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β-blockers and Neovascular Age-related Macular Degeneration
Report b-blockers and Neovascular Age-related Macular Degeneration Neovascular age-related macular degeneration (nAMD) is the leading cause of irreversible visual impairment in elderly people. In recent years, many in vivo and in vitro studies have shown that b-blockers could be a possible new pharmacologic treatment for choroidal neovascularization.1 However, clinical and epidemiologic studies have found inconsistent or even contradictory results.2e5 In those studies that showed increased risk of nAMD in patients taking b-blockers, it is difficult to determine whether it is owing to the effect of b-blockers themselves or owing to the underlying diseases for which b-blockers were taken (e.g., hypertension).2 Hypertension is a common systemic comorbid disease among nAMD patients with about 46% to 69% of nAMD patients having hypertension. b-blockers were frequently used antihypertensive medications. Therefore, this study aims to evaluate the effect of continuous b-blocker use in the incidence of new-onset nAMD in hypertensive patients. This retrospective, population-based, longitudinal cohort study was performed using the National Health Insurance Research Database (NHIRD) in Taiwan. It examined International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes and all claims data from 1999 through 2011 of 1 million beneficiaries randomly selected from the entire population. The Institutional Review Board of Chang Gung Memorial Hospital approved this study, which was conducted in accordance with the tenets of the Declaration of Helsinki. The inclusion criteria were (1) age 50 years, (2) having newly diagnosed hypertension, (3) visiting the outpatient clinic for hypertension 3 times per year, and (4) no macular degeneration before enrollment. The exclusion criteria were (1) longitudinal follow-up <1 year, (2) having pathologic myopia, (3) switch to different regimens during follow-up (switch from b-blockers to noneb-blocker antihypertensive medications, or vice versa), (4) using 4 antihypertensive medications at same time, and (5) inadequate exposure time of antihypertensive medications. Cohort 1 comprised continuous b-blocker users and cohort 2, those who had never used b-blockers. Cohort 1 was further divided into 2 subgroups (cohorts 1A and 1B). The adequate exposure time is defined as use of b-blockers for 180 to 269 days per year in cohort 1A and 270 days per year in cohort 1B. The adequate exposure time in cohort 2 is usage of 1 non-b-blocker antihypertensive medications for 270 days per year. Eligible patients in the 2 cohorts were matched in a ratio of 1:1 by propensity score, which was estimated from a multivariable logistic regression model including baseline conditions (age, gender, diabetes mellitus, myocardial infarction, congestive heart failure, renal disease, and chronic pulmonary diseases) and number of antihypertensive medications used. The index date for patient enrollment was the date on which hypertension first appeared in their diagnosis. Patients were longitudinally followed until onset of nAMD, death,
or the last date of the database. The nAMD was identified by ICD-9-CM code 362.52, or 362.50 in combination with 362.42 or 362.43. The major systemic comorbid diseases including diabetes mellitus, myocardial infarction, congestive heart failure, cerebrovascular disease, peripheral vascular disease, renal disease, chronic pulmonary disease, and dementia were coded as time-dependent covariates according to their time of onset. Cumulative incidence curves and cause-specific Cox models were conducted treating death as a competing risk. Data were analyzed using R software package (R Development Core Team, Vienna, Austria). A total of 1870 Taiwanese patients were enrolled in each cohort. The baseline data are summarized in Table S1 (available at www.aaojournal.org). The cumulative incidence of nAMD in each cohort is shown in Figure 1. The differences between cohorts 1A, 1B, and 2 were significant (log-rank tests; P < 0.001). Cox regression models showed increased risk of nAMD in continuous b-blocker users. The adjusted hazard ratio of nAMD were 1.62 (95% confidence interval, 1.25-2.10; P < 0.001) and 2.60 (95% confidence interval, 1.96-3.43; P < 0.001) in cohorts 1A and 1B, respectively (Table S2, available at www.aaojournal.org). In a retrospective study, Montero et al3 found that nAMD patients under systemic b-blockers required fewer intravitreal bevacizumab injections than the control. In contrast, 2 other retrospective case-control studies showed that b-blockers did not protect patients from developing nAMD.4,5 However, these analyses were limited by small sample size and uncertain b-blocker exposure duration. The