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Macular Degeneration and the Age-Related Eye Disease Study

W. Steven Pray, PhD, DPh
Bernhardt Professor, Nonprescription Products and Devices
College of Pharmacy
Southwestern Oklahoma State University
Weatherford, Oklahoma
 

Gabriel E. Pray, PharmD Candidate
College of Pharmacy
Southwestern Oklahoma State University

Weatherford, Oklahoma
 



4/20/2011

US Pharm
. 2011;36(4):37-41. 

As the average age of the population rises due to the large number of baby boomers, increasing attention is focused on the problems that accompany aging. A federally sponsored landmark study of age-related eye conditions sheds new light on prevention and treatment of age-related macular degeneration (AMD). Further research will go beyond the first study and continue to explore novel methods of preventing and treating eye conditions due to aging. Pharmacists can answer questions regarding these issues and recommend appropriate steps the patient can engage in to better take advantage of emerging research. 

Age-Related Macular Degeneration

AMD is a major cause of visual loss in people aged 60 to 65 years and older.1,2 The prevalence was estimated to be 1.75 million cases in 2004.3 The number of people affected is steadily increasing, and the problem is worse in industrialized countries. Experts estimate that the number of U.S. citizens diagnosed with AMD will increase to 2.95 million by 2020.3 

The morbidity of AMD can be staggering for those affected. The macula is a portion of the retina that provides fine detail vision.4,5 Its degeneration via death of cells destroys sharp central vision. Loss of central vision leads to an inability to see objects clearly, and may restrict such common everyday tasks as sewing, recognizing faces of loved ones, reading, and driving. 

Patients affected with AMD may not notice its onset, as it is painless.4 The progress may be sufficiently gradual that patients adapt to their slowly worsening vision through such coping interventions as increasing the room light when reading. In other cases, however, AMD develops rapidly, preventing patients from devising coping methods and producing bilateral visual loss. 

AMD appears in two forms—dry and wet. Dry AMD is the earlier variant during which light-sensitive macular cells slowly degenerate, causing the gradual blurring and loss of central vision.5 Eventually, the patient may notice the blurred spot in the center of the visual field. While it is more common for both eyes to be affected, some patients experience unilateral visual loss. Dry AMD progresses through three stages: early, intermediate, and advanced. When intermediate and advanced AMD are combined, over 85% of patients have dry AMD, and approximately 33% of patients with advanced AMD have the dry form.6 Staging is partly assigned by the number of drusen (yellow deposits under the retina), because increases in the number or size of drusen are associated with increased risk for both dry and wet AMD. 

The first stage is early dry AMD, in which patients have only a few small or medium-sized drusen. At this stage, vision is normal and there are no symptoms. The condition has advanced to intermediate dry AMD when the patient has many medium-sized drusen or one or more large drusen under the retina. Some of these patients notice blurring of central vision and may compensate by increasing the light when reading. Advanced dry AMD is characterized by drusen as in the second stage, but also by a breakdown of the light-sensitive cells and supporting tissues of the macula. Patients are most likely to have blurred central vision with this stage. 

All people with wet AMD first suffered from dry AMD. For some reason, the dry AMD in some patients (even those with early stage AMD) suddenly becomes wet AMD. Thus, wet AMD is by definition a more severe condition than dry AMD. Wet AMD has no staging, as it is always considered advanced. Wet AMD is a condition wherein abnormal blood vessels develop behind the retina.3 The new blood vessels allow blood and fluid to leak from them owing to their fragility when compared to the patient’s normal vasculature. The combined blood and fluid force the macula to rise from its normal location at the back of the patient’s eye. Patients affected with wet AMD may notice a wavy appearance to lines that should be straight. 

