Age-related macular degeneration (AMD) is the leading cause of blindness in people aged 50 years and older in high-income counties.1–4 More than 60% of all blindness in Australia is caused in part or wholly by AMD.5,6 There have been major changes in the management of neovascular AMD (nAMD) over the last 2 decades. In Australia, the first advance occurred in June 2002, when verteporfin (Visudyne®) for photodynamic therapy (PDT) was listed by the Australian Pharmaceutical Benefits Scheme (PBS), a program by the Australian government that provides public funding for prescription medication dispensed to Australian citizens and permanent residents. Then the anti-vascular endothelial growth factor (anti-VEGF) intravitreal therapy (IVT) agents bevacizumab (Avastin) became available for off-label use in 2006, and ranibizumab (Lucentis®) and aflibercept (Eylea®) were listed on the PBS for treatment of AMD in August 2007 and December 2012, respectively. The Association for the Blind of Western Australia (ABWA), known as VisAbility from 2014, maintains the only state-wide register of blind individuals. Despite the ascertainment limitations of a registry, it can provide a unique perspective of changes in the number of AMD blindness registrations during the last two decades.
A temporal relationship has been reported between IVT and a decrease in blindness registration caused by nAMD.7–9 Bloch et al8 reported the incidence of blindness from AMD and other causes in those aged 50 years or over from 2000 to 2010 in Denmark. They found the incidence of blindness from AMD fell to half the baseline incidence and attributed the majority of this reduction to the introduction of anti-VEGF agents in 2006.8 Similarly, other population-based studies have found the prevalence and incidence of AMD have decreased over recent decades.10–11 A simulation study12 found ranibizumab can reduce the incidence of blindness by 72% in a white non-Hispanic United States population. Despite the temporal association with the introduction of IVT, Bloch et al8 could not exclude the possibility that other factors may have contributed to this reduction in blindness. To date, the impact of PDT and IVT usage on blindness incidence and age at registration has not been thoroughly investigated. Our study incorporates IVT and PDT treatment usage data to further assess temporal changes in the incidence of blindness registrations over three time periods. Since the 2 PBS listed anti-VEGF agents are predominantly publicly funded, it is essential to monitor changes in blindness registrations during the last two decades to determine the impact of their availability.
Pivotal studies have shown ranibizumab, aflibercept and bevacizumab improve visual acuity (VA) letter score when given at regular or variable dosing intervals in eyes with subfoveal nAMD.13–17 However, there remains a paucity of evidence on a population level regarding whether IVT reduces blindness. In this study, we investigated the annual age-standardized incidence of AMD-related newly registered blindness in Western Australia (WA) and its relationship to PDT and IVT usage from 1996 to 2016.
This was a retrospective, observational study of blindness registrations in a population aged 50 years and older residing in Western Australia from 1996 to 2016. Age-standardized rates of blindness were assessed by records from the ABWA/visibility Blind and Vision Impaired Registry, a private state-based organisation founded in 1977 that provides rehabilitation services for blind and visually impaired residents. The methodology was adapted from that described previously by Bloch et al.8
In WA ophthalmologists and optometrists have no formal obligation to ensure patients satisfying the criteria below are referred to or informed about the ABWA registry. Registrations, where AMD was listed as the only cause or as one of the several causes of blindness, were included. AMD cases were further subdivided into neovascular, atrophic or not otherwise specified. Registration was based on signed information from an ophthalmologist or optometrist including sex, age, best-corrected VA (BCVA), visual field span and an ocular diagnosis of the cause of visual impairment in each eye. BCVA in Snellen fraction was converted to logarithm of the minimum angle of resolution (logMAR) units. Blindness was defined as logMAR >1.0 (worse than 20/200) in the better-seeing eye or visual field constriction ≤ 20 degrees diameter with both eyes. All registrations were examined individually for correct primary diagnosis by one of the authors (FKC) and duplicates were removed. Three different registration forms were used by the ABWA registry throughout the study period (Supplementary Digital Content, Material 1, http://links.lww.com/APJO/A84). Demographic information about the Australian population was obtained from the Australian Bureau of Statistics (ABS).
