Abstract
Importance
Exudative age-related macular degeneration (AMD) is the major cause of blindness among U.S. elderly. Developing effective therapies for this disease has been difficult.
Objective
This study assessed the impacts of introducing new therapies for treating exudative AMD on vision of the affected population and other outcomes among newly diagnosed Medicare beneficiaries.
Design
The study used data from a 5% sample of Medicare claims and enrollment data with a combination of a regression continuity design and propensity score matching (PSM) to assess the impacts on introduction/receipt of new technologies on study outcomes during a two-year follow-up period.
Setting
The analysis was based on longitudinal data for the U.S., 1994–2011, for Medicare beneficiaries with fee-for-service coverage.
Participants
The sample was limited to beneficiaries aged 68+ newly diagnosed with exudative AMD as indicated by beneficiaries having no claims with this diagnosis in a three-year look-back period.
Exposures
The comparisons with vision outcomes were after versus before introduction of photodynamic therapy (PDT) and anti-VEGF therapy. The comparisons for depression and long-term care facility admission were between beneficiaries newly diagnosed with exudative AMD who received PDT or anti-VEGF therapy compared to beneficiaries with the diagnosis receiving no therapy for this disease.
Main Outcome and Measure
Onset of decrease in vision, vision loss or blindness, depression, and admission to long term care facilities.
Results
Introduction of anti-VEGF therapy reduced vision loss and onset of severe vision loss and blindness of beneficiaries newly diagnosed with exudative AMD by 43% [0.50 0.66] on average. Such beneficiaries who received anti-VEGF therapy and were not admitted to a long-term care facility during the look-back period were 19% less likely on average to be admitted to a long-term care facility during follow-up.
Conclusions and Relevance
This study demonstrates gains in population vision from the introduction of anti-VEGF therapy for patients with an exudative AMD diagnosis aged 68+ in community-based settings in the U.S.
Age-related macular degeneration (AMD) is a common cause of legal blindness worldwide.1 The prevalence of exudative AMD is much lower than non-exudative AMD, but it tends to lead to worse vision outcomes.2,3 Although common and a major threat to visual health of the elderly, finding effective therapies for exudative AMD has been a lengthy process. Starting in the 1980s, argon laser photocoagulation therapy was the main treatment option for exudative AMD. 4–6 In 2000, the U.S. Food and Drug Administration (FDA) approved photodynamic therapy (PDT)7 for treating subfoveal choroidal neovascularization. About half a decade later, intravitreal corticosteroids8,9 became another treatment option, but because of its adverse side effects profile, and questionable effectiveness, it never diffused widely as a treatment for exudative AMD.10,11 Vascular endothelial growth factor inhibitors (anti-VEGFs) were first introduced in 2004,12,13 with the approval of pegaptanib (Mucagen) by the FDA. However, it was not until the introduction of ranibizumab (Lucentis) and bevacizumab (Avastin) in 2006 that the use of anti-VEGF agents gained popularity. Today anti-VEGF therapy has diffused to the point of being the treatment of choice for exudative AMD.14
Results of randomized clinical trials indicate that anti-VEGF agents improve the clinical course for many patients15 at a substantial cost to Medicare. However, to date, only one study based on Danish data has evaluated the impact of this innovation on visual health on a population level.16,17
The effect of a new technology on population health depends on several factors including: how frequently and competently it is used; the extent to which the technology is applied to patients for whom a change in clinical course can be expected; and the adherence of patients to treatment regimens. Even an effective technology will fail to provide a notable impact on population health if it is not applied widely and appropriately.
This study used a regression discontinuity design18 to assess the effects on vision of introducing two technologies for exudative AMD: photodynamic and anti-VEGF therapy. The study also analyzed incidence of depression and entry into a long-term facility following receipt of anti-VEGF therapies.
METHODS
Data
We used data for 1991–2011 from a randomly selected 5% sample of Medicare beneficiaries. Enrollment information and Medicare claims filed on behalf of beneficiaries were available for the entire sample allowing for longitudinal tracking. Claims data included information on diagnoses (International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM)), procedures (Current Procedural Terminology (CPT-4), Healthcare Common Procedure Coding System (HCPCS)), Center for Medicare and Medicaid Service (CMS) provider specialty codes, and dates and place of service codes. Enrollment data included an indicator for enrollment in a Medicare Advantage (MA) plan. Also included were data on gender, race and ethnicity, dates of birth and death, the latter if the beneficiary died during the observational period. Use of restricted Medicare claims data was approved by the Duke University Institutional Review Board.
