- Email: [email protected]
Do statins prevent age-related macular degeneration?
EDITORIAL Do Statins Prevent Age-related Macular Degeneration? RONALD KLEIN, MD, MPH, AND BARBARA E. K. KLEIN, MD, MPH
A
DVANCED AGE-RELATED MACULAR DEGENERA-
tion (AMD) is an important cause of visual loss in persons 65 years of age or older.1,2 Its pathogenesis remains poorly understood. Until recently, only photocoagulation and photodynamic therapy were shown to have some benefit in preventing severe visual loss but only in a small percentage of patients with the neovascular form of the disease and only for a limited time after treatment.3–5 Aside from antioxidants and zinc, which were shown in the Age-Related Eye Disease Study to reduce progression to advanced AMD (23% vs 28%) in persons with early AMD compared with those not on this treatment, there have been no proven medical interventions for preventing the progression of this disease.6 This is why the paper by Wilson and associates7 appearing in this issue and suggesting a possible protective effect of statins and aspirin for neovascular AMD is of interest. Their study was a retrospective consecutive case series of all 326 patients 60 years of age or older with photographically detected AMD seen in a Veterans Hospital eye clinic. They report that persons with subretinal new vessels were less likely to use statins or aspirin than a group of patients with AMD without subretinal new vessels (defined as five or more soft indistinct drusen with or without geographic atrophy). These observations are consistent with three other publications that reported an inverse association of statins or lipid-lowering agents with AMD.8 –10 In one cross-sectional cohort study of persons 66 to 75 years of age, 76 (22%) of the 352 persons who did not take statins and 1 (4%) of the 27 who were taking statins had signs of AMD.8 This is a statistically significant reduction in the odds of having AMD of 86% in those taking statins. In another study, McCarty and associates,9 reported in a letter, a nonsignificant (P ⫽ .11) fourfold increase in progression of large drusen, a sign of early AMD, in those not taking blood cholesterol-lowering medications comAccepted for publication Jan 14, 2004. From the Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, Wisconsin. This research was supported by grant EY06594 from the National Institutes of Health, Bethesda, MD. Inquiries to Ronald Klein, MD, MPH, Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, 610 North Walnut Street, 460 WARF, Madison, WI 53705–2397; fax: (608) 263– 0279; e-mail: [email protected] 0002-9394/04/$30.00 doi:10.1016/j.ajo.2004.01.037
©
2004 BY
pared with those taking them. In both of these studies, there were large numbers of other drugs that were studied, raising the possibility that the associations were chance findings. In a more recent nested case-control study among patients receiving care in a veterans hospital in Alabama, statins were found to be used 70% less frequently in patients with a history of AMD than in age-matched controls.10 These four studies, taken as a whole, suggest a possible “protective” association of statin for AMD. The authors of these four studies suggest that there is biologic plausibility to support the potential role of anticholesterolemic drugs, especially the statins, protecting against AMD (although not specifically for the neovascular form).7–10 They cite references to the role of oxidative damage, endothelial dysfunction, and lipid-related vascular disease in the development of AMD. However, epidemiologic evidence from other population-based studies is not consistent with these findings.11–13 In the Rotterdam Study, during 26,781 person years of follow-up in 457 persons, those using cholesterol lowering drugs had a similar incidence of AMD to those not using these drugs (hazard ratio 1.0, 95% confidence interval 0.7–1.5).11 Controlling for other confounders did not change this association. The duration of use of statins was not associated with risk of developing AMD. In the Blue Mountains Eye Study, while controlling for age, gender, smoking, and total serum cholesterol, persons who had used statins at baseline had a nonsignificant 2.5 times increase in the odds of 5-year incidence of neovascular AMD compared with those who had never used statins. (Mitchell P, Wang JJ, personal communication). In the Beaver Dam Eye Study, another large prospective population-based cohort, 143 persons (3.9%) of the population were taking statins at the 1993 to 1995 examination and 558 at the 1998 to 2000 examination.12 Of those taking statins at the 1993 to 1995 examination, there were no significant cross-sectional associations between statin use and early or late AMD. While controlling for other risk factors, there was also no association of statin use with the 5-year incidence of neovascular AMD (odds radio [OR] 1.25, 95% confidence interval [CI] 0.16, 9.54, P ⫽ .83). However, if only those being seen at the 1998 to 2000 examination were included, there was a borderline inverse cross-sectional association (OR 0.15, 95% CI 0.02, 1.09, P ⫽ .06) among new users
ELSEVIER INC. ALL
RIGHTS RESERVED.