The population at risk was defined as the number of persons aged 50 years or older living in WA on January 1 in a given year who were not already blind. The incidence of blindness due to AMD and other causes were calculated using age- and sex-specific denominators provided by the ABS and presented as the number of new registrations for blindness per 100,000 person-years. Rates were standardized by the direct standardization method using the 2011 Australian population to account for variations in age between areas. Counts for each new registration for blindness were calculated for each 5-year age bracket and separately for males and females. Multivariable Poisson regression analyses were used to determine changes in the age-standardized incidence of blindness related-AMD from 1996 to 2016. Changes in age at the time of certification and the proportion of male versus female were examined by grouping registrants from three time periods: 1996–2001 (pre-PDT), 2002–2007 (PDT era) and 2008–2016 (IVT era) for the AMD and other causes cohort. Multivariable linear regressions were performed to examine the effect of sex and time periods (pre-PDT, PDT era and IVT era) on age at blindness certification. An interaction term for age and sex was initially included in the regression but was excluded in the final model as it was not statistically significant. The frequency of PDT and IVT usage was plotted against time. Statistical analyses were performed using Strata 15 (StataCorp LLC, Queensland, Australia).
To assess the relationship between AMD treatment utilisation and incidence of blindness, we also extracted data from Medicare Services Australia (MSA) of all PDT and IVT procedures performed in Western Australia using the following Medicare Benefits Schedule (MBS) item numbers: 43005, 43008, 42875, 42881, 42884, 42887, 42990, 42991 and 43021 for PDT in one eye only; 43001, 43014, 42878, 42993, 42996, 42999, 43000 and 43022 for PDT in both eyes, and 42740 and 42738 for IVT.18 It is important to note that 42738 was introduced in 2012 to separate IVT performed as a standalone outpatient procedure from intraocular injections of expansile gas, silicone oil, heavy liquid, steroid or antibiotics in conjunction with vitrectomy or cataract surgery which remained coded as 42740. PDT using verteporfin (Visudyne®; QLT Pharmaceuticals, Vancouver, British Columbia, Canada) for subretinal neovascularisation was first approved by the Pharmaceutical Benefits Schedule (PBS) in Australia in June 2002. Bevacizumab (Avastin®; Roche) was first used off-label by retinal specialists in Australia in 2006. Ranibizumab (Lucentis®; Genentech, Inc) was first listed in the PBS in August 2007 whereas aflibercept (Eylea®; Regeneron Pharmaceuticals) was listed in December 2012 for use in nAMD (Supplementary Digital Content, Material 2, http://links.lww.com/APJO/A84). Implementation followed gradually and was subject to a PBS-listed indication, specifically subfoveal choroidal neovascularisation due to AMD.
This study was approved by the Human Ethics Office of Research Enterprise at The University of Western Australia (RA/4/1/7920).
Incidence of Registration for Blindness due to AMD and Other Causes
A total of 3060 registrations were issued for blindness over the 21-year period and 1828 (60%) were attributed to AMD (Table 1). There was a gradual increase in the count of blindness registration due to causes other than AMD while the count for AMD-related blindness increased significantly in 2003 before returning to a similar level by 2010 (Fig. 1). The percentage of blindness due to AMD in those aged 50 or older peaked at 77% in 2006 and declined at a slope of −2.3% per year to 41% by 2016 (Supplementary Digital Content, Material 3, http://links.lww.com/APJO/A84). The annual age-standardized rate of AMD-related blindness declined from 15.8 to 10.6 per 100,000 people in males and increased from 8.6 to 14.6 per 100,000 people in females between 1996 and 2001. This rate rose rapidly from 2002 to 2006, reaching a peak of 28.7 and 44.0 per 100,000 people in 2004 and 2006 in males and females, respectively. A steep decline in the rate occurred from 2007 to 2008, followed by a gradual decline from 2009 to 2016. The nadir in 2016 recorded 3.3 and 4.9 per 100,000 people in males and females, respectively. Overall, the registration rate declined by 16% (95% CI: 14% to 19%, P < 0.001) for females and 16% (95% CI: 13% to 19%, P < 0.001) for males from 2003 to 2016.
Table 1 -
Incidence of Blindness and Mean Age at Certification in Western Australian Residents Aged 50 or Over from Age-related Macular Degeneration and Other Causes (per 100,000 person-years)
||Population in Western Australia
||Age-related macular degeneration
||Other causes (age ≥ 50)
||Age ≥ 50
∗Age-standardized to the 2011 Australian population census using the direct standardization method, expressed in per 100,000 person-years.
Demographics at the Time of Registration for Blindness due to AMD and Other Causes
The age at registration was older for blindness due to AMD than other causes overall (84.5 vs 74.4 years) (P < 0.001), with an upward trend in the former and a downward trend in the latter (Fig. 2A). With the exceptions of 2014 to 2016 in males, there was a consistent increase in the mean age in both male and female AMD-related blindness (Fig. 2B). The average age of blindness certification was 1.2 years higher for females than males (P < 0.001) (Table 2). There was a statistically significant increase in the average blindness registration age post-2007 (IVT era) compared to pre-2007 (pre-PDT and PDT eras) in both males and females (P < 0.001). Females formed 64% and 53% of the blindness due to AMD and other causes, respectively (Supplementary Digital Content, Material 4, http://links.lww.com/APJO/A84).