Sample Selection
We selected beneficiaries with claims indicating a first diagnosis of exudative AMD (Table 1). To allow for a three-year look-back and two-year follow-up period, we excluded all beneficiaries under the age of 68 at the time of their first diagnosis and those with less than two years of data after the date of first diagnosis. We also excluded beneficiaries who were not continuously enrolled during the look-back and follow-up periods due to death, living outside the United States, or enrollment in a Medicare Advantage (MA) plan. MA plan enrollees were excluded because Medicare 5% claims are not available on these beneficiaries.
Table 1.
List of Condition Codes
| Condition | ICD-9/CPT-4/Service Code |
|---|---|
| Exudative ARMD | 362.52 |
| Moderate Vision Loss | 369.6x 369.7x 369.8x 369.9x |
| Severe Vision Loss | 369.1x 369.2x 369.3x 369.4x |
| Blindness | 369.0x |
| Argon Laser Photocoagulation | primary diagnosis 362.52 with 67210 67220 67228 |
| Photodynamic therapy | primary diagnosis 362.52 with 67221 (year 2000 only) or 67299 (all years) |
| Anti-VEGF therapy | 67028 with J2503 C9128 J3490 J9035 J3590 C9399 J2778 Q2024 |
| Corticosteroid therapy | 67028 with J1870 J1880 J3300 J3301 |
| Diabetes Mellitus | 250.xx |
| Diabetic Retinopathy | 362.01 362.02 |
| Glaucoma | 365.0x-365.5x 365.60 365.61 365.62 365.64 365.65 365.8x 365.9x |
| Cataract | 366.xx |
| Other Eye Diseases | |
| diabetic macular edema | 362.07 |
| cystoid macular degeneration/edema | 362.53 |
| histoplasmosis retinitis | 115.92 |
| progressive high myopia | 360.21 |
| retinal neovascularization | 362.16 |
| retinal edema | 362.83 |
| angioid streaks of the choroid | 363.43 |
| rubeosis iridis | 364.42 |
| glaucoma associated with vascular disorders | 365.63 |
| retinal vascular occlusion | 362.3x |
| chorioretinitis due to toxoplasmosis | 130.2x |
| Depression | 296.0x 296.8x 296.9x 300.xx |
| Long Term Care Facility | 31 32 33 |
Analysis of Introduction of Photodynamic Therapy and Anti-VEGF Therapy on Vision
For analysis of visual outcomes, we divided sampled beneficiaries into three groups: (1) beneficiaries first diagnosed with exudative AMD between 1995 and 1998--the argon-laser photocoagulation therapy (ALPT) group; (2) beneficiaries first diagnosed 2000–3--the photodynamic therapy (PDT) group; and beneficiaries first diagnosed 2005–8--the anti-VEGF group. Although early anti-VEGF agents were initially available in 2004, it was not until 2006 that the therapy first gained popularity.19 Furthermore, Mucagen, the main anti-VEGF agent used in 2004–5 was not as effective as the drugs that became available in 2006. Thus, we considered 2006 as the first anti-VEGF treatment year Since corticosteroids came into use at about the same time as anti-VEGF therapies were first introduced, our analysis could not distinguish between the introduction dates for two innovations, although corticosteroids were much less commonly used than PDT and anti-VEGF therapies were.14 For this reason, changes in vision at the population level after introduction of anti-VEGF therapies are attributable to introduction of this technology rather than to use of corticosteroids.
Outcomes, defined from diagnostic information in claims data for the first two years following exudative AMD diagnosis, were: (1) decline in vision; and (2) onset of severe vision loss or blindness. Decline in vision was a decline from normal to moderate, moderate to severe, or severe to blindness. Moderate vision loss was identified by ICD-9-CM codes for profound impairment in one eye, moderate or severe impairment in one eye, unqualified visual loss in one eye, and unspecified visual loss (Table 1). Severe vision loss was identified from codes for moderate or severe impairment in the better eye with profound impairment in the worse eye, moderate or severe impairment in both eyes, unqualified visual loss in both eyes, and legal blindness as defined in the U.S. Blindness was defined as profound impairment in both eyes.