747
of statins, which is consistent with the findings of Wilson and associates. The difference between the incident and cross-sectional findings in Beaver Dam might be explained, in part, by the observation in the Beaver Dam Eye Study that persons with a high total serum cholesterol level and AMD at the 1993 to 1995 examination were less likely to start taking statins than those with a high total serum cholesterol level without AMD, leading to a finding of a “protective” effect when the data are examined crosssectionally. The association reported in the paper by Wilson and associates, was independent of serum total cholesterol level at baseline, suggesting that this did not account for the inconsistency between their findings and the Beaver Dam and Rotterdam Eye Studies findings. Data from other population-based studies as well as one clinical trial have also not shown any protective association of aspirin use and AMD.14 –17 How can such discrepant findings come about? Case series, while they may serve to describe the various manifestations and correlates of clinical disease, are prey to serious limitations because of the very nature by which they are accumulated. The case series may represent a particularly severe subset of all persons with AMD that was referred for ophthalmologic investigation either by outside practitioners or in this case possibly from other ophthalmologists in the specific medical system. Severe cases of AMD may have different risk factor profiles than all cases of AMD. In the case of the paper by Wilson and associates, the comparison group is more problematic than the “case” group with respect to potential biases that may have an important bearing on the findings.7 In this report, the comparison group is composed in part of persons being worked up for other retinal problems such as diabetic retinopathy and retinal branch vein occlusion. The systemic conditions that are associated with these eye conditions could account for the very high proportion of this group using aspirin (75% compared with 48% of those 60 years of age or older in the general Beaver Dam Eye Study population) and high proportion of statin users (38% compared with 19% of those 60 years of age or older in Beaver Dam in 1998 to 2000). While the unusually high usage rates don’t necessarily imply that these drugs are not effective in forestalling neovascular AMD, it is entirely possible that the extraordinarily higher drug use is significantly influencing the results. One could even consider the aspirin usage pattern as an indicator of severe systemic disease in those without neovascular AMD in this study. Thus, a case series is an inadequate way to assess risk or protection, and one might argue that computing a risk or hazard based on the case series is inappropriate. A case control study, if well designed with more than one control group, could remedy some of these problems and provide estimates of risk. One such study by McGwin and associates involved 550 cases of ARM and 5500 controls (defined by ICD-9CM codes) for AMD.10 They reported that cases were 70% less likely to have received 748
AMERICAN JOURNAL
and filled a statin prescription relative to the controls. One of the main limitations of that study was that more than 90% of those with ARM were classified as “unspecified.” Thus, there may have been significant misclassification that affected their results. The matching in this study was not ideal; there was a significant imbalance in the racial distribution of cases and controls. There were also significant differences in the distribution of known risk factors for AMD between “cases” and “controls” (for example, cardiovascular disease and hypertension status) that might have affected their results. Uncontrolled confounding may also have affected the associations reported. For example, no information on smoking behavior or cataract surgery differences between groups was presented. Evaluating evidence from population-based studies is no less complex than evaluating the observations from case series or case-control studies but has the virtue of evaluating the question in well-defined general populations. Cross-sectional