**Abstract**

Ocular hypertension (OHT) is the only known modifiable risk factor of glaucoma development. Intraocular pressure (IOP)-lowering therapy reduces the risk of glaucoma development. The 5-year risk of glaucoma conversion is <10% for untreated OHT patients. Cost-effectiveness analyses suggested that it is not costeffective to treat all patients with OHT. Treatment should be targeted towards the higher-risk group—namely, patients with older age, a higher level of IOP, a thinner central corneal thickness (CCT), a larger vertical cup-to-disc ratio (VCDR) and a smaller pattern standard deviation (PSD) value on visual field (VF) test. These risk factors were established by the Ocular Hypertension Treatment Study (OHTS) and the European Glaucoma Prevention Study (EGPS). However, there is significant variability in the measurement of the currently known risk factors, especially if the assessment is taken from a longitudinal perspective. This can lead to overtreatment or under-treatment: the former exposing the patient to unnecessary side effects of IOP-lowering eye drops and the latter putting the patient at risk of developing glaucoma. The advancement of new VF algorithm and ocular imaging can lead to the identification of new approaches to risk stratification and, thus, more specific treatment for OHT patients.

**Keywords:** ocular hypertension (OHT), glaucoma 5-year risk calculator, vertical cup-to-disc ratio (VCDR), intraocular pressure (IOP)

## **1. Introduction**

Glaucoma is a leading cause of irreversible blindness worldwide [1]. Subjects with ocular hypertension (OHT) are known to have a higher risk of glaucoma development. OHT is defined as a mean intraocular pressure (IOP) ≥24 mmHg from two separate consecutive measurements without structural and functional evidence of glaucoma [2]. Patients with OHT are usually treated with IOP-lowering therapy based on the effectiveness of reducing the risk of glaucoma development according to the result of the Ocular Hypertension Treatment Study (OHTS) [3], which demonstrated a cumulative probability of 9.5% of developing primary open-angle glaucoma (POAG) in 5 years in the untreated OHT patients, compared with 4.4% in the treated group (patients who received IOP-lowering therapy). Hence, the incidence of POAG could be reduced by about 50% with adequate IOP reduction. In clinical practice, it is not uncommon that we adopt a treatment approach of liberally prescribing IOP-lowering medication based on the study results.

On the other hand, the result of the OHTS also reflects that only <10% of the untreated OHT patients developed glaucoma in 5 years, compared to the 4.4% of the treated group. Hence, the number needed to treat to prevent one glaucoma development is 20. Indeed, it has been shown that treating all patients with OHT is not cost-effective [4, 5]. The estimated incremental cost of treating all OHT patients to prevent one subject from developing glaucoma was US\$89,072 [4]. This is considered not cost-effective according to the standard of The National Institute for Health and Care Excellence (NICE), which classified a treatment as cost-effective at the level of risk when the incremental cost-effectiveness ratio (ICER) is equal to or less than US\$50,000 [6]. Furthermore, long-term treatment with IOP-lowering medications can impose significant inconvenience and undesirable side effects to patients, such as ocular surface disease. For instance, a study that involved 537 OHT and POAG patients showed that side effects from medication can independently contribute to health-related quality of life scores, which could be as worse as 0.11 [7]. This is equivalent to the utility loss of patients with early to moderate stage of glaucoma [8, 9]. Therefore, selective and targeted use of medication is not merely a health economic issue; unnecessarily treating low-risk OHT patients would expose them to undesirable medication side effects without beneficial gain.