To assure that patient mix on observed factors were comparable for the periods before and after the new therapy was introduced, we used propensity score matching (PSM)20 based on the following covariates: age; gender; black race; Hispanic ethnicity; Charlson comorbidity index,21 diagnosis of diabetes mellitus, diabetic retinopathy, glaucoma without vascular disorders, cataract, and other eye diseases. All conditions were identified from claims filed in a three-year look-back period prior to the date of first exudative AMD diagnosis.
Beneficiaries who could not be matched using PSM were dropped, yielding final matched samples of 34,386 for the PDT vision decrease analysis and 31,746 for the PDT severe vision loss and blindness analysis. For the anti-VEGF analysis, the sample sizes were 38,769 and 35,726, respectively. Treatment and control groups were considered to be well-matched if the standardized difference was < 10%.22–25
The regression discontinuity method is designed to overcome the statistical problem of endogeneity of an explanatory variable in observational data, in this context a therapeutic intervention. Endogeneity mainly arises in this context because there is insufficient information about clinical attributes in the claims data that are observable to the provider but not reported by the provider on claims. As a consequence, persons receiving the technology may appear to have worse outcomes. With the regression discontinuity method, the focus is on all persons with the diagnosis rather than the subset of patients receiving the particular treatment for that diagnosis. Thus, the problem of unobserved clinical attributes of patients selected for treatment does not arise.
For each treatment-control group sample, we regressed outcome measures on a binary variable for the treatment and the same covariates used for matching. The parameter estimate on the binary explanatory variable for treatment indicated the effect of introduction of a new technology on a vision outcome. This parameter estimate corresponds to the average treatment effect on the treated (ATT) in PSM.
Analysis of New Technologies for Exudative AMD Treatment on Depression and Admission to Long-Term Care Facilities
Incident depression was based on whether or not there was a primary diagnosis of depression during a two-year follow-up among beneficiaries with no diagnosis of depression on a claim during the three-year look-back period. The dependent variable for incident long-term care facility use was based on Medicare place of service codes for skilled nursing facility (U.S. Centers for Medicare and Medicaid place of service code 31), nursing facility (32), and custodial care facility (33) recorded on a claim during follow-up, again, conditional on the beneficiary having no such claim during the look-back period.
Many other factors contribute to population level effects on depression and long-term care facility use than just the introduction of a new therapeutic technology, which made regression discontinuity unsuitable for these outcomes. Since unobserved attributes of the eye are less likely to be determinants of depression and long-term care facility use endogeneity was not as major a concern. Hence, beneficiaries in the depression and long-term care facility analysis samples were defined as treated if they received a particular therapy within one year of first exudative AMD diagnosis and control if they received no therapy. We excluded beneficiaries who received more than one type of therapy for AMD during the two-year follow-up period from the treatment group. Beneficiaries receiving ALPT or corticosteroid therapy were excluded from the treatment and control groups.
Sample sizes for the analysis of onset of depression and entry into a long-term care facility were substantially smaller than those for vision since the former was limited to the subset of sampled beneficiaries actually receiving PDT or anti-VEGF therapies. There were no statistically significant results for receipt of PDT in either the depression or the admission to long-term facility analyses. Hence, the results are not shown below.
RESULTS
Analysis of Vision Decrease and Onset of Severe Vision Loss or Blindness
Even before propensity score matching, the PDT and ALPT groups (Panel A, Table 2) and the anti-VEGF and the PDT groups (Panel B) used in the analysis of vision decrease were quite similar at first AMD diagnosis with a few exceptions. The exceptions were the proportions of sample with a diabetes mellitus diagnosis (Panel A) and age and proportions with diabetes mellitus and cataract diagnoses (Panel B). Sample proportions with diabetes mellitus are higher in Panel B than in Panel A, reflecting a positive secular trend in diabetes prevalence. The mean age was about 80, roughly two-thirds of sample persons were female, 2% were black, and 1% were Hispanic. After matching, all standardized differences were well under the 10% threshold for a satisfactory match in PSM. Sample characteristics for the analysis of onset of severe vision loss/blindness were very similar to the decrease in vision analysis sample and are not shown.
Table 2.
