Key messages
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"Prognostic factors" are characteristics of a person that can be used to predict whether a person's disease will get worse and how quickly. The worsening or deterioration in health is also known as disease progression.
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We found the following factors were important for predicting the progression of glaucoma: (1) the presence of small bleeding and poor blood flow to the retina and back of the eye, (2) abnormal cell structures, (3) having glaucoma in both eyes, and (4) receiving treatment for glaucoma.
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We were uncertain about the strength of the predictive relationship because most of the identified studies were of low quality and reached different conclusions.
What is glaucoma?
Glaucoma is a chronic disease of the optic nerve – the nerve that takes information from the back of the eye to the brain. Glaucoma is a main cause of blindness worldwide, and needs to be managed by specialist doctors. People with glaucoma do not have any symptoms at the early stage. Treatment for glaucoma is effective at stopping or slowing the worsening of the disease.
The most common type of glaucoma is called primary open-angle glaucoma. Another type of glaucoma, pseudoexfoliation glaucoma, can progress more rapidly to a severe stage of the disease. Both of these types were included in this review.
What did we want to find out?
We wanted to find out which personal characteristics are associated with worsening (progression) of glaucoma. Understanding what factors affect faster progression of glaucoma is useful to identify those at higher risk of losing sight. This helps ophthalmologists to identify those who are at risk of losing sight early and helps to guide management and decision-making on the best treatment options.
What did we do?
We looked at different types of studies to identify the factors that are linked to glaucoma progression. Since glaucoma is a chronic condition, we included studies that assessed participants for at least two years. We also required that studies enrolled adults (18 years or over) with a minimum of 200 people to capture sufficient progression events. We critically evaluated the quality of studies and statistically combined the estimates from studies following standard methods.
What did we find?
We identified 16,188 publications and retrieved the full reports of 239 studies for further assessment. After going through the full-text reports, we included 123 reports of 22 studies (6082 participants) in this review. The average age of the participants in these studies was between 50 and 78 years. We found 40 factors with estimates of association with progression of glaucoma across the included studies. Of these 40, most had inconsistent and low-certainty evidence of an association. We reported three prognostic factors with consistent, very low-to-moderate certainty evidence of a positive or negative association with progression — these included the presence of small bleeding in the back of the eye, having glaucoma in both eyes, and receiving treatment for glaucoma. Though previous studies showed that intraocular pressure, thickness of the clear front surface of the eye, age, female sex, high blood pressure, migraine, problems in the blood circulation and blood vessels and heart problems were associated with faster worsening of glaucoma, we did not find consistent evidence of such associations in our review.
What are the limitations of the evidence?
Most (86%) of the included studies were poor in quality. We found a lot of variation in the ways that prognostic factors were defined and assessed for participants, as well as how the outcomes were defined, measured, and included in the analysis. This meant we were unable to combine estimates for most characteristics and were limited to qualitatively describing most of the evidence.
Authors' conclusions
In our review, we identified several factors that were associated with faster worsening of glaucoma and some evidence that treatment helps to slow the worsening of glaucoma, although we are not confident in these findings. We did not find convincing evidence for other known factors such as high blood pressure that could be associated with worsening of the disease. We propose conducting more good-quality research studies on this topic in the future, in order to gather more and better data that will be useful to prevent blindness due to glaucoma.
How up to date are these findings?
We searched and identified published studies up to 15 August 2024.
Read the full abstract
Glaucoma is the leading cause of irreversible blindness globally, and the second leading cause of blindness in high-income countries. It is a chronic optic nerve disease that can lead to loss of vision, although it is usually asymptomatic until it progresses (worsens) to an advanced stage. Primary open angle glaucoma (POAG) is the most common type of glaucoma, and it is recognized as a multifactorial disorder. Pseudoexfoliative glaucoma (PXFG) is a common form of secondary open-angle glaucoma and has a higher rate of progression. The understanding of prognostic factors is useful for clinicians to estimate the risk of disease progression and to identify those who are at risk of losing sight early.
Objectives
To identify risk factors associated with disease progression, defined as worsening or deterioration of functional visual outcomes and/or structural outcomes, amongst adults with POAG and PXFG.
Search strategy
We searched CENTRAL, Ovid MEDLINE, Ovid Embase, and two trial registries on 15 August 2024. The search was supplemented by checking reference lists of eligible articles. We did not apply any restrictions on language or year of publication.
Selection criteria
We included randomized controlled trials, cohort, and case-control study designs. We excluded any study with less than two years of follow-up and a sample size of < 200. The targeted population consisted of adults ≥ 18 years of age of any sex with glaucoma type restricted to POAG, normal-tension glaucoma (NTG), and PXFG and no previous glaucoma surgery. Two review authors independently screened titles and abstracts, and full-text articles, to determine eligibility. The discrepancies were resolved through discussion with a third reviewer. The time points for the evaluation of outcomes were at a minimum of two years of follow-up.
