Scholarly article on topic 'Regression of Some High-risk Features of Age-related Macular Degeneration (AMD) in Patients Receiving Intensive Statin Treatment'

Regression of Some High-risk Features of Age-related Macular Degeneration (AMD) in Patients Receiving Intensive Statin Treatment Academic research paper on "Clinical medicine"

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{AMD / Statins / High-dose / Reversal / Soft-drusen / "Vision gain"}

Abstract of research paper on Clinical medicine, author of scientific article — Demetrios G. Vavvas, Anthony B. Daniels, Zoi G. Kapsala, Jeremy W. Goldfarb, Emmanuel Ganotakis, et al.

Abstract Importance Age-related macular degeneration (AMD) remains the leading cause of blindness in developed countries, and affects more than 150 million worldwide. Despite effective anti-angiogenic therapies for the less prevalent neovascular form of AMD, treatments are lacking for the more prevalent dry form. Similarities in risk factors and pathogenesis between AMD and atherosclerosis have led investigators to study the effects of statins on AMD incidence and progression with mixed results. A limitation of these studies has been the heterogeneity of AMD disease and the lack of standardization in statin dosage. Objective We were interested in studying the effects of high-dose statins, similar to those showing regression of atherosclerotic plaques, in AMD. Design Pilot multicenter open-label prospective clinical study of 26 patients with diagnosis of AMD and the presence of many large, soft drusenoid deposits. Patients received 80mg of atorvastatin daily and were monitored at baseline and every 3months with complete ophthalmologic exam, best corrected visual acuity (VA), fundus photographs, optical coherence tomography (OCT), and blood work (AST, ALT, CPK, total cholesterol, TSH, creatinine, as well as a pregnancy test for premenopausal women). Results Twenty-three subjects completed a minimum follow-up of 12months. High-dose atorvastatin resulted in regression of drusen deposits associated with vision gain (+3.3 letters, p=0.06) in 10 patients. No subjects progressed to advanced neovascular AMD. Conclusions High-dose statins may result in resolution of drusenoid pigment epithelial detachments (PEDs) and improvement in VA, without atrophy or neovascularization in a high-risk subgroup of AMD patients. Confirmation from larger studies is warranted.

Academic research paper on topic "Regression of Some High-risk Features of Age-related Macular Degeneration (AMD) in Patients Receiving Intensive Statin Treatment"

Accepted Manuscript

EB oMed c ne

Regression of some High-Risk Features of Age-Related Macular Degeneration (AMD) in Patients Receiving Intensive Statin Treatment

Demetrios G. Vavvas, Anthony B. Daniels, Zoi G. Kapsala, Jeremy W. Goldfarb, Emmanuel Ganotakis, John I. Loewenstein, Lucy H. Young, Evangelos S. Gragoudas, Dean Eliott, Ivana K. Kim, Miltiadis K. Tsilimbaris,

Joan W. Miller

PII: S2352-3964(16)30029-9

DOI: doi: 10.1016/j.ebiom.2016.01.033

Reference: EBIOM 460

To appear in: EBioMedicine

Received date: 19 November 2015

Revised date: 26 January 2016

Accepted date: 27 January 2016

Please cite this article as: Vavvas, Demetrios G., Daniels, Anthony B., Kapsala, Zoi G., Goldfarb, Jeremy W., Ganotakis, Emmanuel, Loewenstein, John I., Young, Lucy H., Gragoudas, Evangelos S., Eliott, Dean, Kim, Ivana K., Tsilimbaris, Miltiadis K., Miller, Joan W., Regression of some High-Risk Features of Age-Related Macular Degeneration (AMD) in Patients Receiving Intensive Statin Treatment, EBioMedicine (2016), doi: 10.1016/j.ebiom.2016.01.033

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Regression of Some High-Risk Features of Age-Related Macular Degeneration (AMD) in Patients Receiving Intensive Statin Treatment

Demetrios G. Vavvas, MD, PhD*, Anthony B. Daniels,* MD, Zoi G. Kapsala, MD, Jeremy W. Goldfarb, MD, Emmanuel Ganotakis, MD, John I. Loewenstein, MD, Lucy H. Young, MD, PhD, Evangelos S. Gragoudas, MD, Dean Eliott, MD, Ivana K. Kim, MD, Miltiadis K. Tsilimbaris*, MD, PhD, and Joan W. Miller, MD, FARVO*

Retina Service, Department of Ophthalmology, Mass. Eye and Ear Infirmary, Harvard Medical School, Boston MA USA

Retina Service, Department of Ophthalmology, University of Crete, Heraklion, Crete, Greece Correspondence

*Joan W. Miller, Demetrios G. Vavvas 243 Charles St. Boston MA 02114 USA joan_miller@meei.harvard.edu, vavvas@meei.harvard.edu

HIGHLIGHTS:

• High dose lipophilic statin administration was associated with regression of large soft drusen and vision gain in 10/23 AMD patients.

