Evolving Global Risk Assessment of Ocular Hypertension to Glaucoma Robert D

Evolving global risk assessment of ocular hypertension to glaucoma Robert D. Fechtner and Albert S. Khouri

Purpose of review Introduction To discuss current knowledge of global risk assessment in Risk assessment is part of daily life. Making an invest- ocular hypertension. ment, going for the winning shot, taking the patient to Recent findings surgery – we make risk assessments all the time. In the The ophthalmologist treating patients with ocular context of glaucoma care, risk assessment helps us decide hypertension is frequently faced with the clinical dilemma of on the appropriateness or intensity of treatment. What is which patients to treat and how vigorous treatment should the risk that the patient will get worse? Can I reduce that be. The goal of risk assessment for glaucoma is to identify risk with an appropriate intervention? patients at greatest risk for symptomatic vision loss. Risk factors can be identified by history such as age, race, and The sophistication of the risk assessment depends on the family history or can be clinically observed by examination quality of the information available to us and our famili- such as elevated intraocular pressure, optic nerve head arity with the tools to best use that information. That can appearance, central corneal thickness, and visual field range from simply asking historical questions to reveal abnormalities. Risk assessment is a well accepted tool in risk factors to a calculation based upon a quantitative risk other fields of medicine. Parallels can be drawn between the model. We now have moved along that spectrum, particu- evolution of risk assessment for coronary artery disease and larly for the patient with ocular hypertension (OHT) at glaucoma. Validated risk calculators for ocular hypertension risk for glaucoma. are currently available mostly derived from the Ocular Hypertension Treatment Study. Assessing risk Summary The ophthalmologist treating patients with OHT is fre- The aim of assessing global risk for conversion from ocular quently faced with the clinical dilemma of which patients hypertension to glaucoma is to identify patients who are to treat, when to start treatment, and how vigorous most likely to benefit from early treatment. Calculation of risk treatment goals should be. Not all patients with OHT should be accompanied by thorough analysis of risks, will develop glaucoma. Most with glaucoma will maintain benefits, and alternatives for the individual patient. useful vision for their entire life time. Risk assessment should allow us to identify those at greatest risk for Keywords developing glaucoma and for suffering symptomatic glaucoma, ocular hypertension, risk assessment vision loss. Global risk assessment allows us to apply what we have learned from longitudinal study of patients Curr Opin Ophthalmol 18:104–109. ß 2007 Lippincott Williams & Wilkins. to make individualized risk assessments.

Institute of Ophthalmology and Visual Science, University of Medicine and One of the pivotal studies to highlight the importance of Dentistry of New Jersey/New Jersey Medical School, Newark, New Jersey, USA quantifying risk of progression from OHT to glaucoma Correspondence to Robert D. Fechtner, MD, Institute of Ophthalmology and Visual was the Ocular Hypertension Treatment Study (OHTS) Science, 90 Bergen Street, Suite 6100, Newark, NJ 07103, USA Tel: 973 972 2030; fax: 973 972 1746; e-mail: [email protected] [1,2]. The OHTS was a landmark prospective trial on outcomes of treatment versus observation in subjects Disclosure: The authors have no conflict of interest regarding any of the subjects discussed. with OHT. Risk factors in subjects with OHT such as age, optic nerve appearance, visual field abnormality, Current Opinion in Ophthalmology 2007, 18:104–109 intraocular pressure (IOP), and central corneal thickness Abbreviations as predictors for development of primary open-angle CI confidence interval glaucoma (POAG) were outlined in this paper. According EGPS European Glaucoma Prevention Study IOP intraocular pressure to the OHTS findings, the cumulative probability of OHT ocular hypertension developing glaucoma after 5 years is 9.5% in eyes with OHTS Ocular Hypertension Treatment Study POAG primary open-angle glaucoma untreated OHT. Treatment (20% reduction of IOP) was demonstrated to reduce this risk to 4.4%. Despite this ß 2007 Lippincott Williams & Wilkins important confirmation that reducing IOP can prevent or 1040-8738 delay the onset of glaucoma, perhaps the most important contribution from the OHTS was the identification of risk factors for progressing from OHT to glaucoma.

