Age-related macular degeneration (AMD) is one of the leading causes of blindness in the elderly populations around the world. The stages of AMD are categorized as early, in which visual symptoms are inconspicuous, intermediate, in which the vision deterioration is beginning and late, in which severe loss of vision is usual. Late stage AMD, also known as wet AMD is a cause for poor visual function, anxiety, depression, falls, and impaired activities of daily living. Research suggests that anti-oxidant vitamins could be useful in treating patients with AMD.
A large randomized controlled clinical trial conducted by the age-related eye disease study (AREDS) Research Group showed that provision of high-dose anti-oxidant vitamins and zinc (hereafter known as AREDS formulation) to certain AMD patients (category 3 - extensive intermediate drusen, geographic atrophy not involving the center of the macula, or at least one large druse or category 4 - advanced AMD or visual acuity less than 20/32 due to AMD in eye) was clinically effective in preventing the progression to wet AMD. A recent report on the long-term follow-up of the patients in the AREDS clinical trial also showed a decreased risk of developing wet AMD following the long-term use of AREDS formulation, results being consistent with their previous findings. Another study looking at lutein and anti-oxidant vitamins to treat atrophic AMD showed that lutein alone or lutein plus anti-oxidant vitamins was effective in improving the visual function of atrophic AMD patients.
In addition to being clinically effective, studies have shown that the AREDS formulation is cost-effective in preventing the progression to late stage AMD. However, both these studies were conducted in Caucasian population.
Singapore has a rapidly aging population with over 9% of the resident population being aged 65 years or above in 2012. By the year 2030, it is estimated that one in five resident Singaporeans will be aged 65 years or above. As a result of this rapid aging, the burden of ocular morbidity and visual disability due to age-related eye disorders in Singapore is set to increase. This study aims to determine if providing AREDS formulation to category 3 or 4 AMD patients aged 40–79 years from Singapore is cost-effective in preventing progression to Wet AMD. Being the first cost-effectiveness analysis (CEA) for anti-oxidant vitamin therapy for AMD in Singapore, this study can be used to provide cost-effectiveness information to inform ophthalmic practice for patients diagnosed with category 3 or 4 AMD.
From the 2012 Singapore population trends report, the number of resident Singaporeans aged 40–79 years was obtained (1.72M people), and the proportion of AMD cases was estimated using the age and ethnicity-specific prevalence estimates from a local study conducted by Cheung et al. From this total number of estimated AMD cases, the number of category 3 and 4 AMD patients was estimated using proportions from the AREDS report. This hypothetical cohort of category 3 and 4 AMD patients (n = 66,709) was followed for 5 years to determine the number of patients progressing to wet AMD. Crude annual mortality rate of 4.5/1000 Singaporeans was included in the model. Progression rates for patients receiving AREDS formulation or placebo were taken from the AREDS report (5 years progressing rate was 20% and 28% for vitamins vs. placebo respectively for category 3 and 4 patients). Patients who had progressed to wet AMD were either treated with ranibizumab (on a PRN basis), bevacizumab (monthly) as per CATT study protocol, or aflibercept (treatment regimen as per the VIEW I and VIEW II trials). The average number of ranibizumab injections was taken from the CATT 1 and 2 years trials as well as the HORIZON trial for treatment after the initial 2 years follow-up period. The treatment regimen for aflibercept was taken from the VIEW I and VIEW II trials. We acknowledge that bevacizumab is an off-label treatment for wet AMD but has found widespread use across the world for this indication and has hence been included in this study for analysis. Only one eye for the patients was assumed to be affected with AMD.
Six treatment scenarios were considered, as follows:
- AREDS formulation followed by ranibizumab (as needed) for wet AMD
- Placebo followed by ranibizumab (as needed) for wet AMD
- AREDS formulation followed by bevacizumab (monthly) for wet AMD
- Placebo followed by bevacizumab (monthly) for wet AMD
- AREDS formulation followed by aflibercept (VIEW I and VIEW II treatment protocol)
- Placebo followed by aflibercept (VIEW I and VIEW II treatment protocol).
Detailed information on cost for AREDS formulation (for category 3 and 4 AMD patients), ranibizumab, bevacizumab, aflibercept, injection procedure cost, consultation costs, and diagnostics costs (for wet AMD) were obtained from Tan Tock Seng Hospital Eye Centre and the National Healthcare Group Pharmacy Department.
Cost-effectiveness of AREDS formulation was estimated by computing the cost per disability-adjusted life year (DALY) averted for the 5 years study period. DALY is calculated as the sum of the years of life lost due to disability (YLD) and the years of life lost (YLL) due to premature death (DALY = YLD + YLL). The DALY scale ranges from 0 (perfect health) to 1 (dead).
Years of life lost due to disability = disability weight associated with wet AMD X number of people with wet AMD X number of years lived with wet AMD during the course of the 5 years study period.
The disability weight associated with wet AMD was 0.22/year of life lived with wet AMD for patients within our study age group.