Table 2 -
Average Age of Age-related Macular Blindness Across 3 Epochs of Treatment Availability by Sex
||Average age (SD)
||Average age (SD)
| (PDT era)
| (IVT era)
IVT, intravitreal therapy; PDT, photodynamic therapy; SD, standard deviation.
PDT and IVT Code Utilization in Western Australia
There was a significant rise in the use of PDT from 2002 to 2005, coinciding with the rapid rise in the incidence of blindness registration for AMD (Fig. 3A). From 2006, a sharp drop in PDT services was replaced by a sudden increase in the utilisation of the IVT code, which peaked in 2008 before a small dip in 2009. From 2009, the IVT item number usage increased consistently by 3745 per year (Fig. 3B). The relatively small numbers of item 42740 utilisation in the period 2013–2016 indicated that the contribution of intraocular injections of gas, oil, steroid or antibiotics in conjunction with another intraocular surgery (predominantly vitrectomy) was not the main reason for the significant increase in item 42740 during 2009–2012 (Fig. 3B). The PDT and IVT item number usage was shown in Supplementary Digital Content, Materials 5 and 6, respectively, http://links.lww.com/APJO/A84.
Over the 21-year period (1996–2016), we showed a rapid increase in the incidence of blindness due to AMD around the time that PDT became available. This was followed by a decline from 2007 onwards as PDT was replaced by IVT as the preferred treatment for nAMD. The age at which AMD blindness was certified increased over the two decades, predominantly during the period when the IVT item number utilisation increased.
Bloch et al8 conducted a national blindness registry survey of persons aged 50 years or older over an 11-year period (2000 to 2010) and demonstrated a gradual reduction in AMD blindness from 52.2 to 25.7 cases per 100,000 person-years. The most significant decline occurred in 2007, the year when ranibizumab was introduced.8 The incidence of blindness due to causes other than AMD also decreased from 17.6 to 11.7 cases per 100,000 person-years over the same period.8 We found a unique profile of AMD blindness incidence with a spike after 2002, the year that PDT was made available in Australia following the publication of the pivotal trials demonstrating limited benefit in those with predominantly classic choroidal neovascular membrane.19–21 This pattern was not observed by Bloch et al8 perhaps because PDT was made available in 1999 in Denmark, predating the 11-year span in their study. We hypothesise that the increase in AMD blindness registration observed in our study is due to an ascertainment bias from increased referrals for assessing the suitability of PDT. Optometrists and general practitioners’ increased recognition of PDT as a potential treatment for neovascular AMD may have increased their referral rate of AMD patients to retinal specialists for assessment. More encounters between patients with advanced AMD and ophthalmologists could have prompted more referrals for blindness registration during this period. Although the registration form used throughout the study period had changed, the basic diagnostic categories remained the same. In particular, AMD was listed as the first option for the main cause of blindness. Therefore, the changes in our registration form may not be related to the spike in AMD blindness registrations after 2002. We reported a reduction from 72.5 to 24.4 cases per 100,000 person-years between 2004 and 2010, which was similar to the rates reported by Bloch et al.8 In an Israeli population aged over 65 years of age, Skaat et al4 also found the incidence of blindness registrations from all types of AMD decreased over a 10-year period (1999 to 2008) from almost 6 to 3.5 cases per 100,000 person-years. Although similar downward trends were found by both these studies, neither demonstrated a significant change in the age at blindness registration or an association with IVT service utilisation within the same population. Interestingly, we showed an increase in blindness incidence due to non-AMD causes, which warrants further investigation.
Another important observation by Bloch et al8 was a trend for increasing age at blindness registration, from 80.0 years in 2002 to a maximum of 81.3 years in 2007, which did not reach statistical significance. In contrast, we demonstrated a statistically significant increase in the age at the time of AMD blindness registration from 82.7 to 85.0 years and 83.7 to 86.0 years in males and females, respectively, between the PDT and the IVT era. Although AMD is a disease process that begins with drusen formation in the 6th or 7th decade of life, vision loss tends not to occur until atrophy erodes into the foveal centre or active subfoveal choroidal neovascularisation occurs. Previous data from clinical trials show that the onset of active nAMD was predominantly between the ages of 65 to 85 years, with a mean of 75 years.17,19 In contrast, geographic atrophy trials tend to enrol patients at an older age, with a mean age of 78 years.22–24 The mean age of blindness registration in our cohort was 81 years in males and 83 years in females before 2002. This discrepancy with clinical trial data is expected, given the delay between the first and second eye involvement by late-stage disease (atrophy or neovascularization) may span several years, and trial cohorts tend to be biased toward younger patients with less frequent systemic diseases.25 Other potential explanations for the increasing age in blindness registration may include increased uptake of public health measures promoting healthier diets and regular exercise to improve cardiometabolic status26 as well as the increased accessibility to anti-oxidant supplements by patients with intermediate-stage AMD to prevent late-stage disease.27 It has been noted that the incidence and prevalence of AMD, and more specifically atrophic and neovascular complications of AMD, is higher in females than males in epidemiological studies28,29 and randomized trials.17,19 This was also observed in our study, with females accounting for 64% of the incident AMD-related blindness registration. Further studies are required to examine whether the slight downward trend in the age of certification in males continues beyond 2016 as there is no apparent reason for this deviation from the prevailing trend (Fig. 2B).