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Our model for diagnosing and treating glaucoma has long disease, it makes sense that older age is a risk for greater been based on the principles of detecting structural or severity. functional damage, setting a target IOP at which we believe the pressure-related component of damage will Race be reduced or eliminated, then following the patient to Primary open-angle glaucoma was found in one study [9] monitor for progression. This model has an obvious to be four times more frequent among individuals of limitation: glaucomatous damage is irreversible. If we African American origin compared with white people. make our decision about intensity of treatment based on Other studies [10,11] have also reported a notably higher progression rather than risk factors, we accept that prevalence of glaucoma in blacks compared with other patients must lose additional vision before we react. racial groups.

Our process of risk assessment for OHT and glaucoma Family history has been informed by clinical observation and by sys- Although the exact inheritance pattern is still unknown, tematic study. Practical risk assessment in the office starts POAG is a multifactorial polygenetic disease. Family with identifying risk factors through the history and history of glaucoma increases an individual’s risk of devel- physical examination. Additional testing may add to oping the disease. Several studies have examined family our process. As experienced clinicians we develop a sense history as a risk factor for glaucoma. Self-reporting can be of pattern recognition that roughly translates into ‘More unreliable, but in the Rotterdam Study [12] family history risk factors means greater risk’. Simple counting of risk was ascertained by direct examination of relatives and factors is a crude sort of risk calculation. This has been our not by patient self-report. The lifetime absolute risk of process for many years. glaucoma at age 80 years was found to be almost 10 times higher for individuals having relatives with glaucoma When prospective longitudinal study can determine than for patients with negative family history (22.0 versus hazard ratios for a particular risk factor, we might apply 2.4%). The Barbados Family Study of Open-angle Glau- greater weight to those that confer greater risk. Rather coma [8] investigated inheritance of POAG among black than just counting, we make an estimate of each factor as families and also found family history to be a major risk high risk or lower risk. Finally, development of a risk factor for glaucoma confirmed by direct examination of model can allow us to perform a risk calculation to the relatives. Still, family history alone cannot account for estimate the range of risk over a defined period [3] the observed proportion of the disease, suggesting that (an evidence-based review of individual risk factors and nongenetic factors play a significant role in the overall of global risk assessment in OHT and glaucoma). We occurrence of glaucoma [2]. have now reached this stage of risk assessment for OHT (see ‘Risk calculators for ocular hypertension’ below). Diabetes Diabetes traditionally was viewed as one of the risk Risk factors for glaucoma factors for OHT progression to glaucoma. In the Blue We must be concerned with both the risk of developing Mountains eye study [13], glaucoma prevalence and glaucoma and the risk of disease progression once glau- OHT were more common in people with diabetes [odds coma is established. It might be helpful to think of ratio 2.12, confidence interval (CI) 1.18–3.79; and 1.86 CI glaucoma as a spectrum ranging from a healthy optic 1.09–3.20, respectively]. Other prospective studies of nerve to earliest detectable damage and on to sympto- glaucoma management [14,15] reported a greater like- matic vision loss and blindness. We should not assume lihood of progression in patients with diabetes. The that all the risk factors are the same at all stages of the unexpected findings from OHTS [1,2] suggested that disease. The literature has often described ‘risk factors diabetes protects against progression to glaucoma (hazard for glaucoma’ without specifying whether it is a risk for ratio of 0.37 in the multivariate analysis with P < 0.05). developing the disease or a risk for progression. Some believe that excluding subjects with diabetic reti- nopathy from the OHTS may have influenced the find- Risk factors by history ings. Diabetes was not selected as a predictive factor in Some risk factors can be identified by patient history such the analysis of pooled OHTS–European Glaucoma Pre- as age, race, and family history. vention Study (EGPS) dataset. The effect of diabetes on the development of POAG remains controversial. Age There is strong evidence that prevalence of POAG Other risk factors increases with the age of the population being studied Various factors such as myopia, pseudoexfoliation, and [4–6]. This was also confirmed in other population-based migraine have been reported in the literature as risk studies such as the Visual Impairment Project [7] and the factors. There seems to be an increased frequency of Barbados Family Study [8]. Since glaucoma is a progressive myopia among patients with OHT or POAG. In one

study [16], 60% of eyes progressing from OHT to glau- suggested that race itself did not increase the risk of coma were myopic. There is evidence for pseudoexfolia- glaucoma progression but reflected a higher prevalence tion as a risk factor for glaucoma progression [14]. There of other risk factors in individuals of African origin. That is also an association of pseudoexfoliation and OHT [17]. does not mean that we should ignore race and family Migraine has been reported as a risk factor for glaucoma history when we assess our patients, but other factors progression [18]. In the OHTS [2], however, the positive may be better predictors. The importance of family history association between migraine and the development of remains unclear. Family history of glaucoma is difficult to POAG in the multivariate model was not statistically determine unless first-degree relatives are examined. significant (P > 0.05). This was not done in OHTS.