Epidemiology of AMD

The epidemiology of AMD provides clues to its prevention in some cases. For instance, smokers and obese patients are more prone to experience it, so ceasing smoking and losing weight can help prevent the condition.5 Other nonmodifiable factors are also important, such as increasing age. Race is predictive, as whites are far more likely to undergo AMD-associated visual loss than blacks.5 Those with a family history are also at higher risk, and women’s risk exceeds that of men.7 

Diagnosis of AMD

Diagnosis of AMD requires a comprehensive ophthalmic examination, including a test of visual acuity, an examination of the retina and optic nerve following dilation, and intraocular pressure (IOP) measurements taken with a Goldmann tonometer or other less widely accepted IOP measurement methods.5 Patients are often asked to look at a lined grid known as an Amsler grid. Missing lines or wavy lines within the grid are possible clues to wet AMD. The National Institutes of Health (NIH) cautions seniors that dry AMD can suddenly and without warning become wet AMD, as described above. The organization urges patients to obtain an Amsler grid from their eye care professional and to use it daily to detect the first signs of onset of wet AMD. 

Prognosis of AMD

No treatment can prevent visual loss for patients with advanced dry AMD.1,5 However, appropriate therapy with certain vitamins and minerals may delay and prevent intermediate forms of AMD from moving to the advanced form. 

Wet AMD cannot be cured, but its progression may be arrested with the use of laser surgery, photodynamic therapy, and intraocular injections.5 Lasers can destroy the abnormal blood vessels for a small number of patients with wet AMD, although new vessel growth may necessitate repeated appointments. Photodynamic therapy consists of injections of verteporfin (Visudyne), which adheres to surfaces of newly formed blood vessels, such as those in the eye of patients with wet AMD. The physician shines light of a specific wavelength into the eye for approximately 90 seconds, activating the verteporfin and allowing it to destroy the newly formed blood vessels and slow the progression of wet AMD. It is an in-office procedure, usually completed in 20 minutes. Patients are cautioned to protect the skin and eyes from direct sunlight or even bright indoor light for a period of at least 5 days after photodynamic treatment to avoid damage to those areas. 

Physicians may also administer intraocular injections of a group of products known as antivascular endothelial growth factor (anti-VEGF) medications.5,8 They include bevacizumab (Avastin), pegaptanib (Macugen), and ranibizumab (Lucentis). These products reverse the high levels of VEGF seen with wet AMD, which is responsible for growth of the abnormal new blood vessels. Patients require multiple injections, as often as once monthly. 

Vitamins, Minerals, and the Eyes

Several vitamins and minerals are known to be important in the health of the eyes. There is particular interest in antioxidants and their effect on free radicals. Free radicals have an unshared electron that can form reactive oxygen species, which, in turn, have destructive effects on healthy tissues, such as those of the eye.9 Antioxidants protect tissues from free-radical–induced damage. Researchers have hypothesized that an element of AMD pathogenesis may be retinal damage due to oxidation. 

Vitamin A has the synonym of retinol, referring to its role in producing the pigment in the retina.10,11 It is also responsible for visual acuity, especially in low-light situations, important in driving at night. Beta-carotene is an antioxidant vitamin A precursor, composed of red, orange, and yellow pigments.11,12 It has been used in pregnant women with poor nutrition in order to reduce night blindness.12 

Vitamin C is an antioxidant vitamin that promotes the formation of healthy capillaries in the eye.13 Research suggests that it lowers the risk of cataract formation in certain situations.13,14 Vitamin E also acts as an antioxidant.15 Thus, it may act in concert with the other antioxidants to attenuate free-radical damage.9,16 

Zinc is an essential trace element.17 Its specific role in the eye is to aid transport of vitamin A from the liver to the retina, thereby enhancing its ability to produce melanin, a protective ophthalmic pigment.18,19 Zinc is found in the retina and its underlying vascular layer, a tissue known as the choroid.18,20 Experts have proposed that low intake of zinc in U.S. citizens may be partially responsible for development and/or progression of chronic eye diseases.20 However, zinc supplementation is not without risk. Excessive intake can lead to copper deficiency, a potential cause of sideroblastic anemia.21-23 For this reason, supplements with zinc often include copper. 

