Downloaded from http://bjo.bmj.com/ on April 10, 2015 - Published by group.bmj.com
BJO Online First, published on March 2, 2015 as 10.1136/bjophthalmol-2014-306014 Clinical science
Protocol-driven adjustment of ocular hypotensive medication in patients at low risk of conversion to glaucoma Poemen P M Chan,1 Christopher K S Leung,1 Vivian Chiu,1 Rita Gangwani,1 Abhishek Sharma,1 Sophie So,1 Nathan Congdon1,2,3 1
Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong Eye Hospital, Kowloon, Hong Kong 2 Translational Research for Equitable Eyecare, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong, China 3 ORBIS International, New York, USA Correspondence to Dr Nathan Congdon, Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong Eye Hospital, Kowloon 510060, Hong Kong; [email protected] Received 20 August 2014 Revised 27 January 2015 Accepted 29 January 2015
ABSTRACT Aim To investigate the safety and potential savings of decreasing medication use in low-risk patients with ocular hypertension (OH). Methods Patients with OH receiving pressure-lowering medication identified by medical record review at a university hospital underwent examination by a glaucoma specialist with assessment of visual field (VF), vertical cup-to-disc ratio (vCDR), central corneal thickness and intraocular pressure (IOP). Subjects with estimated 5-year risk of glaucoma conversion 15% and 14 (6.6%) had unreliable baseline VF. At 1 month, 15 patients (29 eyes, 13.7%) defaulted follow-up or refused to discontinue medication and 11 eyes (5.2%) had risk >15%. The remaining 69 patients (107 eyes, 50.7%) successfully discontinued 141 medications and completed 1-year follow-up. Mean IOP (20.5±2.65 mm Hg vs 20.3±3.40, p=0.397) did not change, though mean VF pattern SD (1.58±0.41 dB vs 1.75±0.56 dB, p=0.001) and glaucoma conversion risk (7.31±3.74% vs 8.76±6.28%, p=0.001) increased at 1 year. Mean defect decreased (−1.42±1.60 vs −1.07 ±1.52, p=0.022). One eye (0.47%) developed a repeatable VF defect and 13 eyes (6.1%) had 5-year risk >15% at 1 year. The total 1-year cost of medications saved was US$4596. Conclusions Nearly half (43.9%) of low-risk OH eyes in this setting could safely reduce medications over 1 year, realising substantial savings.
INTRODUCTION
To cite: Chan PPM, Leung CKS, Chiu V, et al. Br J Ophthalmol Published Online First: [ please include Day Month Year] doi:10.1136/bjophthalmol2014-306014
Glaucoma is the leading cause of untreatable blindness worldwide.1 Elevated intraocular pressure (IOP) is a well-known risk factor for glaucoma, though the Ocular Hypertension Treatment Study (OHTS) demonstrated that only a small proportion of patients with untreated ocular hypertension (OH) will develop glaucoma over 5 years.2 Both OHTS3 and the European Glaucoma Prevention Study (EGPS)4 have identified risk factors that make conversion to glaucoma more likely among persons with OH. These factors include the following: older age, higher IOP, thinner central corneal thickness (CCT), larger vertical cup-to-disc ratio (vCDR) and a higher pattern SD (PSD) on visual field (VF) testing.