Risk factors by clinical examination The OHTS [1,2] identified as risk factors findings that Other risk factors can be clinically observable by exam- may have represented early structural or functional ination (e.g. elevated IOP, optic nerve head appearance, damage. The hazard ratios were increased by 32% per and visual field abnormalities among others). In the 0.1 larger vertical cup-to-disc ratio and by 25% per 0.1 future we may be able to add to this list specific genetic larger horizontal cup-to-disc ratio. Similarly, on multi- markers. variate analysis an increased pattern standard deviation (per 0.2 dB greater) on achromatic visual field testing Intraocular pressure was associated with an hazard ratio of 1.27 (95% CI Intraocular pressure is one of the strongest risk factors for 1.06–1.52). Functional loss detected by short-wavelength progression [1,2,4,19,20]. Higher IOP levels are associ- automated perimetry was present in 20% of patients at ated with glaucoma progression. Variability in diurnal OHTS baseline, suggesting that perhaps some patients IOP and large IOP differences between fellow eyes were with existing glaucoma damage were enrolled [26]. found to be more common in patients with OHT (33%) and POAG (36%) than in normal subjects (6%) [21]. One of the most intriguing lessons learned from the OHTS [1,2] was that central corneal thickness was a Optic nerve head appearance strong independent risk factor for progression from There is strong evidence that increased cup-to-disc ratio OHT to POAG. This correlation between central corneal is a risk factor for progression of glaucoma [20,22]. thickness and OHT was evaluated in a separate analysis Whether an elevated cup-to-disc ratio represents a risk of OHTS [27]. This risk was independent of the influ- factor or unconfirmed existing glaucoma damage has ence of central corneal thickness on applanation tono- been debated [23]. Limitations in early detection of metry pressure. Corneal thickness may represent structural damage make it difficult to completely resolve structural differences in the layers of the eye and in this issue. Optic disc hemorrhages were associated with a optical nerve head architecture that may confer protec- sixfold increase (95% CI 3.6–10.1; P < 0.001) in risk of tion against progression to glaucoma. It may also reflect developing POAG in OHTS participants [24]. the possibility that in subjects with higher central corneal thickness, Goldmann IOP measurements are overesti- Progression from ocular hypertension to mated and actual IOP is lower [27,28]. primary open-angle glaucoma As discussed above, a major contribution from OHTS [2] After these risk factors were identified, we were left with was the systematic study of possible risk factors for the the challenge of how best to use them. We were able to progression of OHT to OAG. In the univariate analysis benefit from the experience of other fields in medicine age, African American origin, sex (male), diabetes melli- such as cardiology. tus, heart disease, IOP, corneal thickness (per 40 mm thinner), pattern standard deviation (per 0.2 dB greater), Lessons in risk modeling learned from horizontal cup-to-disc ratio (per 0.1 larger), and vertical cardiovascular medicine cup-to-disc ratio (per 0.1 larger) were significantly associ- Risk assessment is a well accepted tool in other fields of ated with development of glaucoma. The multivariate medicine. Perhaps the best known example is in cardio- analysis of risk identified as strong risk factors age (per vascular medicine. Studies of the natural history of decade), baseline IOP, central corneal thickness, optic cardiovascular disease have been underway for 50 years. nerve appearance, and visual field parameters. Older age This allows accurate modeling of long-term risk. Initially, has also been found to be an independent risk factor for the risk factors were identified. This allowed intervention progression of OHT. This has been reported in multiple based on risk before the first event. No one wishes to studies [2,4,14,25]. Interestingly, in the OHTS [1,2] learn of their risk by having the first heart attack. Risk African American race was associated with an increased assessment and modification are the fundamental risk of progression from OHT to glaucoma in the uni- tools for preventing coronary artery disease. Although variate but not in the multivariate analysis. This potential treatment outcomes for the two diseases differ