• Duration of treatment before a positive response was observed was usually 1-1.5 years.

• Patients on high-dose statin appeared to be protected from progression to "wet" neovascular-AMD.

RESEARCH IN CONTEXT:

There is a lack of effective therapies for dry age-related macular degeneration (AMD), one of the leading causes of blindness affecting millions. Although AMD shares similarities with atherosclerosis, prior studies on statins and AMD have failed to show improvement. A limitation of these studies has been the heterogeneity of AMD disease and the lack of standardization in statin dosage. Here, we present for the first time evidence that treatment with high-dose atorvastatin (80mg) is associated with regression of lipid deposits and improvement in visual acuity, without atrophy or neovascularization, in high-risk AMD patients.

KEYWORDS: AMD, STATINS, HIGH-DOSE, REVERSAL, SOFT-DRUSEN, VISION GAIN

ABSTRACT

Importance: Age-related macular degeneration (AMD) remains the leading cause of blindness in developed countries, and affects more than 150 million worldwide. Despite effective anti-angiogenic therapies for the less prevalent neovascular form of AMD, treatments are lacking for the more prevalent dry form. Similarities in risk factors and pathogenesis between AMD and atherosclerosis have led investigators to study the effects of statins on AMD incidence and progression with mixed results. A limitation of these studies has been the heterogeneity of AMD disease and the lack of standardization in statin dosage.

Objective: We were interested in studying the effects of high-dose statins, similar to those showing regression of atherosclerotic plaques, in AMD.

Design: Pilot multicenter open-label prospective clinical study of 26 patients with diagnosis of AMD and the presence of many large, soft drusenoid deposits. Patients received 80mg of atorvastatin daily and were monitored at baseline and every 3 months with complete ophthalmologic exam, best corrected visual acuity (VA), fundus photographs, optical coherence tomography (OCT), and blood work (AST, ALT, CPK, total cholesterol, TSH, creatinine, as well as a pregnancy test for premenopausal women). Results: Twenty-three subjects completed a minimum follow-up of 12 months. High-dose atorvastatin resulted in regression of drusen deposits associated with vision gain (+3.3 letters, p=0.06) in 10 patients. No subjects progressed to advanced neovascular AMD.

Conclusions: High-dose statins may result in resolution of drusenoid pigment epithelial detachments (PEDs) and improvement in VA, without atrophy or neovascularization in a high-risk subgroup of AMD patients. Confirmation from larger studies is warranted.

INTRODUCTION

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the developed world1,2. The non-neovascular or "dry" form accounts for 85% of all AMD and is

characterized by accumulation of extracellular deposits, termed drusen , between the basal lamina of retinal pigmented epithelium (RPE) and inner collagenous layer of Bruch's membrane (BM), which is the inner wall of the choroid. Progression to advanced AMD involves atrophy of the RPE and overlying photoreceptors (geographic atrophy), and/or choroidal neovascularization (neovascular or "wet" AMD). While there are effective anti-angiogenic therapies for the less prevalent neovascular AMD, there are no effective treatments for the more prevalent dry form1.

Several clinical and epidemiological studies have established cardiovascular risk factors (including smoking, hypertension, and serum lipid status) to be associated with AMD development and progression, and both diseases share susceptibility genes1,4-7. This suggests that both diseases share similarities in their pathogenesis, and that interventions that reduce cardiovascular disease risk factors may be useful in AMD.

Bruch's membrane (BM) lies under the RPE and forms the inner margin of the choriocapillaris, and thus

is considered the structural analog of the vascular intima . Analogous aging changes in the vascular intima and BM are thought to relate to the pathogenesis of atherosclerosis and AMD, respectively9. Similarities in the protein molecular composition of drusen and arteriosclerotic deposits corroborate this perception10. In both conditions, apolipoprotein B (apo B) and cholesterol accumulate, with subsequent modification, oxidation, and aggregation. Drusen components are derived from local tissues (retina/RPE secreting apo B,E-containing lipoproteins11,12) and from the circulation13,14, and both AMD and atherosclerotic coronary artery disease involve lipoprotein retention. In AMD, an inflammatory response to the accumulated material may ensue with activation of complement and other components of the immune system, which can lead to atrophy of RPE cells and/or induction of a pro-angiogenic state and neovascular AMD.