Decrease in vision: sample characteristics before and after propensity score matching
| Panel A: Photodynamic therapy |
|||||||||
|---|---|---|---|---|---|---|---|---|---|
| Before Matching |
After Matching |
||||||||
| Covariate | Photodynamic therapy (treatment) |
Argon-laser photocoagulation (control) |
Standardized difference |
Photodynamic Therapy (treatment) |
Argon-laser photocoagulation (control) |
Standardized difference |
|||
| Age | 80.01 | 79.58 | 6.62 | 79.70 | 79.60 | 1.62 | |||
| Male | 0.34 | 0.34 | 0.04 | 0.34 | 0.34 | −0.55 | |||
| Black | 0.02 | 0.02 | −3.74 | 0.02 | 0.02 | −0.71 | |||
| Hispanic | 0.01 | 0.01 | 2.00 | 0.01 | 0.01 | −0.46 | |||
| Charlson | 2.22 | 2.04 | 8.68 | 2.02 | 2.04 | −0.98 | |||
| Diabetes mellitus | 0.25 | 0.21 | 11.05 | 0.20 | 0.21 | −0.33 | |||
| Diabetic retinopathy | 0.06 | 0.04 | 4.80 | 0.04 | 0.05 | −0.92 | |||
| Glaucoma | 0.24 | 0.22 | 4.73 | 0.22 | 0.22 | −0.17 | |||
| Cataract | 0.69 | 0.69 | 0.56 | 0.70 | 0.69 | 1.48 | |||
| Other eye complications | 0.21 | 0.20 | 4.42 | 0.19 | 0.20 | −0.91 | |||
| N = 34,386 | N = 31,746 | ||||||||
|
Panel B: Anti-VEGF therapy |
|||||||||
|
Before Matching |
After Matching |
||||||||
| Covariate |
Anti-VEGF therapy (treatment) |
Photodynamic therapy (control) |
Standardized difference |
Anti-VEGF therapy (treatment) |
Photodynamic therapy (control) |
Standardized difference |
|||
| Age | 80.86 | 80.08 | 11.78 | 80.38 | 80.28 | 1.54 | |||
| Male | 0.33 | 0.34 | −2.39 | 0.34 | 0.34 | 0.21 | |||
| Black | 0.02 | 0.02 | 0.49 | 0.02 | 0.02 | 0.34 | |||
| Hispanic | 0.01 | 0.01 | 4.77 | 0.01 | 0.01 | −1.25 | |||
| Charlson | 2.14 | 2.26 | −5.78 | 2.18 | 2.20 | −0.96 | |||
| Diabetes mellitus | 0.32 | 0.26 | 12.42 | 0.28 | 0.27 | 2.23 | |||
| Diabetic retinopathy | 0.07 | 0.06 | 4.32 | 0.06 | 0.06 | −0.65 | |||
| Glaucoma | 0.27 | 0.24 | 7.90 | 0.26 | 0.24 | 2.83 | |||
| Cataract | 0.63 | 0.68 | −10.35 | 0.67 | 0.67 | −0.52 | |||
| Other eye complications | 0.20 | 0.21 | −1.13 | 0.20 | 0.20 | −0.60 | |||
| N = 38,769 | N = 35,726 | ||||||||
In the PDT sample, 2.95% of beneficiaries experienced decreased vision as documented in the claims data in the two years following a first exudative AMD diagnosis (Table 3). The corresponding percentage in the anti-VEGF sample was 2.74%. Judging from the odds ratio on the covariate for treatment, the odds of decreased vision increased by 21 percent following introduction of photodynamic therapy (odds ratio (OR) = 1.21; 95 confidence interval (CI): 1.06, 1.38). By contrast, the odds of decreased vision fell by 41% following introduction of anti-VEGF therapy (OR = 0.59; 95% CI: 0.52, 0.68).
Table 3.