studies, in which the disease (AMD or neovascular AMD) and the exposure (drug, other environmental factors) are measured at the same point in time cannot really inform as to the temporal nature of the associations. Prospective population-based studies offer the best observational design, because the temporal relationships are clear. Prospective cohort studies such as Beaver Dam, Blue Mountains, and Rotterdam Eye Studies provide inferences regarding the antecedent consequent nature of the associations, but because of the infrequency of the risk factor and end point they have limited power to detect an association.11,12 However, the Rotterdam study reported a power of 80% to show a relative risk of 0.7 or lower for lipidlowering agent use and incident AMD.11 The consistency of the prospective findings from Beaver Dam, Rotterdam, and the Blue Mountains of no relationship suggests that statin use at baseline is not associated with the 5-year incidence of neovascular AMD.11,12 Further follow-up of these large cohorts, with more persons taking statins, will provide better insights regarding this association. However, even with such follow-up and even when the findings are consistent among studies, there is always the possibility of unmeasured confounding, selective survival, and other study limitations that may result in erroneous conclusions. Although one might entertain the prospect of a randomized, controlled clinical trial, as advocated by McCarty and associates,9 there are several considerations that should temper the enthusiasm to do this. To attempt to divorce the drug effect from confounding as a result of underlying disease one would need to randomize persons with normal lipid levels (and low risk of other confounding conditions). The time from onset of treatment to expected disease might be long, so that a very large sample would need to be chosen with costly clinical evaluations included. There is some concern about use of statins in those without underlying lipid disorders, although known serious side- and toxic effects of these drugs are relatively uncomOF
OPHTHALMOLOGY
APRIL 2004
mon. One would need to consider the possibility of interacting drug effects (possibly aspirin and statin interactions) and premature termination of the drug regimen because of the development of cardiovascular disease as the subjects age. For example, in Beaver Dam, 33% of subjects 55 to 75 years of age with early AMD developed hypercholesterolemia, coronary artery disease, or started taking lipid-lowering agents over 5 years of follow-up (Klein R, unpublished data). Another important consideration is the question of which end point is appropriate. Should it be the development of early AMD manifested by large soft retinal drusen, or geographic atrophy, neovascular AMD, or all late lesions of AMD? There are many more questions to be resolved before contemplating such a large and costly undertaking. For the interim, there should be careful follow-up of extant cohorts where information on the exposures and end points is collected by specific protocols. There will need to be consideration given to pooling results from several such studies to ensure adequate sample sizes for late stages of AMD. At the moment, the relationship of statins to AMD should be considered unresolved.
REFERENCES 1. Tielsch JM. Vision problems in the U.S. A report on blindness and vision impairment in adults age 40 and older. Schaumburg, IL: Prevent Blindness America, 1995:1–20. 2. Klein R, Wang Q, Klein BEK, Moss SE, Meuer SM. The relationship of age-related maculopathy, cataract, and glaucoma to visual acuity. Invest Ophthalmol Vis Sci 1995;36: 182–191. 3. Bressler NM, Bressler SB, Fine SL. Age-related macular degeneration. Surv Ophthalmol 1988;32:375–413. 4. Five-year follow-up of fellow eyes of patients with age-related macular degeneration and unilateral extrafoveal choroidal neovascularization. Arch Ophthalmol 1993;111:1189 –1199. 5. Bressler NM. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials– TAP report 2. Arch Ophthalmol 2001;119:198 –207. 6. Age-Related Eye Disease Study Research Group. A random-
VOL. 137, NO. 4
7.
8. 9.
10. 11.
12.
13.
14.
15.
16.