Given these observations and similarities between atherosclerosis and AMD, it has been hypothesized that statin treatment may affect AMD status and/or progression15. Statins suppress cholesterol synthesis by inhibiting HMG-CoA reductase (the enzyme catalyzing the rate limiting step in cholesterol biosynthesis). In addition, they increase liver LDL receptors levels16, reduce apo B synthesis17 and suppress prenylation (the addition of hydrophobic molecules to a protein that is a physiologic process

that control localization and function) 18. Multiple epidemiological studies have examined this relationship with conflicting data19. A 2015 Cochrane report20 concluded that "[evidence is] insufficient to conclude if statins have a role in preventing or delaying the onset or progression of AMD." A small, proof-of-concept, randomized, placebo-controlled study of the effect of simvastatin on the course of AMD was recently published, and suggested that simvastatin at 40mg (equivalent to 20mg atorvastatin)

daily may slow progression of early/intermediate AMD, especially for those with the at-risk complement

factor H (CFH) genotype CC (Y402H) . Another recent study in patients with elevated plasma lipid

levels found that statin use for more than a year was associated with an increased hazard for neovascular

AMD22, and the authors postulated that these patients were resistant to statin treatment, rather than statins leading to increased risk for neovascular AMD. The Alienor study suggested that elderly patients with high HDL concentration may be at increased risk for AMD; furthermore, it found that HDL dysfunction might be implicated in AMD pathogenesis23. In contrast, data from a recent meta-analysis of three population-based cohorts over a 20-year follow-up period did not show a significant association between lipid levels or lipid pathway genes with the incidence or progression of AMD24. A major limitation in almost all studies thus far is the large heterogeneity of AMD disease (more than 100 at-risk genes and several phenotypes)1,25 and lack of standardization in statin dosage19,20 or

• • • • 14 26 27 • • m ' m

lipophilicity , , . There is clear evidence from the cardiovascular literature that statin dose does

28 29 30

matter , . The PROVE-IT study suggested that statin dose may be more important than LDL-c levels,

whereas the REVERSAL and ASTEROID trials showed benefit of aggressive over moderate intensity/dosage therapy31-33. The ASTEROID trial even showed regression of coronary atherosclerosis with very high-intensity statin therapy32. Similarly, Yu et al. showed that intensive but not regular-dose atorvastatin therapy resulted in regression of carotid atherosclerotic disease34 and two magnetic resonance (MR) imaging studies have shown regression of the lipid core of atheromatous plaque after high-dose statin35'36.

Here we present the first evidence that treatment with high dose atorvastatin may result in regression of drusen and improvement of visual acuity (VA) in patients with AMD with high-risk features for progression.

METHODS

A case report and pilot multicenter phase1-2 prospective interventional study (Mass. Eye and Ear, Boston, United States, and University of Crete, Heraklion, Greece) were conducted with institutional review board (IRB) approval, and informed consent was obtained from all participants. Since there is some evidence in the literature that hydrophilic statins (such as pravastatin) may not be equivalent to hydrophobic statins14,26,27 we use the hydrophobic atorvastatin (80mg, daily). Pilot study inclusion were as follows: patients over 50 years of age with diagnosis of AMD and the presence of many large (>300 microns in diameter and more than 100 microns in height) soft drusenoid PEDs. Exclusion criteria were as follows: presence (or history) of significant geographic atrophy or choroidal neovascularization in either eye; other eye diseases that could reduce VA (excluding mild cataract); history of eye surgery (other than cataract extraction); statin therapy (within the previous 2 years) at a dose equivalent to atorvastatin >40mg; history of liver disease, rhabdomyolysis, or allergy to statins; pregnancy or nursing; current use of medications known to interact with statins (e.g., cyclosporine, systemic itraconazole, clarithromycin, HIV protease inhibitors); and elevated transaminases or creatine phosphokinase (CPK) at baseline. Pseudophakia was not a reason for exclusion, unless accompanied by significant posterior capsular opacity. Patients received 80mg of atorvastatin daily. Baseline complete ophthalmologic exam, best-corrected VA by Early Treatment Diabetic Retinopathy Study (ETDRS) chart, fundus photographs, fundus autofluorescence, optical coherence tomography (OCT) and blood work (AST, ALT, CPK, total cholesterol, TSH, creatinine, as well as a pregnancy test for premenopausal women) were obtained. If there was any suspicion of occult neovascular AMD and FA and ICG were performed. Patients were monitored every 3 months with an eye exam, OCT imaging and AST, ALT, total cholesterol, and CPK monitoring. Best corrected VA acuity (EDTRS) and fundus photography were obtained every 6 months and at exit from the study. Duration of treatment was a minimum of 1 year. Physicians trained in internal medicine were involved in the design of the pilot study and in monitoring the patients during the study. Statistics were performed using GraphPad Statistical Software analysis (La Jolla, CA 92037 USA). The primary endpoint was reduction of drusenoid pigment epithelial detachment (PED) volume > 50% based on OCT imaging at exit from the study. Drusen volume was measured by automated analysis of macular retinal pigment epithelium (RPE) elevations with the Cirrus HD-OCT. Any automated measurement can have artifacts in segmentation especially if the quality of OCT obtain is not adequate. All scans were verified that the segmentation was appropriate.

