAG & OHT | Drop‐out due to AE |
| Beta‐blockers vs. placebo or untreated | 0.67 (0.45 to 1.00; n=935) | 1.24 (0.59 to 2.58; n=503) | ||
| Longterm trials | 0.67 (0.45 to 1.01; n=882) | |||
| Sensitivity analysis | 0.64 (0.34 to 1.19; n=499) | |||
| Timolol vs. placebo or untreated | 0.66 (0.41 to 1.05; n=579) | 2.48 (0.61 to 10.10; n=147) | ||
| Timolo vs. carteolol | 0.18 (0.05 to 0.62; n=171) + | |||
| Timolol vs. levobunolol | 2.20 (1.17 to 4.14; n=290) # | 0.80 (0.34 to 1.87; n=290) | ||
| Timolol vs. betaxolol | 0.07dB (‐0.43dB to 0.57dB; n=158) $ | 2.40 (1.04 to 5.53; n=238) § | ||
| Timolol vs. brimonidine | 1.11 (0.60 to 2.04; n=671) | 0.21 (0.14 to 0.31; n=957) ++ | ||
| All treatment vs. placebo or untreated | 0.62 (0.47 to 0.81; n=3648) | |||
| Sensitivity analysis | 0.58 (0.42 to 0.81; n=3212) | |||
| Sensitivity analysis without OHTS | 0.66 (0.44 to 0.98; n=1576) | |||
| + favours timolol; # favours levobunolol; | $ 14 participants with OHT included | § favours betaxolol | ++ favours timolol |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incidence of visual field defect progression Show forest plot | 8 | 935 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.67 [0.45, 1.00] |
| 1.1 Timolol versus placebo or untreated | 7 | 579 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.66 [0.41, 1.05] |
| 1.2 Betaxolol versus placebo or untreated | 1 | 356 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.70 [0.32, 1.51] |
| 2 Drop‐out due to drug‐related adverse events Show forest plot | 4 | 503 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.24 [0.59, 2.58] |
| 2.1 Timolol versus placebo | 3 | 147 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.48 [0.61, 10.10] |
| 2.2 Betaxolol versus placebo | 1 | 356 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.95 [0.40, 2.26] |
| 3 Sensitivity analysis concerning the incidence of visual field defect progression Show forest plot | 4 | 499 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.64 [0.34, 1.19] |
| 3.1 Timolol versus placebo or untreated | 3 | 143 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.54 [0.19, 1.54] |
| 3.2 Betaxolol versus placebo or untreated | 1 | 356 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.70 [0.32, 1.51] |
| 4 Long‐term studies concerning the incidence of visual field progression Show forest plot | 6 | 882 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.67 [0.45, 1.01] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incidence of visual field defect progression Show forest plot | 2 | 171 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.18 [0.05, 0.62] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incidence of visual field defect progression Show forest plot | 2 | 290 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.20 [1.17, 4.14] |
| 2 Drop‐out due to drug‐related adverse events Show forest plot | 2 | 290 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.80 [0.34, 1.87] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Change of visual field mean sensitivity Show forest plot | 6 | 258 | Mean Difference (IV, Fixed, 95% CI) | 0.07 [‐0.43, 0.57] |
| 2 Drop‐out due to drug‐related adverse events Show forest plot | 5 | 238 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.40 [1.04, 5.53] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incidence of visual field defect progression Show forest plot | 2 | 671 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.11 [0.60, 2.04] |
| 2 Drop‐out due to drug‐related adverse events Show forest plot | 3 | 957 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.21 [0.14, 0.31] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incidence of visual field defect progression Show forest plot | 10 | 3648 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.62 [0.47, 0.81] |
| 2 Sensitivity analysis concerning the incidence of visual field progression Show forest plot | 6 | 3212 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.58 [0.42, 0.81] |
| 3 Sensitivity analysis concerning the incidence of visual field progression; without OHTS study Show forest plot | 5 | 1576 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.66 [0.44, 0.98] |