Vision change before and after introduction of photodynamic and anti-VEGF therapies
| Decrease in vision, OR (95% CI) | Vision loss/blindness, OR (95% CI) | |||
|---|---|---|---|---|
| Covariate | Photodynamic therapy |
Anti-VEGF therapy |
Photodynamic therapy |
Anti-VEGF therapy |
| Treatment | 1.21** | 0.59** | 1.40** | 0.54** |
| (1.06,1.38) | (0.52,0.68) | (1.19,1.63) | (0.47,0.63) | |
| Age | 1.01 | 1.02** | 1.02** | 1.03** |
| (0.99,1.02) | (1.01,1.03) | (1.01,1.03) | (1.01,1.04) | |
| Male | 0.83* | 0.90 | 0.91 | 0.90 |
| (0.72,0.96) | (0.79,1.04) | (0.77,1.08) | (0.77,1.06) | |
| Black | 0.49* | 0.70 | 0.47 | 0.62 |
| (0.25,0.96) | (0.39,1.25) | (0.21,1.05) | (0.31,1.26) | |
| Hispanic | 0.63 | 1.26 | 0.68 | 1.62 |
| (0.23,1.69) | (0.67,2.39) | (0.22,2.14) | (0.83,3.18) | |
| Charlson Index | 1.02 | 1.03 | 0.99 | 1.02 |
| (0.99,1.05) | (1.00,1.06) | (0.96,1.04) | (0.98,1.05) | |
| Diabetes mellitus | 1.02 | 0.87 | 0.90 | 0.83 |
| (0.85,1.22) | (0.74,1.03) | (0.72,1.13) | (0.68,1.01) | |
| Glaucoma | 1.13 | 1.01 | 1.28** | 1.12 |
| (0.97,1.31) | (0.87,1.17) | (1.07,1.53) | (0.94,1.32) | |
| Diabetic Retinopathy | 0.84 | 1.09 | 1.24 | 1.24 |
| (0.59,1.2) | (0.81,1.47) | (0.84,1.83) | (0.89,1.74) | |
| Cataract | 1.18* | 0.87* | 1.10 | 0.87 |
| (1.02,1.37) | (0.76,0.99) | (0.93,1.31) | (0.75,1.02) | |
| Other Eye Complication | 1.46** | 1.27** | 1.42** | 1.21* |
| (1.25,1.69) | (1.09,1.48) | (1.19,1.70) | (1.01,1.45) | |
| N | 31,746 | 35,726 | 31,536 | 35,400 |
| Percent with Outcome | 2.95 | 2.62 | 2.97 | 2.64 |
Abbreviations: OR, odds ratio; CI, confidence interval
p<0.01,
p<0.05
Vision loss or blindness was first diagnosed in 2.10% of beneficiaries in the PDT sample and 2.04% of beneficiaries in the anti-VEGF sample in the two years following a first exudative AMD diagnosis. The result for photodynamic therapy again implies introduction of PDT increased the probability of vision loss (OR = 1.40; 95% CI: 1.19, 163) while introduction of anti-VEGF therapy showed a strong protective effect, a 46% reduction (OR = 0.54; 95% CI: 0.47, 0.63).
Analysis of Depression and Admission to a Long-Term Care Facility
The depression analysis sample contained no standardized differences greater than 10% even before matching (Table 4). In the long-term care facility admission analysis sample, the only standardized difference before matching was for age. After matching, all standardized differences were below the 10% threshold.
Table 4.
Depression and long-term care facility admissions: sample characteristics before and after propensity score matching
| Panel A: Depression |
||||||
|---|---|---|---|---|---|---|
| Before Matching |
After Matching |
|||||
| Anti-VEGF | Anti-VEGF |
|||||
| Covariate | Therapy (treatment) | No treatment (control) | Standardized difference | Therapy (treatment) | No treatment | Standardized |
| Age | 81.09 | 80.60 | 7.27 | 81.10 | 81.12 | −0.36 |
| Male | 0.35 | 0.35 | 1.19 | 0.35 | 0.34 | 2.57 |
| Black | 0.01 | 0.02 | −6.67 | 0.01 | 0.01 | 2.18 |
| Charlson | 2.02 | 2.13 | −5.45 | 2.02 | 1.92 | 4.88 |
| Diabetes mellitus | 0.31 | 0.33 | −4.99 | 0.31 | 0.29 | 4.75 |
| Diabetic retinopathy | 0.06 | 0.07 | −4.00 | 0.06 | 0.05 | 4.45 |
| Glaucoma | 0.25 | 0.29 | −7.26 | 0.25 | 0.25 | 1.67 |
| Cataract | 0.64 | 0.62 | 3.08 | 0.64 | 0.64 | 0.28 |
| Other eye complications | 0.22 | 0.18 | 9.78 | 0.22 | 0.20 | 5.47 |
| N = 15,561 | N = 13,258 | |||||
|
Panel B: Long-term care facility |
||||||
|
Before Matching |
After Matching |
|||||
| Anti-VEGF | Anti-VEGF | |||||
| Covariate | Therapy (treatment) | No treatment (control) | Standardized difference | Therapy (treatment) | No treatment (control) | Standardized difference |
| Age | 80.53 | 79.85 | 10.43 | 80.55 | 80.58 | −0.54 |
| Male | 0.36 | 0.35 | 0.83 | 0.36 | 0.35 | 1.77 |