RESULTS. Report of Initial Case

An otherwise healthy 63-year-old man with AMD on Age-Related Eye Disease Study (AREDS) vitamin supplements presented for a second opinion because of deteriorating VA. Baseline VA was 20/25 in each eye with significant distortion. Fundoscopy revealed bilateral extensive confluent large soft drusen and pigmentary alterations (Figure 1, top row). Spectral domain OCT (SD-OCT) confirmed significant drusenoid PEDs as well as architectural distortion of the overlying RPE and photoreceptor layers (Figure

2, top row). No subretinal or intraretinal fluid was present. Standard AREDS vitamin supplementation was continued. One year later, the patient became more symptomatic, and VA was slightly decreased to 20/30 in each eye. After extensive discussion, the patient was started on atorvastatin, beginning with 10mg daily and increasing gradually over 9 months by a predetermined rate (two-month intervals of 10mg/day, 20mg/day, 40mg/day, 60mg/day, and 80mg/day) to the target 80mg daily dose. Six months after reaching a daily dose of 80mg atorvastatin, VA improved by 12 letters to 20/20, and examination with fundus examination and SD-OCT revealing complete disappearance of the drusen without accompanying atrophy of the RPE. Intraretinal hyper-reflective foci remained (Fig 1 and 2, bottom row).

Pilot Study

Given these dramatic results, we initiated a pilot open-label multicenter interventional prospective trial at two academic medical centers, one in the United States and one in Europe, to determine if these effects might be generalizable. Of 26 patients enrolled in the two centers, 23 completed the pilot study (10 from Europe, 13 from the United States). All patients were Caucasians, and seven were men. Three patients exited the study: one because of cramps, one because of muscle aches, and one because the patient felt the drug was inducing hair loss. No patient exhibited elevated liver function tests (LFTs) that required exit from the study.

Ten of 23 patients (Table 1) responded to the treatment with significant regression of drusen deposits, with eight patients showing near complete regression (similar to Fig. 2). Responders (4 from United States, 6 from Europe, p=0.1221) had a reduction in volume from 0.57 +/- 0.47 mm3 to 0.049 +/- 0.051 mm3 (p=0.012). Non-responders volume changed from 0.23 +/- 0.20 mm3 to 0.35 +/- 0.32 mm3. On average, responders gained 3 letters whereas the non-responders lost 2.3 letters. The average time to response (resolution of the drusenoid deposits without atrophy) was 11.7 months (range 3-22). Six patients responded by 12 months and nine by month 18. The average person-years of follow-up were ~30. None of the patients converted to neovascular AMD. According to the online risk calculator (http://caseyamdcalc.ohsu.edu ), it would be expected that 14% of our cases (3-4/23 patients) would convert to neovascular AMD. Our alpha error in detecting zero cases is 2.1% Responders were slightly older than non-responders (70.6 +/- 6.2 vs. 66.2 +/- 5.5, p=0.081) and had equal baseline cholesterol levels (210 +/- 33.4 vs. 207 +/-37.4 p=0.86). Reduction of cholesterol levels did not appear to correlate with response status (49 +/-31.2 in responders vs. 71+/-35.9 in non-responders, p=0.14). Women had a higher odds ratio (7.71) of being responders, but this was not statistically significant (95% confidence limits 0.746 - 79.7746, p=0.0886). There were no apparent differences in multivitamin use, aspirin use, fish oil consumption, or anti-hypertensive medications. There was only one smoker in our study. Atorvastatin did not appear to have a positive or negative effect on progression of pigmentary changes in fundus photographs or on intraretinal hyper-reflective foci.