A risk calculator derived from prediction models using the combined data of OHTS and EGPS is available for estimating the 5-year glaucoma conversion risk.5 6 Cost-effectiveness analyses based on these risk models have suggested that treating patients with an annual glaucoma risk of ≥2% is appropriate from a societal perspective,7 while expert panels have suggested treating all patients with a 5-year risk of ≥15%.8 Existing equipment for monitoring the VF allows changes to be identified in patients who do experience glaucoma conversion before any detectable change has occurred in the vision, and available evidence suggests that the impact on quality of life (QOL) of early VF loss is quite modest.9 As with many other chronic diseases, treatment of OH, once initiated, can be life-long. The costs involved may be significant, and can be expected to rise as the population ages. In Hong Kong, for example, between 2001 and 2006, the annual cost for out-patient ophthalmic drugs, of which glaucoma medications are by far the largest part, rose by 265%, from HK$9.3 M to 34.0 M (US$ 1.19M–4.36M).10 The government-funded universal healthcare system in Hong Kong makes it relatively easy to estimate these costs, but clearly the amounts involved are far higher in larger populations, where increases with ageing are likely occurring as well. A study published in 2008 estimated that the total 5-year cost of medication treatment for glaucoma (including office visits) was US$6571 per patient in the USA,11 for a total cost which could exceed US$15 billion. Validated risk calculators for conversion to glaucoma among patients with OH5 6 offer an evidence-based approach to reduce the growing cost of glaucoma medications, particularly in settings such as Hong Kong where a single payer for medical care can set policies on drug coverage. Simulation studies have shown that access to risk calculators affects glaucoma clinical decisionmaking and reduces inconsistency between specialists.12 Nonetheless, to the best of our knowledge, no published studies have assessed the economic and medical consequence of applying risk calculators systematically to optimise the use of topical medication. The aims of this study are to: (1) estimate the proportion of patients with OH in a public eye clinic in Hong Kong that could undergo medication reduction based on a predetermined risk cut-off value for conversion to glaucoma; (2) assess the short-term (1 month) fluctuation in IOP
Chan PPM, et al. Br J Ophthalmol 2015;0:1–6. doi:10.1136/bjophthalmol-2014-306014
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd under licence.
1
Downloaded from http://bjo.bmj.com/ on April 10, 2015 - Published by group.bmj.com
Clinical science and calculated risk, and the medium-term (1 year) change in calculated risk and indices of VF damage after targeted cessation of medication; and (3) calculate the potential cost savings in this cohort.
METHODS This was a prospective, longitudinal study, the protocol for which was approved in full by the Institutional Review Board of the Chinese University of Hong Kong. Written informed consent was obtained from all subjects, and the tenets of the Declaration of Helsinki were followed throughout.
Patient enrolment and eligibility Medical records of patients followed in the general ophthalmology and glaucoma clinics in Hong Kong Eye Hospital during the period between November 2010 and October 2011 were reviewed systematically. One or both eyes of a subject could be enrolled, and eligibility and exclusion criteria were as follows: diagnosis with OH, IOP >21 mm Hg in ≥1 eye documented on ≥1 follow-up visit, receiving ≥1 IOP-lowering medication with no identifiable secondary cause for IOP elevation. Such patients were invited to attend a screening visit for further examination. After obtaining written informed consent, a full ophthalmic assessment was carried out by a fellowship-trained glaucoma specialist (PPMC), including measurement of visual acuity and IOP (Goldmann applanation tonometry), dark room gonioscopy, anterior segment slit-lamp biomicrosopy, and examination of the fundus and optic disc with dilation of the pupil. Eyes were excluded if the