Years of life lost = reduced life expectancy due to mortality attributed to the disease (legal blindness due to wet AMD).
Since no local data were available for the life expectancy of wet AMD patients, we assumed that patients with wet AMD dying during the 5 years study period had negligible loss of life due to premature death associated with wet AMD-related causes like vision loss. We do acknowledge that in reality, this might not be the case.
Although utility values for AMD in Singapore were available from a publication, the authors had concluded that these health status utilities may not be sufficiently robust for healthcare economic analyses. In addition, applying utility values from other studies conducted in Caucasian populations might not accurately represent the disease burden to the society in Singapore. Hence, we opted to use the “cost per DALY averted” measure to determine cost-effectiveness rather than the utility value based “cost per Quality Adjusted Life Year (QALY) saved.” The analysis was carried out from the providers’ perspective, and all costs were presented in Singapore dollars (1 SGD ≈ 0.80 USD as on September 2014). The costs were discounted at an annual rate of 3%.
Our CEA model had several assumptions; there was no dropout of patients for the 5 years of follow-up although mortality was incorporated into the model; patients were fully compliant with prescribed treatment; proportion of category 3 and 4 AMD patients and progression rates were similar to the reported proportions from the AREDS report; treatment for wet AMD with ranibizumab was similar to that reported in the CATT 1 and 2 years study as well as the HORIZON study for post-2 years follow-up and treatment with aflibercept was similar to the regimen in the VIEW I and II trials; and finally, cost of consultation, treatment and diagnostic investigations did not change during the 5 years of follow-up. As this is a simulation study, no Institutional Review Board approval was needed.
Sensitivity analysis was performed to assess the robustness of the CEA model. The progression rates (based on treatment with AREDS formulation vs. placebo) for the hypothetical cohort of category 3 and 4 AMD patients were varied by constructing confidence intervals (CIs) for the point estimate progression rates that were obtained from the AREDS study. Based on the lower and upper limits of the CI for the progression rates, the CEA model was re-analyzed for the six treatment scenarios mentioned above and cost per DALY averted was calculated for the same.
Using Singapore resident population information for 2012 and recently published AMD prevalence estimates, the estimated number of AMD patients aged 40–79 years was 123,537 and the corresponding number of category 3 and 4 AMD patients was 66,709 [Table 1]. This hypothetical cohort of 66,709 patients was followed for 5 years, and progression to wet AMD was estimated. The input parameters for the progression model are shown in Table 2. Cumulatively, 5493 patients could have been prevented from progressing to wet AMD over 5 years, had AREDS formulation been prescribed. Details of the progression model are available in Appendix 1.
Disability-adjusted life years were computed for patients receiving AREDS formulation versus placebo [Table 3]. The cost for treatment and the corresponding DALYs accumulated over the follow-up period for the six treatment options was presented [Fig. 1]. The number of DALYs averted as a result of prescribing AREDS formulation was 2734.3 over 5 years. The cost per DALY averted as a result of prescribing AREDS formulation was $23,662.3 and $21,138.8 for the ranibizumab and aflibercept arms, respectively [Table 4]. However, bevacizumab (monthly 1 injection) alone was more cost-effective when compared to the AREDS formulation bevacizumab combination.
By varying the progression rates (using constructed 95% CI of the progression rates from AREDS), the number of DALYs averted ranged from 2055.6 to 3436.6 if AREDS formulation was prescribed [Table 3]. Cost per DALY averted ranged from $2432.3 to $24,209.9 if ranibizumab was prescribed for wet AMD [Table 5]. However, cost-effectiveness of AREDS formulation followed by bevacizumab or aflibercept (for wet AMD) was inconclusive after sensitivity analysis was conducted [Table 5].
The World Health Organization (WHO) guidelines for cost-effectiveness state that an intervention is considered “extremely cost-effective” if the cost-effectiveness ratio is less than the per-capita gross domestic product (GDP) of the country. The GDP per-capita for Singapore in the year 2012 was USD$51,709 (SGD ≈: $65,454,4). Our study shows that prescribing AREDS formulation to category 3 and 4 AMD patients is extremely cost-effective in preventing progression to wet AMD for Singaporean patients.
With an aging population, the number of AMD cases in Singapore is going to increase with time. The burden of AMD on the society is tremendous. Brown et al. showed that mild AMD caused a 17% decrease in the quality of life of the average patient, which is similar to that encountered with moderate cardiac angina or symptomatic human immunodeficiency virus syndrome; Moderate AMD caused a 32% decrease in the average patient's quality of life, comparable to severe cardiac angina or a fractured hip. Severe AMD caused a 53% decrease in quality, which is more than that of renal hemodialysis. Very severe AMD caused a 60% decrease in the average AMD patient's quality of life, similar to that encountered with end-stage prostate cancer or a catastrophic stroke.