considerably (e.g. glaucoma results in gradual vision loss Risk calculators for ocular hypertension whereas coronary artery disease can result in sudden Many believe the first basic evidence-based risk calcu- death), the approach to developing prevention strategies lator was included in the OHTS publication [2] as two may be similar [29] (discusses how disease prevention 3 Â 3 tables that included central corneal thickness and strategies learned from risk assessment models for either IOP or vertical cup-to-disc ratios. It was possible to coronary heart disease can be applied to OHT and combine the two risk factors and derive an estimate of glaucoma). individual risk for the development of glaucoma. These tables were provided, in part, to illustrate the impact of Epidemiologic research [30] in preventive cardiology has central corneal thickness on risk and allowed the simul- shown that atherosclerotic cardiovascular events are taneous use of two risk factors to assess risk. associated with measurable predisposing factors such as dyslipidemia, hypertension, and diabetes. Persons with An interactive calculator by Mansberger [38] based on the one or more of these risk factors were shown to be at OHTS publication was first posted on the Internet in high risk for cardiovascular events. Controlled clinical October 2003 and the latest version is currently available trials in cardiology [31] have also provided evidence that at http://www.discoveriesinsight.org/GlaucomaRisk.htm. modification of some of these predisposing risk factors The calculator uses the six OHTS variables predictive reduced the risk of coronary artery disease. Such evi- of developing glaucoma (patient age, IOP, central dence has provided the basic foundation for guidelines on corneal thickness, visual field pattern standard deviation, the prevention, recognition, and management of risk vertical cup-to-disc ratio, and diabetes status) to calculate factors for coronary artery disease [32,33]. Validated risk risk of developing glaucoma within 5 years without and calculators have become an accepted tool in risk assess- with treatment. ment for coronary artery disease. We readily accept treatment to modify and reduce risk before the first heart A risk model based on the OHTS results has been attack as the appropriate approach to this disease. For this published [39] that uses the same six variables to calculate reason, almost every adult American is aware of their the probability of glaucoma conversion in 5 years. It was blood pressure and serum cholesterol level. validated with an independent population of subjects with OHT who were followed at the University of Parallels can be drawn between the evolution of risk California, San Diego, in 2005 (the first validated assessment for coronary artery disease and glaucoma. Our predictive model of conversion from OHT to glaucoma understanding of the risk factors involved in the pro- based on the OHTS results in an independent patient gression from OHT to glaucoma is still ongoing. Both population). The risk model serves as the basis for card- coronary artery disease and glaucoma are similar in that board slide rule and a digital handheld risk calculator. they both have known modifiable risk factors (cholesterol A validated risk model from the OHTS study was pre- and IOP, respectively). Our conception of what is sented at the Annual Meeting of the American Academy of ‘normal’ for both cholesterol and IOP also has changed. Ophthalmology in November 2006 (http://ohts.wustl.edu/ The understanding that there is no cutoff for abnormal risk). A prediction model [40] was developed from IOP, but rather a continuous relationship between the the observation group of the OHTS and then tested on level of IOP and the prevalence and incidence of glau- the placebo group of the EGPS. A calculator to estimate coma down to IOPs in the low–normal range [34,35] is the 5-year risk of developing POAG, based on the pooled currently widely accepted. OHTS–EGPS predictive model, will be a useful tool for clinicians and patients in deciding the