visual acuity was ≤6/12, the posterior trabecular meshwork could not be visualised for >180° or evidence of other ocular disease was present. Two IOP measurements were recorded for each eye. If the two readings differed by ≤2 mm Hg, then the mean was recorded as the IOP measurement, otherwise a third reading was performed and the median recorded.13 CCT was measured with ultrasound pachymetry (Pachette 500, DGH Technology, Frazer, Pennsylvania, USA), and the median readings recorded.14 Standard automated white-on-white perimetry (SITA Standard 24-2, Humphrey Field Analyzer, Carl Zeiss Meditec, Dublin, California, USA) was performed in both eyes, and the vCDR was assessed by optical coherence tomography imaging of the optic disc (Cirrus HD-OCT, Carl Zeiss Meditec). Only VFs with fixation losses, false-positive and false-negative errors ≤20% and OCT scans with signal strength ≥6 were accepted. Eyes with evidence of glaucomatous damage on VF (defined as a cluster of ≥3 non-edge points in the PSD plot in a single hemifield with a value of p 30 mm Hg. Patients were then followed every 3–4 months for monitoring of IOP and other routine care as needed for 1 year. IOP-lowering medication(s) were resumed if the IOP was >30 mm Hg. At the 1 year follow-up visit, subjects having discontinued ≥1 IOP-lowering medication underwent measurements of VF PSD, CCT, vertical CDR and IOP as mentioned above. The risk of glaucoma conversion was then calculated again based on these data. Any patients with suspicion of having developed a VF defect underwent repeated VF testing on three occasions as per the OHTS protocol.13
Statistical methods Analyses were performed using Microsoft Excel and SPSS for Windows V.15.0 (SPSS, Chicago Illinois, USA). Continuous variables were expressed as mean (±SD), categorical variables as individual counts and proportions. IOP, CCT, vCDR, median deviation (MD), PSD and 5-year risk of glaucoma conversion and average retinal nerve fibre layer (RNFL) thickness were compared between 1 month and 1 year after discontinuation of IOP-lowering medication with linear mixed modelling, to account for similarities between eyes of the same individual. Random intercepts were included at both the subject and eye levels (each eye nested within subject). The number of bottles of drops going unused as a result of the protocol-driven discontinuation in the study was calculated, assuming that one bottle of drops would be used each month, whether the patient was using the medication in one or both eyes. This reflects current prescription practice in the clinics where the study was carried out.
RESULTS A total of 9080 charts were reviewed and 328 (3.6%) patients with a chart diagnosis of OH receiving ≥1 IOP-lowering medication were identified. Among these, 208 (63.4%) patients were successfully contacted and agreed to participate in the screening examination. After excluding eyes with ocular disease or glaucomatous damage on VF or disc examination, 212 eyes of 126 (60.6%) patients with OH receiving ≥1 IOP-lowering medication were identified (figure 1). Among these, 44 eyes (20.8%) of 33 patients had 5-year conversion risk >15% and 14 eyes (6.6%) of 12 patients had unreliable baseline VF on repeated attempts, and were excluded per protocol. One or more medication was discontinued in each of the remaining 154 eyes (72.6%) at the time of the screening visit (figure 1). At 1 month follow-up, seven eyes (3.3%) of four patients had IOP >30 mm Hg, 11 eyes (5.2%) of 9 patients had recalculated risk >15%, and 19 patients (29 eyes, 13.7%) defaulted follow-up or refused to discontinue IOP-lowering medications. In total, 69 patients (107 eyes, 50.5%) discontinued ≥1 IOP-lowering medication for 1 year (figure 1). Among these, 14 eyes were pseudophakic at the time of enrolment and none underwent intraocular surgery during the 1 year follow-up. Table 1 shows demographic and clinical information for patients Chan PPM, et al. Br J Ophthalmol 2015;0:1–6. doi:10.1136/bjophthalmol-2014-306014
Downloaded from http://bjo.bmj.com/ on April 10, 2015 - Published by group.bmj.com
Clinical science Figure 1 Flow charts of patients’ recruitment and follow-up through the study.