## **2. Risk stratification and cost-effectiveness of treating ocular hypertension**

A more cost-effective approach is to treat OHT subjects who have higher risk of developing POAG—namely, an older age, a higher level of IOP, a thinner central corneal thickness (CCT), a larger vertical cup-to-disc ratio (VCDR) and a smaller pattern standard deviation (PSD) value on visual field (VF) test. These are risk factors of POAG development according to the joint data of the OHTS [2] and the European Glaucoma Prevention Study (EGPS) [10]. These are the two major multicentre, randomised control trials (RCTs) that involved patients with OHT. Stewart et al. suggested that it is cost-effective to treat patients with older age (≥76 years old), higher intraocular pressure (≥29 mmHg), thinner central corneal thickness (≤533 μm) and wider vertical cup-to-disc ratio (≥0.6) [4]. Kymes et al. suggested that treating OHT patients with IOP ≥24 mmHg and a ≥ 2% annual risk of glaucoma development is likely to be cost-effective [5]. Weinreb et al. suggested a risk stratification strategy: observation for patients with lower than average risk of POAG conversion (5-year risk of <5%), collaborative treatment decision between doctor and well-informed patient for those with moderate risk (5-year risk of 5–15%) and treatment for all subjects with higher than average risk (5-year risk of >15%) [11]. Based on this risk stratification strategy, it was demonstrated that nearly half (43.9%) of low-risk OHT eyes could safely have their medications reduced over 1 year, realising substantial savings [12]. In this study, only 1 out of 107 eyes (0.93%) developed a repeatable VF defect in the first year [12].

The 5-year risk of POAG development can be calculated using the available risk calculator, which was developed based on a predictive model that utilised the joint data of OHTS and EGPS [13]. The calculation is based on the risk factors as mentioned—age, IOP, CCT, VCDR and PSD value of VF. It has the advantage of integrating multiple risk factors into one quantitative, estimated percentage risk of glaucoma development in OHT subjects. This can facilitate treatment decision because high-risk subjects can be identified based on simultaneous and quantitative consideration of all these available risk factors; thus, allows a more straightforward

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*Risk Assessment of Ocular Hypertension and the Use of Medication*

characteristics as the participants in the OHTS and EGPS.

when interpreting PSD value as a stand-alone figure.

and cost-effective approach of treatment; and reduces unnecessary patient expo-

It is important to note that, similar to most multivariate prediction models derived from prospective studies [14], we are making several assumptions when we apply the 5-year risk calculator to guide treatment decision: [1] we assume that the baseline variables that were measured are the most predictive of the risk of glaucoma development, [2] the model also assumes that the risk of glaucoma progression is linear, and [3] patients who are being assessed have similar clinical

However, the variability of baseline risk factor measurements is a known phenomenon. IOP is well known to vary from visit to visit [15], which can be due to regression to the mean phenomenon, diurnal variation as well as order of IOP measurement [15]. This variability is also observed in the performance of VF, hence the PSD value [16]. Results of VF examination can be affected by patients' subjectivity and the substantial test-retest variability. The PSD value is a weighted standard deviation of the differences between the measured and normal reference visual field at each test location. A higher PSD value merely suggests a more irregular 'hill of vision', which can contribute to variability in patients' responses and/or areas of focal loss. Given that, by definition, OHT subjects do not have glaucomatous VF defect, the PSD value tends to be low. Therefore, a slight variability in patients' responses can contribute to a significant change in its value. Care must be taken

Therefore, the apparently more comprehensive risk stratification strategy that is based on the 5-year risk calculator can face several fundamental challenges. As discussed, the variability of IOP measurement and PSD value, even during baseline assessment, may add a considerable source of error to the risk calculation. Furthermore, due to the within-subject changes in risk factors' values during follow-up, the correlation between baseline and updated values may diminish with time [17]. One study has demonstrated that risk calculation is variable over time and that longitudinal changes in baseline variables correspond with changes in the risk estimation of glaucoma development [18]. In the study, the 5-year risk of POAG development was calculated by incorporating different measurements that assume the best-case scenario (baseline age, lowest PSD, highest CCT and lowest IOP) and the worst-case scenario (final age, highest PSD, lowest CCT and highest IOP). For the VCDR, a value of ±0.2 was applied to model interobserver and intraobserver variability (i.e. -0.2 in addition to the best-case scenario and + 0.2 in addition to the worst-case scenario). It was found that, within the same individual, the mean risk of POAG conversion could increase by almost 10-fold when comparing the worst- and best-case scenarios (5.0% vs. 45.7%, *P* < 0.01). Hence, risk stratification is dynamic, and risk estimations should be recalculated during follow-up visits as

variables can fluctuate significantly within the same individual over time.