17.
ized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age- related macular degeneration and vision loss. AREDS Report No. 8. Arch Ophthalmol 2001;119:1417–1436. Wilson HL, Schwartz DM, Bhatt HRF, McCulloch CE, Duncan JL. Statin and aspirin therapy are associated with decreased rates of choroidal neovascularization among agerelated macular degeneration patients. Am J Ophthalmol 2004;137:615– 624. Hall NF, Gale CR, Syddall H, Phillips DIW, Martyn CN. Risk of macular degeneration in users of statins: cross sectional study. BMJ 2001;323:375–376. McCarty CA, Mukesh BN, Guymer RH, Baird PN, Taylor HR. Cholesterol-lowering medications reduce the risk of age-related maculopathy progression. Let Med J Aust 2001; 175:340. McGwin G Jr., Owsley C, Curcio CA, Crain RJ. The association between statin use and age related maculopathy. Br J Ophthalmol 2003;87:1121–1125. van Leeuwen R, Vingerling JR, Hofman A, de Jong PTVM, Stricker BHC. Cholesterol lowering drugs and risk of age related maculopathy: prospective cohort study with cumulative exposure measurement. BMJ 2003;326:255–256. Klein R, Klein BEK, Tomany SC, Danforth LG, Cruickshanks KJ. Relation of statin use to the 5-year incidence and progression of age-related maculopathy. Arch Ophthalmol 2003;121:1151–1155. Delcourt C, Michel F, Colvez A, Lacroux A, Delage M, Vernet MH. Associations of cardiovascular disease and its risk factors with age-related macular degeneration: the POLA study. Ophthal Epidemiol 2001;8:237–249. van Leeuwen R, Tomany SC, Wang JJ, et al. Is medication use associated with the incidence of early age-related maculopathy? Pooled findings from three continents. Ophthalmology. Forthcoming. Tomany SC, Wang JJ, van Leeuwen, Klein R et al. Risk factors for incident age-related macular degeneration: pooled findings from three continents. Ophthalmology. Forthcoming. Klein R, Klein BEK, Jensen SC, Cruickshanks JK, et al. Medication use and the 5-year incidence of early age-related maculopathy: The Beaver Dam Eye Study. Arch Ophthalmol 2001;119:1354 –1359. Christen WG, Glynn RJ, Ajani UA, et al. Age-related maculopathy in a randomized trial of low-dose aspirin among US physicians. Arch Ophthalmol 2001;119:1143–1149.
749
A
DVANCED AGE-RELATED MACULAR DEGENERA-
tion (AMD) is an important cause of visual loss in persons 65 years of age or older.1,2 Its pathogenesis remains poorly understood. Until recently, only photocoagulation and photodynamic therapy were shown to have some benefit in preventing severe visual loss but only in a small percentage of patients with the neovascular form of the disease and only for a limited time after treatment.3–5 Aside from antioxidants and zinc, which were shown in the Age-Related Eye Disease Study to reduce progression to advanced AMD (23% vs 28%) in persons with early AMD compared with those not on this treatment, there have been no proven medical interventions for preventing the progression of this disease.6 This is why the paper by Wilson and associates7 appearing in this issue and suggesting a possible protective effect of statins and aspirin for neovascular AMD is of interest. Their study was a retrospective consecutive case series of all 326 patients 60 years of age or older with photographically detected AMD seen in a Veterans Hospital eye clinic. They report that persons with subretinal new vessels were less likely to use statins or aspirin than a group of patients with AMD without subretinal new vessels (defined as five or more soft indistinct drusen with or without geographic atrophy). These observations are consistent with three other publications that reported an inverse association of statins or lipid-lowering agents with AMD.8 –10 In one cross-sectional cohort study of persons 66 to 75 years of age, 76 (22%) of the 352 persons who did not take statins and 1 (4%) of the 27 who were taking statins had signs of AMD.8 This is a statistically significant reduction in the odds of having AMD of 86% in those taking statins. In another study, McCarty and associates,9 reported in a letter, a nonsignificant (P ⫽ .11) fourfold increase in progression of large drusen, a sign of early AMD, in those not taking blood cholesterol-lowering medications comAccepted for publication Jan 14, 2004. From the Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, Wisconsin. This research was supported by grant EY06594 from the National Institutes of Health, Bethesda, MD. Inquiries to Ronald Klein, MD, MPH, Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, 610 North Walnut Street, 460 WARF, Madison, WI 53705–2397; fax: (608) 263– 0279; e-mail: [email protected] 0002-9394/04/$30.00 doi:10.1016/j.ajo.2004.01.037
©
2004 BY