successfully discontinuing medications, and those excluded at the baseline and 1-month examinations. All 69 patients (107 eyes, 100%) completed follow-up at 1 year. There was a statistically significant, though modest (10%) increase in IOP after 1 month of reducing medication (18.6±3.09 at baseline to 20.5±2.65 at 1 month; p15% at 1 year, though none of these developed VF defects. One eye did develop repeatable VF defects, although the calculated risk was only 6.43% at 1-year follow-up. IOP-lowering medication was reinstilled for this eye. Thus, 93 eyes (43.9%) discontinued medications over 1 year without excessive risk or harm (figure 1). A total of 910 bottles of 141 IOP-lowering medications (figure 3) went unused by participants over the course of the
Table 1 Baseline demographic and clinical information for patients included in and excluded from the study
Total number of eyes Females n (% of persons) Age (years) Visual acuity
BJO Online First, published on March 2, 2015 as 10.1136/bjophthalmol-2014-306014 Clinical science
Protocol-driven adjustment of ocular hypotensive medication in patients at low risk of conversion to glaucoma Poemen P M Chan,1 Christopher K S Leung,1 Vivian Chiu,1 Rita Gangwani,1 Abhishek Sharma,1 Sophie So,1 Nathan Congdon1,2,3 1
Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong Eye Hospital, Kowloon, Hong Kong 2 Translational Research for Equitable Eyecare, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong, China 3 ORBIS International, New York, USA Correspondence to Dr Nathan Congdon, Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong Eye Hospital, Kowloon 510060, Hong Kong; [email protected] Received 20 August 2014 Revised 27 January 2015 Accepted 29 January 2015
ABSTRACT Aim To investigate the safety and potential savings of decreasing medication use in low-risk patients with ocular hypertension (OH). Methods Patients with OH receiving pressure-lowering medication identified by medical record review at a university hospital underwent examination by a glaucoma specialist with assessment of visual field (VF), vertical cup-to-disc ratio (vCDR), central corneal thickness and intraocular pressure (IOP). Subjects with estimated 5-year risk of glaucoma conversion 15% and 14 (6.6%) had unreliable baseline VF. At 1 month, 15 patients (29 eyes, 13.7%) defaulted follow-up or refused to discontinue medication and 11 eyes (5.2%) had risk >15%. The remaining 69 patients (107 eyes, 50.7%) successfully discontinued 141 medications and completed 1-year follow-up. Mean IOP (20.5±2.65 mm Hg vs 20.3±3.40, p=0.397) did not change, though mean VF pattern SD (1.58±0.41 dB vs 1.75±0.56 dB, p=0.001) and glaucoma conversion risk (7.31±3.74% vs 8.76±6.28%, p=0.001) increased at 1 year. Mean defect decreased (−1.42±1.60 vs −1.07 ±1.52, p=0.022). One eye (0.47%) developed a repeatable VF defect and 13 eyes (6.1%) had 5-year risk >15% at 1 year. The total 1-year cost of medications saved was US$4596. Conclusions Nearly half (43.9%) of low-risk OH eyes in this setting could safely reduce medications over 1 year, realising substantial savings.
INTRODUCTION
To cite: Chan PPM, Leung CKS, Chiu V, et al. Br J Ophthalmol Published Online First: [ please include Day Month Year] doi:10.1136/bjophthalmol2014-306014
Glaucoma is the leading cause of untreatable blindness worldwide.1 Elevated intraocular pressure (IOP) is a well-known risk factor for glaucoma, though the Ocular Hypertension Treatment Study (OHTS) demonstrated that only a small proportion of patients with untreated ocular hypertension (OH) will develop glaucoma over 5 years.2 Both OHTS3 and the European Glaucoma Prevention Study (EGPS)4 have identified risk factors that make conversion to glaucoma more likely among persons with OH. These factors include the following: older age, higher IOP, thinner central corneal thickness (CCT), larger vertical cup-to-disc ratio (vCDR) and a higher pattern SD (PSD) on visual field (VF) testing.