frequency of tests Despite the similarities, we must acknowledge that a and examinations and advisability of initiating preventive number of differences exist between coronary artery treatment. disease and glaucoma. First, measurement of IOP is less well defined than are measurements of cholesterol and These OHT risk calculators are based on rigorous data lipoproteins. Second, glaucoma prevention presently collection during the OHTS strict trial conditions, which relies almost solely on decreasing IOP, whereas coronary may not necessarily represent data from examinations of artery disease has multiple modifiable risk factors, such as patients with OHT in an eye care provider’soffice. They treating dyslipidemia, smoking cessation, and diabetes probably can provide a reasonable estimate of risk for the control. Finally, while both diseases are chronic and progression to glaucoma even when data are collected progressive, treating dyslipidemia decreases the risk of less rigorously [41]. sudden life-threatening events, while treating elevated IOP decreases the risk of an initially asymptomatic Assessing risk in a patient with ocular and gradual degeneration of the optic nerve that in hypertension many cases may never affect the patient’s quality of life The aim of assessing global risk for conversion from OHT [36,37]. to glaucoma in an individual patient is to identify patients

3 Friedman DS, Wilson MR, Liebmann JM, et al. An evidence-based assess- who are most likely to benefit from early institution of ment of risk factors for the progression of ocular hypertension and glaucoma. treatment. Just as with all medical decisions, calculation Am J Ophthalmol 2004; 138:S19–S31. of risk should go along with a thorough analysis of risks, 4 Quigley HA, Enger C, Katz J, et al. Risk factors for the development of glaucomatous visual field loss in ocular hypertension. Arch Ophthalmol 1994; benefits, and alternatives for the individual patient. The 112:644–649. OHTS multivariate regression contained six variables 5 Martinez GS, Campbell AJ, Reinken J, Allan BC. Prevalence of ocular disease that were found to be predictive of developing glaucoma in a population study of subjects 65 years old and older. Am J Ophthalmol from OHT: age, central corneal thickness, IOP, pattern 1982; 94:181–189. 6 Leske MC, Connell AM, Wu SY, et al. Risk factors for open-angle glaucoma: standard deviation, vertical cupping, and diabetic status the Barbados Eye Study. Arch Ophthalmol 1995; 113:918–924. (although controversial). A recent OHTS analysis also 7 Mukesh BN, McCarty CA, Rait JL, Taylor HR. Five-year incidence of open- found optic disc hemorrhages to be significantly associ- angle glaucoma: the Visual Impairment Project. Ophthalmology 2002; ated with conversion to POAG. The large number of 109:1047–1051. 8 Leske MC, Nemesure B, He Q, et al. Patterns of open-angle glaucoma in the different combinations of variables for any individual Barbados Family Study. Ophthalmology 2001; 108:1015–1022. patient with OHT can make it challenging to subjec- 9 Tielsch JM, Sommer A, Katz J, et al. Racial variations in the prevalence tively estimate global risk. A risk calculator can help the of primary open-angle glaucoma: the Baltimore Eye Survey. JAMA 1991; 266:369–374. clinician determine whom to treat and when to treat. 10 Friedman DS, Jampel HD, Munoz B, West SK. The prevalence of open-angle glaucoma among blacks and whites 73 years and older: the Salisbury Eye Individual judgement and other factors must be con- Evaluation Glaucoma Study. Arch Ophthalmol 2006; 124:1625–1630. A recent report of significantly increased risk of OAG in an elderly population of sidered. For example, while age is a risk factor, younger black compared with white individuals. patients have more years in which they are subjected to 11 Lichter PR, Musch DC, Gillespie BW, et al. Interim clinical outcomes in the the risk. The clinician should take into account that older Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery. Ophthalmology 2001; 108:1943– patients have a shorter life expectancy and glaucomatous 1953. loss may never impact their quality of life. Thus a 12 Wolfs RC, Klaver CC, Ramrattan RS, et al. Genetic risk of primary open-angle younger patient with a lower 5-year