Data collection and analysis
Two review authors independently extracted data from included studies using pre-piloted data extraction forms in Covidence, SRDR+ and Microsoft Excel. We used the Quality in Prognosis Studies (QUIPS) tool to assess the risk of bias in Covidence. We conducted meta-analyses where homogeneous outcomes were reported, using a random-effects, generic inverse variance model. We reported hazard ratios (HR), odds ratio (OR), and risk ratios (RR) separately for each available prognostic factor and outcome, stratified by different time points and multivariable or univariable prognostic estimates, where possible. We evaluated and reported the certainty of evidence using the GRADE guidelines.
Main results
We screened 16,188 titles and abstracts and retrieved 487 full-text reports from 239 studies for assessment. After full-text screening, we included 123 reports of 22 studies in this review. The 22 studies included 6082 participants. The mean ages of participants ranged from 50 to 78 years across studies. Sixteen of the included studies used visual field (VF) deterioration alone to detect and measure glaucoma progression. In six studies, disease progression was assessed by both functional and structural outcomes (e.g. retinal nerve fiber layer thickness changes by spectral-domain optical coherence tomography). We judged 19 of the 22 (86%) included studies to be at a high risk of bias overall.
We found some prognostic factors had consistent evidence of a relationship with progression. Specifically, presence of disc hemorrhage (adjusted HR 2.03, 95% CI 1.55 to 2.67, 1068 participants, 3 studies; unadjusted HR 1.51, 95% CI 1.12 to 2.02, 961 participants, 3 studies; low certainty), presence of bilateral disease (adjusted HR 1.77, 95% CI 1.35 to 2.32, 771 participants, 2 studies; moderate certainty), and treatment for glaucoma (adjusted HR 0.44, 95% CI 0.31 to 0.61, 961 participants, 3 studies; unadjusted HR 0.56, 95% CI 0.44 to 0.72, 771, 2 studies; low certainty).
The remaining factors had mixed evidence as to their prognostic associations with glaucoma progression, including a few factors that were expected to be important based on other literature. With regard to intraocular pressure (IOP) at baseline, our meta-analysis of the HR had sufficient evidence for an effect (adjusted HR 1.08, 95% CI 1.03 to 1.13, 913 participants, 3 studies, low certainty) while the OR did not (adjusted OR 0.96, 95% CI 0.84 to 1.10, 458 participants, 2 studies, low certainty) and more than half the studies reporting IOP found no evidence of an effect. Similarly, the pooled adjusted HR per 1-year increase in age at baseline was 1.01 (95% CI 0.97 to 1.05; 865 participants, 4 studies) with very low certainty of evidence, and studies had mixed results for its association with progression. Regarding sex, the combined adjusted analyses of two studies suggest females may have a 64% greater hazard of progression than males (HR 1.64, 95% CI 1.15 to 2.34; 961, 3 studies; low certainty). However, other study estimates for sexes that could not be combined were mixed in their directions of effect.
We did not find consistent evidence to suggest that central corneal thickness (adjusted HR 1.13, 95% CI 0.85 to 1.51, 425 participants, 2 studies; unadjusted HR 1.00, 95% CI 1.00 to 1.00, 706 participants, 2 studies, very low certainty), systemic hypertension (adjusted HR 1.33, 95% CI 0.68 to 2.60, 731 participants, 3 studies; unadjusted HR 0.89, 95% CI 0.67 to 1.17, 771 participants, 2 studies; very low certainty), cardiovascular disease (adjusted HR 1.06, 95% CI 0.75 to 1.49, 771 participants, 2 studies; low certainty), migraine (unadjusted HR 1.06, 95% CI 0.75 to 1.49, 961 participants, 3 studies; very low certainty), or Raynaud’s syndrome (unadjusted HR 1.21, 95% CI 0.85 to 1.73, 961 participants, 3 studies; very low certainty), have an effect on visual field progression.
Authors' conclusions
There is moderate-certainty evidence to support the finding that bilateral disease is a prognostic factor associated with VF progression in people with glaucoma. There is low-certainty evidence that female sex and the presence of disc hemorrhage are associated with progression, while treatment with pharmacologics is protective of progression. The evidence is uncertain about the associations between progression and all other prognostic factors that we identified. Properly designed prognostic factor research studies are required in the future.
Funding
NIH (NEI: UG1EY020522), USA; HRB, Ireland; HSC PHA (CBES-2018-001), Ireland
Registration
Protocol available at doi.org/10.1002/14651858.CD015436