pared with those taking them. In both of these studies, there were large numbers of other drugs that were studied, raising the possibility that the associations were chance findings. In a more recent nested case-control study among patients receiving care in a veterans hospital in Alabama, statins were found to be used 70% less frequently in patients with a history of AMD than in age-matched controls.10 These four studies, taken as a whole, suggest a possible “protective” association of statin for AMD. The authors of these four studies suggest that there is biologic plausibility to support the potential role of anticholesterolemic drugs, especially the statins, protecting against AMD (although not specifically for the neovascular form).7–10 They cite references to the role of oxidative damage, endothelial dysfunction, and lipid-related vascular disease in the development of AMD. However, epidemiologic evidence from other population-based studies is not consistent with these findings.11–13 In the Rotterdam Study, during 26,781 person years of follow-up in 457 persons, those using cholesterol lowering drugs had a similar incidence of AMD to those not using these drugs (hazard ratio 1.0, 95% confidence interval 0.7–1.5).11 Controlling for other confounders did not change this association. The duration of use of statins was not associated with risk of developing AMD. In the Blue Mountains Eye Study, while controlling for age, gender, smoking, and total serum cholesterol, persons who had used statins at baseline had a nonsignificant 2.5 times increase in the odds of 5-year incidence of neovascular AMD compared with those who had never used statins. (Mitchell P, Wang JJ, personal communication). In the Beaver Dam Eye Study, another large prospective population-based cohort, 143 persons (3.9%) of the population were taking statins at the 1993 to 1995 examination and 558 at the 1998 to 2000 examination.12 Of those taking statins at the 1993 to 1995 examination, there were no significant cross-sectional associations between statin use and early or late AMD. While controlling for other risk factors, there was also no association of statin use with the 5-year incidence of neovascular AMD (odds radio [OR] 1.25, 95% confidence interval [CI] 0.16, 9.54, P ⫽ .83). However, if only those being seen at the 1998 to 2000 examination were included, there was a borderline inverse cross-sectional association (OR 0.15, 95% CI 0.02, 1.09, P ⫽ .06) among new users
ELSEVIER INC. ALL
RIGHTS RESERVED.
747
of statins, which is consistent with the findings of Wilson and associates. The difference between the incident and cross-sectional findings in Beaver Dam might be explained, in part, by the observation in the Beaver Dam Eye Study that persons with a high total serum cholesterol level and AMD at the 1993 to 1995 examination were less likely to start taking statins than those with a high total serum cholesterol level without AMD, leading to a finding of a “protective” effect when the data are examined crosssectionally. The association reported in the paper by Wilson and associates, was independent of serum total cholesterol level at baseline, suggesting that this did not account for the inconsistency between their findings and the Beaver Dam and Rotterdam Eye Studies findings. Data from other population-based studies as well as one clinical trial have also not shown any protective association of aspirin use and AMD.14 –17 How can such discrepant findings come about? Case series, while they may serve to describe the various manifestations and correlates of clinical disease, are prey to serious limitations because of the very nature by which they are accumulated. The case series may represent a particularly severe subset of all persons with AMD that was referred for ophthalmologic investigation either by outside practitioners or in this case possibly from other ophthalmologists in the specific medical system. Severe cases of AMD may have different risk factor profiles than all cases of AMD. In the case of the paper by Wilson and associates, the comparison group is more problematic than the “case” group with respect to potential biases that may have an important bearing on the findings.7 In this report, the comparison group is composed in part of persons being worked up for other retinal problems such as diabetic retinopathy and retinal branch vein occlusion. The systemic conditions that are associated with these eye conditions could account for the very high proportion of this group using aspirin (75% compared with 48% of those 60 years of age or older in the general Beaver Dam Eye Study population) and high proportion of statin users (38% compared with 19% of those 60 years of age or older in Beaver Dam in 1998 to 2000). While the unusually high usage rates don’t necessarily imply that these drugs are not effective in forestalling neovascular AMD, it is entirely possible that the extraordinarily higher drug use is significantly influencing the results. One could even consider the aspirin usage pattern as an indicator of severe systemic disease in those without neovascular AMD in this study. Thus, a case series is an inadequate way to assess risk or protection, and one might argue that computing a risk or hazard based on the case series is inappropriate. A case control study, if well designed with more than one control group, could remedy some of these problems and provide estimates of risk. One such study by McGwin and associates involved 550 cases of ARM and 5500 controls (defined by ICD-9CM codes) for AMD.10 They reported that cases were 70% less likely to have received 748