It is important to note that the VCDR data that derived the risk calculator was based on VCDR measurements on the optic disc stereophotography of the OHTS and EGPS cohorts. In the RCTs, the measurement and evaluation of the optic nerve head (ONH) were performed by highly trained, independent graders at designated optic disc centres that followed a strict protocol in a non-clinical setting [19]. In clinical practice, the assessment of ONH and the measurement of VCDR by individual ophthalmologists

**3. Variability of risk factor measurement and the effects on risk** 

*DOI: http://dx.doi.org/10.5772/intechopen.90804*

sure to medication side effects.

**assessment**

*Visual Impairment and Blindness - What We Know and What We Have to Know*

**2. Risk stratification and cost-effectiveness of treating ocular** 

A more cost-effective approach is to treat OHT subjects who have higher risk of developing POAG—namely, an older age, a higher level of IOP, a thinner central corneal thickness (CCT), a larger vertical cup-to-disc ratio (VCDR) and a smaller pattern standard deviation (PSD) value on visual field (VF) test. These are risk factors of POAG development according to the joint data of the OHTS [2] and the European Glaucoma Prevention Study (EGPS) [10]. These are the two major multicentre, randomised control trials (RCTs) that involved patients with OHT. Stewart et al. suggested that it is cost-effective to treat patients with older age (≥76 years old), higher intraocular pressure (≥29 mmHg), thinner central corneal thickness (≤533 μm) and wider vertical cup-to-disc ratio (≥0.6) [4]. Kymes et al. suggested that treating OHT patients with IOP ≥24 mmHg and a ≥ 2% annual risk of glaucoma development is likely to be cost-effective [5]. Weinreb et al. suggested a risk stratification strategy: observation for patients with lower than average risk of POAG conversion (5-year risk of <5%), collaborative treatment decision between doctor and well-informed patient for those with moderate risk (5-year risk of 5–15%) and treatment for all subjects with higher than average risk (5-year risk of >15%) [11]. Based on this risk stratification strategy, it was demonstrated that nearly half (43.9%) of low-risk OHT eyes could safely have their medications reduced over 1 year, realising substantial savings [12]. In this study, only 1 out of 107 eyes (0.93%) developed a repeatable VF defect in the first

The 5-year risk of POAG development can be calculated using the available risk calculator, which was developed based on a predictive model that utilised the joint data of OHTS and EGPS [13]. The calculation is based on the risk factors as mentioned—age, IOP, CCT, VCDR and PSD value of VF. It has the advantage of integrating multiple risk factors into one quantitative, estimated percentage risk of glaucoma development in OHT subjects. This can facilitate treatment decision because high-risk subjects can be identified based on simultaneous and quantitative consideration of all these available risk factors; thus, allows a more straightforward

On the other hand, the result of the OHTS also reflects that only <10% of the untreated OHT patients developed glaucoma in 5 years, compared to the 4.4% of the treated group. Hence, the number needed to treat to prevent one glaucoma development is 20. Indeed, it has been shown that treating all patients with OHT is not cost-effective [4, 5]. The estimated incremental cost of treating all OHT patients to prevent one subject from developing glaucoma was US\$89,072 [4]. This is considered not cost-effective according to the standard of The National Institute for Health and Care Excellence (NICE), which classified a treatment as cost-effective at the level of risk when the incremental cost-effectiveness ratio (ICER) is equal to or less than US\$50,000 [6]. Furthermore, long-term treatment with IOP-lowering medications can impose significant inconvenience and undesirable side effects to patients, such as ocular surface disease. For instance, a study that involved 537 OHT and POAG patients showed that side effects from medication can independently contribute to health-related quality of life scores, which could be as worse as 0.11 [7]. This is equivalent to the utility loss of patients with early to moderate stage of glaucoma [8, 9]. Therefore, selective and targeted use of medication is not merely a health economic issue; unnecessarily treating low-risk OHT patients would expose them to undesirable medication side effects without

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year [12].

beneficial gain.

**hypertension**

and cost-effective approach of treatment; and reduces unnecessary patient exposure to medication side effects.