Discussion

AMD is the leading cause of irreversible vision loss in adults in the industrialized world . Hallmarks of this disease include lipid-rich basal linear deposits and drusen between the RPE basal lamina and the

1113 • • 37

remainder of BM , , which are known to contain complement and several immunogenic and toxic

38 • 39

materials, such as 7-ketocholesterol and amyloid. In many studies, drusen sampled for analysis are not confined to the macula; this is important to note because peripheral drusen (which can differ from macular drusen) may predominate 37 0. Lipidation of BM is thought to impair transport of compounds necessary for the health of the retina and RPE 41-45. Elimination of these deposits is widely regarded as of potential benefit to patients. Although drusen can regress spontaneously, new lesions may appear in other locations46,47 and most often, development of late stages of disease (geographic atrophy and or choroidal neovascularization) is often preceded by drusen reduction.46-48. Several trials have studied

ways to reduce drusen, notably the Prophylactic Treatment of Age-related Macular Degeneration (PTAMD) Study, which used 810nm laser to treat drusen,49 and the more recently complement C5 inhibitor trial50. Unfortunately, both studies failed to show regression or prevention of progression to late AMD or improvement in visual acuity. Here we present a case report and results of an open-label pilot prospective study that provide the first evidence that medical intervention with high-dose atorvastatin may cause regression of large drusen without progression to advanced AMD, and with possible improvement in VA.

AMD is a heterogeneous disease, with several different phenotypes, including types and size of drusen1. Prior epidemiological studies examining the role of statins in AMD15,19-24,51,52 did not stratify or distinguish patients based on AMD subtype. It is unlikely that statins would have across-the-board effectiveness in a heterogeneous disease, and for this reason we focused on patients with large soft drusen and drusenoid PEDs, which are known risk factors for progression to advanced disease. AMD is also multifactorial, with >100 reported at-risk genes that can be grouped into pathways1 with a subset of

25 53 58

AMD-related genes that can be aligned on an atherosclerosis-like progression25,53-58. Although prior studies showed negative overall association between AMD and statin use, they did suggest a potential protective role in a subset of patients with soft drusen or in patient with the at risk CFH genotype CC

21 51 52

(Y402H) risk gene , , . These findings, taken together with our study, suggest that statins may have a particular role in certain (intermediate-high risk, large drusenoid deposits), but not all, AMD patients. Cardiovascular studies suggest that the effect of statins on regression of atheromatous pathology may not be related to actual serum LDL or HDL levels achieved, as shown by the PROVE-IT trial30 or by a more recent head-to-head comparison of atorvastatin 80mg vs. rosuvastatin 40mg59. Likewise, we did not observe any differences in cholesterol level reduction between responders and non-responders in our pilot study, suggesting that factors other than lipid lowering response may be important for the observed phenomena. That does not mean that lipid lowering is not needed; lipid lowering may be a permissive state for drusen regression to happen via other mechanisms. Aging macrophages have reduced levels of the cholesterol transporter ABCA1, impaired cholesterol efflux, and a pro-angiogenic polarization60. Increased cholesterol intake recapitulates these "aging" changes in macrophages and leads to advanced neovascular AMD pathology in mice60. Mechanistically, lipid lowering by statins may reverse this "aging" of macrophages and thereby improve AMD pathology. In addition, mice fed a high-fat diet exhibit RPE and BM changes similar to human aging and AMD, such as lipid droplets in the BM; administration of simvastatin led to significant reversal of these changes61. This suggests that lipid lowering may be a necessary factor in reversing AMD pathology61.

Statins are thought to have antioxidant properties62. The RPE, bathed by the high oxygen tension environment of the choriocapillaris63,64, is susceptible to chronic oxidative stress, which may play a role in AMD pathogenesis65-69. Statins have been shown to reduce oxidative stress-induced injury to the RPE

and increase viability , . Statins modulate ApoB100 secretion in cultured human RPE cells via modulation of RPE cholesterol levels14, although not all statins are equivalent, with lipophilic ones (like atorvastatin) being more effective than hydrophilic ones (such as pravastatin). This differential effect of statin class on RPE function is yet another potential confounding variable that can affect results of epidemiological studies that do not distinguish between classes of statins.