Beaver Dam Eye Study was a populationbased investigation that found an association between oral b-blocker usage and an increased incidence of nAMD (hazard ratio, 1.71; 95% confidence interval, 1.04e2.82) over the 20-year period.2 The present findings also supported that continuous b-blocker use is associated with a higher risk of nAMD. However, the current research was different in design. First, all patients included in this study had newly diagnosed hypertension and the duration of hypertension was clearly defined. Thus, hypertension itself is no longer a confounding factor. Second, this study had strict inclusion and exclusion criteria that helped to ensure the medication exposure time in the studied patients. Patients with inadequate exposure and switching to different regimens before the end of the observation period were excluded. Third, 180 and 270 days per year were used as cutoffs to evaluate the effect of b-blocker in different exposure time. These cutoffs were chosen because patients usually can get a 90-day refill prescription at each outpatient visit. With each refill, a copayment is required; hence, patients with poor compliance usually would not get their refills on time and would not achieve adequate drug exposure requirement of this study. We found that the longer b-blocker exposure time per year, the greater the risk of nAMD. The major limitation of the current study is that the severity of hypertension is not available in NHIRD. Therefore, the 2 cohorts were matched appropriately by hypertension-related end-organ diseases and the number of antihypertensive medications used. The strength of this study is that NHIRD contains an enormous amount
1
Ophthalmology Volume -, Number -, Month 2016 Center, Chang Gung Memorial Hospital, Keelung, Taiwan; Laboratory for Epidemiology, Department of Health Care Management and Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan; 8Department of Urology, Chang Gung Memorial Hospital, Taoyuan, Taiwan 7
Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article. Supported by 3 grants from the Chang Gung Medical Research Foundation (No. CLRPG2C0021, No. CLRPG2C0022, and No. CLRPG2C0023). The sponsoring organization had no role in the design or conduct of this research. Author Contributions: Conception and design: Yeung, Huang, Sun Analysis and interpretation: Yeung, Huang, Sun, Hsu Data collection: Yeung, Huang, Lin, Huang Obtained funding: Sun Overall responsibility: Yeung, Sun
Figure 1. Cumulative incidences of neovascular age-related macular degeneration (nAMD) in 3 different cohorts. Cohort 1A: continuous b-blocker users with medication exposure 180 to 269 days per year; cohort 1B: continuous b-blocker users with medication exposure 270 days per year; cohort 2: noneb-blocker users.
Correspondence: Chi-Chin Sun, MD, PhD, Department of Ophthalmology, Chang Gung Memorial Hospital, 222 Mai Chin Road, An Leh District, Keelung, Taiwan. E-mail: [email protected].
References of patient data; hence, patients with more consistent medication use could be selected for each cohort. This may be difficult to achieve in other prospective epidemiology studies. Among hypertensive patients aged 50 years, continuous b-blocker use was associated with higher risk of nAMD than those nonusers.
LING YEUNG, MD1,2 TING-SHUO HUANG, MD, PHD3,4,5,6 YUN-HSUAN LIN, MD1 KUANG-HUNG HSU, PHD7,8 JERRY CHIEN-CHIEH HUANG, MD1,2 CHI-CHIN SUN, MD, PHD1,4,5 1 Department of Ophthalmology, Chang Gung Memorial Hospital, Keelung, Taiwan; 2College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Department of General Surgery, Chang Gung Memorial Hospital, Keelung, Taiwan; 4Department of Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 5Osteoporosis Prevention and Treatment Center, Chang Gung Memorial Hospital, Keelung, Taiwan; 6Community Medicine Research
2
1. Casini G, Dal Monte M, Fornaciari I, et al. The beta-adrenergic system as a possible new target for pharmacologic treatment of neovascular retinal diseases. Prog Retin Eye Res. 2014;42C: 103-129. 2. Klein R, Myers CE, Klein BE. Vasodilators, blood pressure-lowering medications, and age-related macular degeneration: the Beaver Dam Eye Study. Ophthalmology. 2014;121:1604-1611. 3. Montero JA, Ruiz-Moreno JM, Sanchis-Merino E, et al. Systemic beta-blockers may reduce the need for repeated intravitreal injections in patients with wet age-related macular degeneration treated by bevacizumab. Retina. 2013;33:508-512. 4. Davis A, Cohen SM, Pautler SE, et al. Beta blocker use and age-related macular degeneration. Acta Ophthalmol. 2012;90(2):e162-163. 5. Thomas AS, Redd T, Hwang T. Effect of systemic beta-blockers, ace inhibitors, and angiotensin receptor blockers on development of choroidal neovascularization in patients with age-related macular degeneration. Retina. 2015;35:1964-1968.