Our PDT and IVT service utilisation data provided insight into the clinical uptake of approved nAMD treatment in the sampled population. We showed the expected increase in PDT usage from 2002 and a sudden drop in 2006 when bevacizumab became available for off-label use. The spike in IVT usage in 2007–2008 is unlikely to be solely related to anti-VEGF therapy as this coincided with the short-term widespread misuse of the IVT code for intracameral injection of prophylactic antibiotics following cataract surgery.30 Jorstad et al31 described a trend of IVT use over 13 years (2006–2018) by comparing the number of unique patients treated per year. They reported the number of annual IVT injections increased 100-fold from 228 to 25,570 over the same period. We found a similar trend over a 13-year period (2004–2016), with the use of IVT increasing from 474 to 31,040, a 65-fold increase. This increase in IVT service delivery may be explained by the expanding list of approved indications for IVT (Supplementary Digital Content, Material 2, http://links.lww.com/APJO/A84) as well as the more intense and prolonged treatment course advised. The latter may explain the continued decline in AMD blindness incidence from 2004 to 2016. Johnston et al32 studied the incidence of blindness in treatment-naïve patients receiving ranibizumab for nAMD in the United Kingdom over a 5-year period. They used prospective VA data collected as per routine care within an electronic medical record system at multiple sites to measure the real-world incidence of blindness. The incidence of blindness was 5.1% and 15.6% at 1 and 4 years, respectively, and this was shown to decrease during the study period, indicating prevention of blindness from IVT. However, their methodology could not generate the incidence of blindness on a population level given the lack of a precise denominator. Campbell et al7 compared the prevalence of blindness in 84 patients from 2002 (before IVT was available) to 41 patients from 2008 (after IVT accepted as standard treatment). They found 29% of patients were blind after 24 months of follow-up from the 2002 cohort compared to only 2% in the 2008 cohort. The simultaneous reduction in incident blindness due to AMD after 2006 and the initial increase in IVT in 2006 suggest an association, even if not causal.
This study assessed a well-defined, clinically meaningful endpoint in a large Australian population where a uniform treatment strategy for nAMD was made available. Registration of blindness, however, is a lagging indicator, reflecting both treated and untreated cases after the introduction of anti-VEGF IVT in 2006. Our study was limited by its retrospective design, different registration forms used during the study period and the absence of a state-wide compulsory registration program for visual impairment and blindness. Underreporting of blindness may have been a confounding factor, as demonstrated by a previous capture-recapture validation study where only 40% of those who were legally blind were registered by ABWA in 2008–2009.5 Clinician referral patterns and patient preferences to participate in the registry may have changed during the study period. Furthermore, the incidence of blindness may have been underestimated given the incomplete capture of blindness registrations. Some cases had multiple diagnoses listed as the cause of their vision loss and it was not always obvious which one was the main contributor to blindness. The majority of AMD blindness cases were thought to be registered by the ABWA as they were under active surveillance by ophthalmologists and received financial and transportation benefits once registered as legally blind.
In this study, we investigated the annual age-standardized incidence of AMD-related newly registered blindness in Western Australia over a 21-year period and its relationship to PDT and IVT usage. The percentage of reported blindness due to AMD in those aged 50 or older peaked at 77% in 2006 and declined to 41% by 2016 but the association between the introduction of IVT and this decline does not provide conclusive evidence of the effectiveness of these therapies given limitations of registry data. An understanding of IVT usage and its effect on public health resources such as the incidence of blindness registrations is important to better allocate financial resources for further improvement. The results of this study have implications for future health policy.
The authors thank Ms Julie Crewe and Mr James Semmens for their input into study design at the outset of the study, and Drs Wilson Heriot, Alex P. Hunyor and Jennifer Arnold for their assistance with finding the old MBS codes for photodynamic therapy.
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