A risk calculator derived from prediction models using the combined data of OHTS and EGPS is available for estimating the 5-year glaucoma conversion risk.5 6 Cost-effectiveness analyses based on these risk models have suggested that treating patients with an annual glaucoma risk of ≥2% is appropriate from a societal perspective,7 while expert panels have suggested treating all patients with a 5-year risk of ≥15%.8 Existing equipment for monitoring the VF allows changes to be identified in patients who do experience glaucoma conversion before any detectable change has occurred in the vision, and available evidence suggests that the impact on quality of life (QOL) of early VF loss is quite modest.9 As with many other chronic diseases, treatment of OH, once initiated, can be life-long. The costs involved may be significant, and can be expected to rise as the population ages. In Hong Kong, for example, between 2001 and 2006, the annual cost for out-patient ophthalmic drugs, of which glaucoma medications are by far the largest part, rose by 265%, from HK$9.3 M to 34.0 M (US$ 1.19M–4.36M).10 The government-funded universal healthcare system in Hong Kong makes it relatively easy to estimate these costs, but clearly the amounts involved are far higher in larger populations, where increases with ageing are likely occurring as well. A study published in 2008 estimated that the total 5-year cost of medication treatment for glaucoma (including office visits) was US$6571 per patient in the USA,11 for a total cost which could exceed US$15 billion. Validated risk calculators for conversion to glaucoma among patients with OH5 6 offer an evidence-based approach to reduce the growing cost of glaucoma medications, particularly in settings such as Hong Kong where a single payer for medical care can set policies on drug coverage. Simulation studies have shown that access to risk calculators affects glaucoma clinical decisionmaking and reduces inconsistency between specialists.12 Nonetheless, to the best of our knowledge, no published studies have assessed the economic and medical consequence of applying risk calculators systematically to optimise the use of topical medication. The aims of this study are to: (1) estimate the proportion of patients with OH in a public eye clinic in Hong Kong that could undergo medication reduction based on a predetermined risk cut-off value for conversion to glaucoma; (2) assess the short-term (1 month) fluctuation in IOP
Chan PPM, et al. Br J Ophthalmol 2015;0:1–6. doi:10.1136/bjophthalmol-2014-306014
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd under licence.
1
Downloaded from http://bjo.bmj.com/ on April 10, 2015 - Published by group.bmj.com
Clinical science and calculated risk, and the medium-term (1 year) change in calculated risk and indices of VF damage after targeted cessation of medication; and (3) calculate the potential cost savings in this cohort.
METHODS This was a prospective, longitudinal study, the protocol for which was approved in full by the Institutional Review Board of the Chinese University of Hong Kong. Written informed consent was obtained from all subjects, and the tenets of the Declaration of Helsinki were followed throughout.
Patient enrolment and eligibility Medical records of patients followed in the general ophthalmology and glaucoma clinics in Hong Kong Eye Hospital during the period between November 2010 and October 2011 were reviewed systematically. One or both eyes of a subject could be enrolled, and eligibility and exclusion criteria were as follows: diagnosis with OH, IOP >21 mm Hg in ≥1 eye documented on ≥1 follow-up visit, receiving ≥1 IOP-lowering medication with no identifiable secondary cause for IOP elevation. Such patients were invited to attend a screening visit for further examination. After obtaining written informed consent, a full ophthalmic assessment was carried out by a fellowship-trained glaucoma specialist (PPMC), including measurement of visual acuity and IOP (Goldmann applanation tonometry), dark room gonioscopy, anterior segment slit-lamp biomicrosopy, and examination of the fundus and optic disc with dilation of the pupil. Eyes were excluded if the visual acuity was ≤6/12, the posterior trabecular meshwork could not be visualised for >180° or evidence of other ocular disease was present. Two IOP measurements were recorded for each eye. If the two readings differed by ≤2 mm Hg, then the mean was recorded as the IOP measurement, otherwise a third reading was performed and the median recorded.13 CCT was measured with ultrasound pachymetry (Pachette 500, DGH Technology, Frazer, Pennsylvania, USA), and the median readings