or the last date of the database. The nAMD was identified by ICD-9-CM code 362.52, or 362.50 in combination with 362.42 or 362.43. The major systemic comorbid diseases including diabetes mellitus, myocardial infarction, congestive heart failure, cerebrovascular disease, peripheral vascular disease, renal disease, chronic pulmonary disease, and dementia were coded as time-dependent covariates according to their time of onset. Cumulative incidence curves and cause-specific Cox models were conducted treating death as a competing risk. Data were analyzed using R software package (R Development Core Team, Vienna, Austria). A total of 1870 Taiwanese patients were enrolled in each cohort. The baseline data are summarized in Table S1 (available at www.aaojournal.org). The cumulative incidence of nAMD in each cohort is shown in Figure 1. The differences between cohorts 1A, 1B, and 2 were significant (log-rank tests; P < 0.001). Cox regression models showed increased risk of nAMD in continuous b-blocker users. The adjusted hazard ratio of nAMD were 1.62 (95% confidence interval, 1.25-2.10; P < 0.001) and 2.60 (95% confidence interval, 1.96-3.43; P < 0.001) in cohorts 1A and 1B, respectively (Table S2, available at www.aaojournal.org). In a retrospective study, Montero et al3 found that nAMD patients under systemic b-blockers required fewer intravitreal bevacizumab injections than the control. In contrast, 2 other retrospective case-control studies showed that b-blockers did not protect patients from developing nAMD.4,5 However, these analyses were limited by small sample size and uncertain b-blocker exposure duration. The Beaver Dam Eye Study was a populationbased investigation that found an association between oral b-blocker usage and an increased incidence of nAMD (hazard ratio, 1.71; 95% confidence interval, 1.04e2.82) over the 20-year period.2 The present findings also supported that continuous b-blocker use is associated with a higher risk of nAMD. However, the current research was different in design. First, all patients included in this study had newly diagnosed hypertension and the duration of hypertension was clearly defined. Thus, hypertension itself is no longer a confounding factor. Second, this study had strict inclusion and exclusion criteria that helped to ensure the medication exposure time in the studied patients. Patients with inadequate exposure and switching to different regimens before the end of the observation period were excluded. Third, 180 and 270 days per year were used as cutoffs to evaluate the effect of b-blocker in different exposure time. These cutoffs were chosen because patients usually can get a 90-day refill prescription at each outpatient visit. With each refill, a copayment is required; hence, patients with poor compliance usually would not get their refills on time and would not achieve adequate drug exposure requirement of this study. We found that the longer b-blocker exposure time per year, the greater the risk of nAMD. The major limitation of the current study is that the severity of hypertension is not available in NHIRD. Therefore, the 2 cohorts were matched appropriately by hypertension-related end-organ diseases and the number of antihypertensive medications used. The strength of this study is that NHIRD contains an enormous amount
1
Ophthalmology Volume -, Number -, Month 2016 Center, Chang Gung Memorial Hospital, Keelung, Taiwan; Laboratory for Epidemiology, Department of Health Care Management and Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan; 8Department of Urology, Chang Gung Memorial Hospital, Taoyuan, Taiwan 7
Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article. Supported by 3 grants from the Chang Gung Medical Research Foundation (No. CLRPG2C0021, No. CLRPG2C0022, and No. CLRPG2C0023). The sponsoring organization had no role in the design or conduct of this research. Author Contributions: Conception and design: Yeung, Huang, Sun Analysis and interpretation: Yeung, Huang, Sun, Hsu Data collection: Yeung, Huang, Lin, Huang Obtained funding: Sun Overall responsibility: Yeung, Sun
Figure 1. Cumulative incidences of neovascular age-related macular degeneration (nAMD) in 3 different cohorts. Cohort 1A: continuous b-blocker users with medication exposure 180 to 269 days per year; cohort 1B: continuous b-blocker users with medication exposure 270 days per year; cohort 2: noneb-blocker users.
Correspondence: Chi-Chin Sun, MD, PhD, Department of Ophthalmology, Chang Gung Memorial Hospital, 222 Mai Chin Road, An Leh District, Keelung, Taiwan. E-mail: [email protected].
References of patient data; hence, patients with more consistent medication use could be selected for each cohort. This may be difficult to achieve in other prospective epidemiology studies. Among hypertensive patients aged 50 years, continuous b-blocker use was associated with higher risk of nAMD than those nonusers.
LING YEUNG, MD1,2 TING-SHUO HUANG, MD, PHD3,4,5,6 YUN-HSUAN LIN, MD1 KUANG-HUNG HSU, PHD7,8 JERRY CHIEN-CHIEH HUANG, MD1,2 CHI-CHIN SUN, MD, PHD1,4,5 1 Department of Ophthalmology, Chang Gung Memorial Hospital, Keelung, Taiwan; 2College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Department of General Surgery, Chang Gung Memorial Hospital, Keelung, Taiwan; 4Department of Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 5Osteoporosis Prevention and Treatment Center, Chang Gung Memorial Hospital, Keelung, Taiwan; 6Community Medicine Research
2
1. Casini G, Dal Monte M, Fornaciari I, et al. The beta-adrenergic system as a possible new target for pharmacologic treatment of neovascular retinal diseases. Prog Retin Eye Res. 2014;42C: 103-129. 2. Klein R, Myers CE, Klein BE. Vasodilators, blood pressure-lowering medications, and age-related macular degeneration: the Beaver Dam Eye Study. Ophthalmology. 2014;121:1604-1611. 3. Montero JA, Ruiz-Moreno JM, Sanchis-Merino E, et al. Systemic beta-blockers may reduce the need for repeated intravitreal injections in patients with wet age-related macular degeneration treated by bevacizumab. Retina. 2013;33:508-512. 4. Davis A, Cohen SM, Pautler SE, et al. Beta blocker use and age-related macular degeneration. Acta Ophthalmol. 2012;90(2):e162-163. 5. Thomas AS, Redd T, Hwang T. Effect of systemic beta-blockers, ace inhibitors, and angiotensin receptor blockers on development of choroidal neovascularization in patients with age-related macular degeneration. Retina. 2015;35:1964-1968.