| Black | 0.01 | 0.02 | −7.47 | 0.01 | 0.01 | 1.01 |
| Charlson | 1.92 | 1.98 | −3.11 | 1.92 | 1.82 | 5.05 |
| Diabetes mellitus | 0.30 | 0.31 | −3.40 | 0.30 | 0.27 | 5.88 |
| Diabetic retinopathy | 0.06 | 0.07 | −4.43 | 0.06 | 0.04 | 6.32 |
| Glaucoma | 0.25 | 0.29 | −8.03 | 0.25 | 0.25 | −0.22 |
| Cataract | 0.65 | 0.64 | 2.92 | 0.65 | 0.66 | −1.13 |
| Other eye complications | 0.22 | 0.19 | 9.42 | 0.22 | 0.21 | 4.56 |
| N = 14,300 | N = 12,282 | |||||
A first diagnosis of depression during follow-up occurred in 1.98% of the eligible study population (Table 5). There was no statistical difference in the probability of a first depression diagnosis among beneficiaries with an exudative AMD diagnosis who received anti-VEGF therapy and those who did not. Males were 42% less likely to be diagnosed with depression for the first time during follow-up (OR = 0.58; 95% CI: 0.99, 1.04); for each additional point on the Charlson index, (mean value about 2) led to an increase of 6% in the probability of a first depression diagnosis (OR = 1.06; 95% CI: 1.00, 1.13).
Table 5.
Other outcomes: depression and long term care facility admissions
| Covariate | Depression, OR (95% CI) | Long term care facility, OR (95% CI) |
|---|---|---|
| Treatment | 0.90 | 0.81** |
| (0.71,1.15) | (0.72,0.91) | |
| Age | 1.02 | 1.10** |
| (0.99,1.04) | (1.09,1.11) | |
| Male | 0.58** | 0.68** |
| (0.44,0.78) | (0.60,0.78) | |
| Black | 0.58 | 1.02 |
| (0.14,2.38) | (0.60,1.75) | |
| Charlson Index | 1.06* | 1.10** |
| (1.00,1.13) | (1.07,1.13) | |
| Diabetes mellitus | 1.11 | 1.02 |
| (0.82,1.49) | (0.88,1.19) | |
| Glaucoma | 0.88 | 1.06 |
| (0.66,1.17) | (0.93,1.22) | |
| Diabetic Retinopathy | 1.04 | 1.26 |
| (0.61,1.78) | (0.95,1.68) | |
| Cataract | 1.08 | 0.88 |
| (0.83,1.40) | (0.78,1.00) | |
| Other Eye Complication | 1.08 | 0.98 |
| (0.80,1.46) | (0.84,1.15) | |
| N | 13,258 | 12,282 |
| Percent with Outcome | 1.98 | 10.13 |
Abbreviations: OR, odds ratio; CI, confidence interval
p<0.01,
p<0.05
A tenth (10.13%) of beneficiaries with a first exudative AMD diagnosis were admitted to a long-term care facility during the follow-up period, conditional on not having been admitted to such facilities during the look-back period. Receipt of anti-VEGF therapy was associated with a 19% lower probability of entry into a long-term care facility (OR = 0.81; 95% CI: 0.72, 0.91). Higher age (OR = 1.10; 95% CI: 1.-9, 1.11) and higher values on the Charlson index (OR = 1.10; 95% CI: 1.07, 1.13) increased the probability of admission while being male (OR = 0.68; 95% CI: 0.60, 0.78) decreased it. Thus, anti-VEGF treatment had about the same effect on the probability of being admitted to a long-term care facility as doubling of the Charlson index from its observational mean did.
Discussion
Our study yielded two key findings. First, introduction of anti-VEGF therapy reduced vision loss and onset of severe vision loss and blindness in a national longitudinal sample of U.S. elderly newly diagnosed with exudative AMD. Second, such beneficiaries who received anti-VEGF therapy and were not admitted to a long-term care facility during the three-year look-back period were substantially less likely to be admitted to a long-term care facility during a two-year follow-up. To our knowledge, this is the third study to demonstrate gains in population visual health for patients with an AMD diagnosis and the first to demonstrate this for the U.S. or other large high-income countries and to document gains in vision specifically for exudative AMD. Furthermore, our study benefited from being based on a large national longitudinal sample of U.S. elderly and employing statistical techniques--, propensity score matching, regression discontinuity, and controlling for common confounders designed to mitigate endogeneity of treatment.