AMERICAN JOURNAL
and filled a statin prescription relative to the controls. One of the main limitations of that study was that more than 90% of those with ARM were classified as “unspecified.” Thus, there may have been significant misclassification that affected their results. The matching in this study was not ideal; there was a significant imbalance in the racial distribution of cases and controls. There were also significant differences in the distribution of known risk factors for AMD between “cases” and “controls” (for example, cardiovascular disease and hypertension status) that might have affected their results. Uncontrolled confounding may also have affected the associations reported. For example, no information on smoking behavior or cataract surgery differences between groups was presented. Evaluating evidence from population-based studies is no less complex than evaluating the observations from case series or case-control studies but has the virtue of evaluating the question in well-defined general populations. Cross-sectional studies, in which the disease (AMD or neovascular AMD) and the exposure (drug, other environmental factors) are measured at the same point in time cannot really inform as to the temporal nature of the associations. Prospective population-based studies offer the best observational design, because the temporal relationships are clear. Prospective cohort studies such as Beaver Dam, Blue Mountains, and Rotterdam Eye Studies provide inferences regarding the antecedent consequent nature of the associations, but because of the infrequency of the risk factor and end point they have limited power to detect an association.11,12 However, the Rotterdam study reported a power of 80% to show a relative risk of 0.7 or lower for lipidlowering agent use and incident AMD.11 The consistency of the prospective findings from Beaver Dam, Rotterdam, and the Blue Mountains of no relationship suggests that statin use at baseline is not associated with the 5-year incidence of neovascular AMD.11,12 Further follow-up of these large cohorts, with more persons taking statins, will provide better insights regarding this association. However, even with such follow-up and even when the findings are consistent among studies, there is always the possibility of unmeasured confounding, selective survival, and other study limitations that may result in erroneous conclusions. Although one might entertain the prospect of a randomized, controlled clinical trial, as advocated by McCarty and associates,9 there are several considerations that should temper the enthusiasm to do this. To attempt to divorce the drug effect from confounding as a result of underlying disease one would need to randomize persons with normal lipid levels (and low risk of other confounding conditions). The time from onset of treatment to expected disease might be long, so that a very large sample would need to be chosen with costly clinical evaluations included. There is some concern about use of statins in those without underlying lipid disorders, although known serious side- and toxic effects of these drugs are relatively uncomOF
OPHTHALMOLOGY
APRIL 2004
mon. One would need to consider the possibility of interacting drug effects (possibly aspirin and statin interactions) and premature termination of the drug regimen because of the development of cardiovascular disease as the subjects age. For example, in Beaver Dam, 33% of subjects 55 to 75 years of age with early AMD developed hypercholesterolemia, coronary artery disease, or started taking lipid-lowering agents over 5 years of follow-up (Klein R, unpublished data). Another important consideration is the question of which end point is appropriate. Should it be the development of early AMD manifested by large soft retinal drusen, or geographic atrophy, neovascular AMD, or all late lesions of AMD? There are many more questions to be resolved before contemplating such a large and costly undertaking. For the interim, there should be careful follow-up of extant cohorts where information on the exposures and end points is collected by specific protocols. There will need to be consideration given to pooling results from several such studies to ensure adequate sample sizes for late stages of AMD. At the moment, the relationship of statins to AMD should be considered unresolved.