recorded.14 Standard automated white-on-white perimetry (SITA Standard 24-2, Humphrey Field Analyzer, Carl Zeiss Meditec, Dublin, California, USA) was performed in both eyes, and the vCDR was assessed by optical coherence tomography imaging of the optic disc (Cirrus HD-OCT, Carl Zeiss Meditec). Only VFs with fixation losses, false-positive and false-negative errors ≤20% and OCT scans with signal strength ≥6 were accepted. Eyes with evidence of glaucomatous damage on VF (defined as a cluster of ≥3 non-edge points in the PSD plot in a single hemifield with a value of p 30 mm Hg. Patients were then followed every 3–4 months for monitoring of IOP and other routine care as needed for 1 year. IOP-lowering medication(s) were resumed if the IOP was >30 mm Hg. At the 1 year follow-up visit, subjects having discontinued ≥1 IOP-lowering medication underwent measurements of VF PSD, CCT, vertical CDR and IOP as mentioned above. The risk of glaucoma conversion was then calculated again based on these data. Any patients with suspicion of having developed a VF defect underwent repeated VF testing on three occasions as per the OHTS protocol.13
Statistical methods Analyses were performed using Microsoft Excel and SPSS for Windows V.15.0 (SPSS, Chicago Illinois, USA). Continuous variables were expressed as mean (±SD), categorical variables as individual counts and proportions. IOP, CCT, vCDR, median deviation (MD), PSD and 5-year risk of glaucoma conversion and average retinal nerve fibre layer (RNFL) thickness were compared between 1 month and 1 year after discontinuation of IOP-lowering medication with linear mixed modelling, to account for similarities between eyes of the same individual. Random intercepts were included at both the subject and eye levels (each eye nested within subject). The number of bottles of drops going unused as a result of the protocol-driven discontinuation in the study was calculated, assuming that one bottle of drops would be used each month, whether the patient was using the medication in one or both eyes. This reflects current prescription practice in the clinics where the study was carried out.
RESULTS A total of 9080 charts were reviewed and 328 (3.6%) patients with a chart diagnosis of OH receiving ≥1 IOP-lowering medication were identified. Among these, 208 (63.4%) patients were successfully contacted and agreed to participate in the screening examination. After excluding eyes with ocular disease or glaucomatous damage on VF or disc examination, 212 eyes of 126 (60.6%) patients with OH receiving ≥1 IOP-lowering medication were identified (figure 1). Among these, 44 eyes (20.8%) of 33 patients had 5-year conversion risk >15% and 14 eyes (6.6%) of 12 patients had unreliable baseline VF on repeated attempts, and were excluded per protocol. One or more medication was discontinued in each of the remaining 154 eyes (72.6%) at the time of the screening visit (figure 1). At 1 month follow-up, seven eyes (3.3%) of four patients had IOP >30 mm Hg, 11 eyes (5.2%) of 9 patients had recalculated risk >15%, and 19 patients (29 eyes, 13.7%) defaulted follow-up or refused to discontinue IOP-lowering medications. In total, 69 patients (107 eyes, 50.5%) discontinued ≥1 IOP-lowering medication for 1 year (figure 1). Among these, 14 eyes were pseudophakic at the time of enrolment and none underwent intraocular surgery during the 1 year follow-up. Table 1 shows demographic and clinical information for patients Chan PPM, et al. Br J Ophthalmol 2015;0:1–6. doi:10.1136/bjophthalmol-2014-306014
Downloaded from http://bjo.bmj.com/ on April 10, 2015 - Published by group.bmj.com
Clinical science Figure 1 Flow charts of patients’ recruitment and follow-up through the study.
successfully discontinuing medications, and those excluded at the baseline and 1-month examinations. All 69 patients (107 eyes, 100%) completed follow-up at 1 year. There was a statistically significant, though modest (10%) increase in IOP after 1 month of reducing medication (18.6±3.09 at baseline to 20.5±2.65 at 1 month; p15% at 1 year, though none of these developed VF defects. One eye did develop repeatable VF defects, although the calculated risk was only 6.43% at 1-year follow-up. IOP-lowering medication was reinstilled for this eye. Thus, 93 eyes (43.9%) discontinued medications over 1 year without excessive risk or harm (figure 1). A total of 910 bottles of 141 IOP-lowering medications (figure 3) went unused by participants over the course of the
Table 1 Baseline demographic and clinical information for patients included in and excluded from the study
Total number of eyes Females n (% of persons) Age (years) Visual acuity