risk may potentially glaucoma: population-based familial aggregation study. Arch Ophthalmol 1998; 116:1640–1645. have a greater benefit from treatment than an elderly 13 Mitchell P, Smith W, Chey T, Healey PR. Open-angle glaucoma and diabetes: patient with a higher risk profile. As in the cardiovascular the Blue Mountains eye study, Australia. Ophthalmology 1997; 104:712– model, a calculator would be an adjunct to, and not a 718. substitute for, the experience and judgement of a knowl- 14 Leske MC, Heijl A, Hussein M, et al. Factors for glaucoma progression and the effect of treatment: the Early Manifest Glaucoma Trial. Arch Ophthalmol edgeable physician [42] (a review of global risk assess- 2003; 121:48–56. ment in OHT emphasizing glaucoma progression as a 15 The Advanced Glaucoma Intervention Study (AGIS): 12. Baseline risk factors for sustained loss of visual field and visual acuity in patients with advanced continuum and analyzing data from multiple large pro- glaucoma. Am J Ophthalmol 2002; 134:499-512. spective trials to estimate risk of OHT progression). 16 Perkins ES, Phelps CD. Open angle glaucoma, ocular hypertension, low-tension glaucoma, and refraction. Arch Ophthalmol 1982; 100:1464– Conclusion 1467. The aim of assessing global risk for conversion from OHT 17 Mitchell P, Wang JJ, Hourihan F. The relationship between glaucoma and pseudoexfoliation: the Blue Mountains eye study. Arch Ophthalmol 1999; to glaucoma is to identify patients who are most likely to 117:1319–1324. benefit from early institution of treatment. OHT risk 18 Drance S, Anderson DR, Schulzer M. Risk factors for progression of visual field abnormalities in normal-tension glaucoma. Am J Ophthalmol 2001; calculators are currently available and can probably pro- 131:699–708. vide reasonable estimation of risk for progression to 19 Kass MA, Gordon MO, Hoff MR, et al. Topical timolol administration reduces glaucoma. Calculation of risk should go along with a the incidence of glaucomatous damage in ocular hypertensive individuals: a randomized, double-masked, long-term clinical trial. Arch Ophthalmol 1989; thorough analysis of risks, benefits, alternatives, and 107:1590–1598. preferences for the individual patient. 20 Schulzer M, Drance SM, Douglas GR. A comparison of treated and untreated glaucoma suspects. Ophthalmology 1991; 98:301–307. Acknowledgements 21 Wilensky JT, Kaufman PL, Frohlichstein D, et al. Follow-up of angle-closure Supported in part by Research to Prevent Blindness, and The glaucoma suspects. Am J Ophthalmol 1993; 115:338–346. Glaucoma Research and Education Foundation. 22 Epstein DL, Krug JH Jr, Hertzmark E, et al. A long-term clinical trial of timolol therapy versus no treatment in the management of glaucoma suspects. References and recommended reading Ophthalmology 1989; 96:1460–1467. Papers of particular interest, published within the annual period of review, have 23 Cioffi GA, Liebmann JM. Translating the OHTS results into clinical practice. been highlighted as: J Glaucoma 2002; 11:375–377. of special interest 24 Budenz DL, Anderson DR, Feuer WJ, et al. Detection and prognostic sig- of outstanding interest nificance of optic disc hemorrhages during the Ocular Hypertension Treat- Additional references related to this topic can also be found in the Current ment Study. Ophthalmology 2006; 113:2137–2143. World Literature section in this issue (p. 177). 25 Georgopoulos G, Andreanos D, Liokis N, et al. Risk factors in ocular hypertension. Eur J Ophthalmol 1997; 7:357–363. 1 Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypoten- 26 Johnson CA, Keltner JL, Cello KE, et al. Baseline visual field characteristics in sive medication delays or prevents the onset of primary open-angle glaucoma. the Ocular Hypertension Treatment Study. Ophthalmology 2002; 109:432– Arch Ophthalmol 2002; 120:701–713; discussion 829–830. 437. 2 Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment 27 Brandt JD, Beiser JA, Kass MA, Gordon MO. Central corneal thickness in the Study: baseline factors that predict the onset of primary open-angle glaucoma. Ocular Hypertension Treatment Study (OHTS). Ophthalmology 2001; 108: Arch Ophthalmol 2002; 120:714–720; discussion 829–830. 1779–1788.

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