REFERENCES 1. Tielsch JM. Vision problems in the U.S. A report on blindness and vision impairment in adults age 40 and older. Schaumburg, IL: Prevent Blindness America, 1995:1–20. 2. Klein R, Wang Q, Klein BEK, Moss SE, Meuer SM. The relationship of age-related maculopathy, cataract, and glaucoma to visual acuity. Invest Ophthalmol Vis Sci 1995;36: 182–191. 3. Bressler NM, Bressler SB, Fine SL. Age-related macular degeneration. Surv Ophthalmol 1988;32:375–413. 4. Five-year follow-up of fellow eyes of patients with age-related macular degeneration and unilateral extrafoveal choroidal neovascularization. Arch Ophthalmol 1993;111:1189 –1199. 5. Bressler NM. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials– TAP report 2. Arch Ophthalmol 2001;119:198 –207. 6. Age-Related Eye Disease Study Research Group. A random-
VOL. 137, NO. 4
7.
8. 9.
10. 11.
12.
13.
14.
15.
16.
17.
ized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age- related macular degeneration and vision loss. AREDS Report No. 8. Arch Ophthalmol 2001;119:1417–1436. Wilson HL, Schwartz DM, Bhatt HRF, McCulloch CE, Duncan JL. Statin and aspirin therapy are associated with decreased rates of choroidal neovascularization among agerelated macular degeneration patients. Am J Ophthalmol 2004;137:615– 624. Hall NF, Gale CR, Syddall H, Phillips DIW, Martyn CN. Risk of macular degeneration in users of statins: cross sectional study. BMJ 2001;323:375–376. McCarty CA, Mukesh BN, Guymer RH, Baird PN, Taylor HR. Cholesterol-lowering medications reduce the risk of age-related maculopathy progression. Let Med J Aust 2001; 175:340. McGwin G Jr., Owsley C, Curcio CA, Crain RJ. The association between statin use and age related maculopathy. Br J Ophthalmol 2003;87:1121–1125. van Leeuwen R, Vingerling JR, Hofman A, de Jong PTVM, Stricker BHC. Cholesterol lowering drugs and risk of age related maculopathy: prospective cohort study with cumulative exposure measurement. BMJ 2003;326:255–256. Klein R, Klein BEK, Tomany SC, Danforth LG, Cruickshanks KJ. Relation of statin use to the 5-year incidence and progression of age-related maculopathy. Arch Ophthalmol 2003;121:1151–1155. Delcourt C, Michel F, Colvez A, Lacroux A, Delage M, Vernet MH. Associations of cardiovascular disease and its risk factors with age-related macular degeneration: the POLA study. Ophthal Epidemiol 2001;8:237–249. van Leeuwen R, Tomany SC, Wang JJ, et al. Is medication use associated with the incidence of early age-related maculopathy? Pooled findings from three continents. Ophthalmology. Forthcoming. Tomany SC, Wang JJ, van Leeuwen, Klein R et al. Risk factors for incident age-related macular degeneration: pooled findings from three continents. Ophthalmology. Forthcoming. Klein R, Klein BEK, Jensen SC, Cruickshanks JK, et al. Medication use and the 5-year incidence of early age-related maculopathy: The Beaver Dam Eye Study. Arch Ophthalmol 2001;119:1354 –1359. Christen WG, Glynn RJ, Ajani UA, et al. Age-related maculopathy in a randomized trial of low-dose aspirin among US physicians. Arch Ophthalmol 2001;119:1143–1149.
749