Despite the high-risk characteristics of our patient cohort, none of them progressed to neovascular or wet AMD. As noted earlier, mice fed high cholesterol diet had a switch to the proangiogenic type of macrophages and increased wet AMD phenotype60. Statins have been shown to reduce inflammatory cytokine IL-672, to downregulate VEGF expression in TNFa-induced tortuosity of retinal vessels in

mice, and to reduce laser-induced choroidal neovascularization in a mouse model of neovascular

AMD , suggesting a beneficial role of statins in preventing conversion to neovascular AMD. In addition, statins may benefit patients with large lipid-rich sub-RPE drusenoid deposits through multiple potential mechanisms: by preventing their accumulation through reduction of local and

systemic production, increasing the ability of macrophages and/or RPE to clear debris, and/or by reducing oxidative damage and by stabilizing the vascular supply to the macula. Our open-label pilot safety/efficacy study suggests that intensive statin treatment may cause regression of high-risk features of AMD, such as drusen, without progression to advanced AMD and without the vision loss that often accompanies spontaneous disappearance of drusen. These results are consistent with the "locally produced oil-spill" hypothesis13 of AMD pathogenesis. Of course there are several obvious limitations of our study. It is an open label, non-randomized pilot study with a small and rather homogeneous sample size that is followed on average for only 1.5 years. It is known that rarely, spontaneous reduction or collapse of drusen without atrophy can occur and it is conceivable that our narrow cohort selected for such patients. In addition, we do not know how long the effects can last and how long statins should be administered. Finally, the effects of statins in cases with preexisting atrophy are not addressed in this pilot study. For these reasons, future larger randomized prospective studies are needed to assess the exact role of statins in AMD. These studies should take into account genotype and phenotype subgroups of AMD, as well as dosing, lipophilicity, and potency of the statin tested.

Author contributions

DGV conceived the study. DGV, ABD, JWG, EG, MKT and JWM were involved in the design of the pilot study and writing of the manuscript. JWG, EG, ZGK, JIL, LHY, ESG, DE, IKK, contributed patients, data gathering, analytical discussions, and contributed to writing.

Disclosures

There are no relevant financial disclosures. Acknowledgements/Funding

We like to thank Wendy Chao Ph.D. for professional editing of the manuscript. The study was supported by the Yeatts Family foundation, the Mass. Eye and Ear Neovascular AMD funds, the Loefflers Family foundation, and the Research to Prevent Blindness Foundation (DGV and JWM). The funders had no role in study design, data collection, data analysis, interpretation, or writing of the report.

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Figure Legends Figure 1.

Color fundus images of a 63-year-old man with AMD and large soft drusen and drusneoid pigment epithelial detachments. Upper panel at presentation, middle panels one year later at start of atorvastatin and lower panels a year after atorvastatin treatment.

Figure 2.

High resolution optical coherence tomography of patient in Figure 1. Upper panel prior to initiation of atorvastatin treatment and lower panels a year after atorvastatin treatment. Intraretinal hyperreflective foci remained at the end of treatment.

TABLE 1. Characteristics of responders vs non-responders

All (n=23) Responders (n= 10) Non Responders (n=13)

Age (years) 68.1 +/-6 70.6 +/- 6.2 66.2 +/- 5.5 p=0.08137

Hypertension 10 5/10 5/13 Fisher 0.685018

Initial Cholesterol (total Chol mg/dL) 208 +/- 34.9 210 +/- 33.4 207 +/-37.4 p=0.859484

Last Cholesterol 147 +/- 31 161 +/- 34.2 136 +/- 24.4 p=0.057162

Chol. Reduction -62 +/-35 -49 +/-31.2 ^ -71+/-35.9 p=0.140764

Eye Vitamins 14 7/10 7/13 Fisher 0.669269

Vitamin D use 5 3/10 2/13 Fisher 0.635117

Fish oil Use 5 2/10 3/13 Fisher 1

Aspirin use 7 3/10 4/13 Fisher 1

Initial VA (Letters) 77.6 +/- 8.3 74.2 +/- 9.9 80.2 +/- 6 p=0.089024

Last VA (letters) 77.7 +/-8.4 77.5 +/-10.3 77.9 +/- 7.1 p=0.908481

VA gain (loss) +3.3 -2.3 p=0.061144

ACCEPTED MANUSCRIPT

---1 2009

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Fig. 1

2010 OD VA 20/30

2010 OS VA 20/30

Fig. 2