The only other studies documenting trends in visual outcomes at a population level are comparisons of legal blindness in Denmark and Israel.16,17 Rates of legal blindness among persons in Denmark age 50 and over with an AMD diagnosis, not only with exudative AMD, fell by 50%between 2000 and 2010, with most of the decline occurring after 2006, i.e., soon after anti-VEGF therapies were introduced. Our results for severe vision loss and blindness, a broader definition of vision loss, imply about half as much improvement as in the Danish study. We used a narrower age range, and our results only applied to new diagnoses of exudative AMD with outcomes observed during a two-year follow-up period. Although smaller than the Danish study, our results nevertheless indicate substantial improvements in vision for the population of U.S. elderly newly diagnosed with exudative AMD following introduction of anti-VEGF therapies. A study conducted in Israel also showed a decline in age-standardized rates of certification of blindness among persons with an AMD diagnosis starting in 2004.17 The rate of decline was somewhat larger during 2004–6 than during 2006–8. Although no data on volume of anti-VEGF procedures were presented as in the U.S., volume increases during 2006–8 presumably substantially exceeded those during 2004–6. Thus, the relatively higher rate of decline during 2004–6 than during 2006–8 in Israel is puzzling.
Rather than rely on a single data base as in this study, Bressler and colleagues26 applied evidence on visual acuity outcomes from phase 3 ranibizumab clinical trials to incidence rates of exudative AMD from population-based data sources. The effect sizes were larger than in our study, possibly because visual outcomes are better measured in trials than in claims data. However, it is also possible that true underlying effect sizes in a controlled environment of a trial exceed effect sizes in community settings.
Previous studies have documented a link between depression and AMD.27–29 Our study’s contribution was to relate receipt of anti-VEGF therapy to incident diagnosis of depression. Receipt of anti-VEGF therapy did not lead to statistically significant reductions in newly diagnosed depression during follow-up. There is also a documented relationship between AMD and vision loss more generally and long-term care facility use.29–31 In this study we report a reduction in long-term facility admissions in the two years following first receipt of anti-VEGF therapy.
The use of Medicare claims data in health outcomes research has a number of well-known limitations.32,33 In particular, claims data are used for the purpose of paying providers of care, and diagnostic information must only be provided to the extent that it supports a claim for payment of care rendered. Although procedure coding is presumably accurate as a matter of law, diagnostic information is limited by available codes and may only be provided in detail sufficient for obtaining payment. Diagnostic codes descriptive of visual acuity are not needed for payment, and this raises the question as to their accuracy and most directly the possibility of under coding of visual acuity and the diagnosis of blindness.32–34 One study assessed the quality of such data in Medicare claims, concluding that the prevalence estimates derived from such data are consistent with data provided by epidemiologic studies.34
Another issue is lack of eye-specific codes in the ICD-9-CM system. Thus, we lacked an ability to measure the spread of exudative AMD to the second eye with Medicare claims data. It has been estimated that on average, patients with exudative AMD in one eye will experience involvement of the second eye at a rate of roughly 10% per year.35 Thus this under-ascertainment is exacerbated by the relatively short two-year follow up period used in this study. Even so, this limitation implies that our estimates are likely to be, if anything downward biased.
In sum, the introduction of anti-VEGF therapies has led to important improvements in visual health among elderly persons newly diagnosed with exudative AMD and reductions in long-term care facility use. Such improvements are not only observable in randomized controlled trials but, as this study shows, in the population of individuals afflicted with this disease. The reductions in long-term facility use attributable to use of anti-VEGF therapies is important not only for its implications for health care spending but also for the improvement in functional status which underlies the reduction and is not at all well-measured by ICD-9-CM or CPT-4 codes.
ACKNOWLEDGEMENTS
Research for this article was supported in part by the National Institute on Aging (grant R01-AG017473). The sponsor had no role in design and conduct of the study, collection, management, analysis, interpretation of the data, preparation, review, approval of the manuscript, nor decision to submit the manuscript for publication. Dr. Sloan had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Footnotes
The authors have no financial conflicts of interest to disclose.
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