The economic burden of AMD is also high. A study conducted by Rein et al. in the US showed that the direct medical cost for treating AMD in patients 40 years and older was $575 million for calendar year 2004. Another study conducted by Garattini et al. in Italy found the direct cost to the hospital's ophthalmology department to be, on average, € 383 (~509 USD) per AMD patient per year, with cost being the highest for patients with wet AMD. Thus preventing progression to wet AMD will not only benefit the patient in terms of quality of life, but also the healthcare provider by reducing the direct costs associated with wet AMD.
To date, two studies reported the cost-effectiveness of anti-oxidant vitamins in preventing the progression to wet AMD. Hopley conducted an economic evaluation of screening for early AMD followed by prophylactic treatment with vitamins for patients who were diagnosed with the disease. This study showed that the cost per QALY gained was £ 22,700 (~35,185 USD). Another study conducted by Rein et al. showed that the cost per QALY gained for anti-oxidant treatment versus no treatment was USD$21,387. Based on the accepted threshold value for the “willingness to pay” to gain a QALY, both studies concluded that it was cost-effective to prescribe anti-oxidant vitamins to early AMD patients.
In our study, we used the cost per DALY averted measure to determine cost-effectiveness. Although utility values associated with AMD were available in the local setting, the authors concluded that they were not suitable to be used for health economic evaluations. Hence, we used reported disability weights to compute the number of DALYs for patients receiving ARED formulation versus placebo. The accepted threshold for cost-effectiveness set by the WHO is 1–3 times the GDP per-capita. Our results fall well within the WHO stated range, suggesting it is cost-effective to prescribe anti-oxidant vitamins and zinc to category 3 and 4 AMD patients from Singapore.
In our study, we noted that AREDS formulation followed by ranibizumab was cost-effective compared to placebo-ranibizumab while the reverse was true for bevacizumab. The reason for this is the high-cost difference between the two drugs (almost 1/5th of the price assuming no dose titrations are done). However, sensitivity analysis showed that the results for bevacizumab were inconclusive. A meta-analysis and systematic review conducted by Schmucker et al. showed that bevacizumab was associated with an increased risk of ocular and multiple systemic adverse events compared to ranibizumab for the treatment of wet AMD. The CATT trial showed a statistically significant higher rate of gastrointestinal adverse events for bevacizumab treated patients compared to ranibizumab treated patients. Although there are significant cost differences between bevacizumab and ranibizumab, this may perhaps be mitigated if adverse event rates for the different drugs are taken into consideration. This would be hampered, however, by a paucity of data regarding the comparative safety of anti-vascular endothelial growth factor (VEGF) treatments currently.
We acknowledge that our study suffers from several limitations. First, since no progression rates were available for Singaporean patients, we applied rates from the AREDS report to the local Singaporean context. However, in order to test our model assumptions, we did conduct a sensitivity analysis by varying the progression rates based on treatment with AREDS formulation versus placebo. Second, our model accounted for only the prevalent cases of AMD and not the incident cases as no local incidence data were available. Third, we assumed that compliance to treatment for anti-oxidant vitamins as well as anti-VEGF treatment was 100%. This might not be the case in the real world scenario. The disability weight associated with wet AMD was not available from local literature and hence we used the weight of 0.22, obtained from a foreign study, to compute the YLD in the DALY calculation.
A study conducted by Bandello et al. suggested that on average, 2 years of life are lost due to premature death associated with consequences of developing wet AMD. As ours was a hypothetical cohort study, we had no way to estimate the YLL in our study population. Had we assumed that all cases of wet AMD dying during the study period died due to wet AMD-related causes, and that on average each patient that had died had lost 2 years of life due to premature death (maximum possible YLL for our cohort), our CEA results would still hold true. In reality, the YLL would lie between 0 and this maximum number, but as no local data are available at this point in time, we assumed YLL to be zero. Nevertheless, any value of YLL for our study period, lying between 0 and the maximum, based on Bandello et al.’s estimate mentioned above, would not have impacted our CEA results (data not shown).
Our study provides evidence of the effectiveness of AREDS formulation for patients with intermediate AMD. These results will help physicians make an informed decision on the treatment options for intermediate and wet AMD in Singapore. This study forms the basis for an in-depth analysis of AREDS treatment for prophylaxis use among a cohort of patients in the real world setting.
Prophylactic treatment with AREDS formulation for category 3 and 4 AMD patients from Singapore is cost-effective in preventing progression to wet AMD. AREDS formulation followed by ranibizumab was cost-effective compared to placebo-ranibizumab while the sensitivity analysis suggested no difference between AREDS-bevacizumab/aflibercept and placebo-bevacizumab/aflibercept. These findings have implications for intermediate AMD treatment and healthcare planning in Singapore.
The authors would like to thank Mr. Kelvin Teo Wee Sheng, Health Economist at National Healthcare Group, Department of Health Services and Outcomes Research for his inputs on the cost-effectiveness model.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
Brief description of Cognitive rehabilitation package of attention, concentration (Seven-level Model of Attention Training, Parente and Anderson-Parente 1991) and memory
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