The Age-Related Eye Disease Study

In 2001, a groundbreaking study regarding the use of nonprescription products in slowing progression of AMD and vision loss appeared in the Archives of Ophthalmology.1 The Age-Related Eye Disease Study (AREDS) was supported by the National Eye Institute, a subsection of the NIH.1,24,25 More than 4,700 patients were enrolled in 1998, and the study was completed and published in 2001. 

The purpose of the research was to examine the effects of high doses of vitamins C and E, beta-carotene, and zinc on AMD and visual acuity. Patients received one of four treatment interventions.1,26 One group received antioxidant supplements that provided a total daily oral intake of 500 mg of vitamin C, 400 IU of vitamin E, and 15 mg of beta-carotene. (One IU of vitamin A is equivalent to 0.6 mcg of beta-carotene, so the equivalent daily dose ingested by study patients in terms of vitamin A was approximately 25,000 IU.27

Another group of patients received a supplement containing 80 mg of zinc as zinc oxide, with 2 mg of copper as cupric oxide added to prevent potential anemia. A third group received a combination of the antioxidant and the zinc-copper formula. The fourth group received placebos. All four of the tablet formulations were identical in external appearance and similar in internal appearance and taste. Bausch & Lomb, a collaborator in the study, supplied the nonprescription product used.1,26

Results of AREDS

AREDS demonstrated that the antioxidant-zinc supplement reduced the risk of AMD and its associated vision loss (there was no effect on cataract).25 However, the supplements should not be taken indiscriminately. The NIH explained to seniors that supplementation is only appropriate for those at high risk of developing advanced AMD, as diagnosed by a physician.5 Those patients include anyone with intermediate AMD in one or both eyes, or advanced AMD (dry or wet) in one eye but not the other eye.5,26 Patients who are already taking another supplement should be advised to speak with their physician before taking any new supplement. Pharmacists should be aware that most AREDS participants were concurrently consuming multivitamins that included recommended daily amounts of most vitamins and minerals.26 A summary of the types of AMD, their characteristics, and the recommendations for supplementation are listed in TABLE 1

Patients with early stage AMD have no justification for ingesting the supplement, as there was no benefit for them in AREDS.5 Pharmacists may explain to concerned early-stage patients that once the AMD has progressed to the intermediate stage, they should then discuss taking the supplement with their physician. In the meanwhile, they may be advised to institute healthy lifestyle changes such as smoking cessation, losing weight, exercising, eating a diet high in green leafy vegetables and fish, and maintaining their blood pressure within normal limits.5 

Taking the supplements used in the AREDS formula was not without risk for study subjects. Subjects taking antioxidants were hospitalized more frequently for infections (1.6% versus 0.8% in those not taking antioxidants), although those taking antioxidants experienced a reduced rate of hospitalizations for such mild/moderate problems as chest pain/discomfort, vasovagal episodes, and fever (7.4% versus 10.1%). Patients taking zinc experienced a higher rate of hospitalizations for genitourinary problems, specifically urinary tract infection and prostatic enlargement in men and stress incontinence in women. The rates were 7.5% for male subjects taking zinc and 4.9% for males not taking zinc, and 8.6% versus 4.4%, respectively, for women. Subjects taking zinc were also hospitalized more frequently (9.7% versus 7.8%). All differences were statistically significant.1 

Nonprescription Products

Two nonprescription vitamin products are advertised as “AREDS Formulas.” One product, PreserVision Eye Vitamin AREDS Formula Tablets, suggests that the patient take 4 tablets daily.28 At that dose, the patient will ingest 28,640 IU of vitamin A (as beta-carotene), 452 mg of vitamin C, 400 IU of vitamin E, 69.6 mg of zinc (zinc oxide), and 1.6 mg of copper (cupric oxide). This formula is roughly equal to the doses given to patients in the study. Bausch & Lomb also supplies PreserVision AREDS Soft Gel Formula, which provides the same levels of the nutrients in two daily soft gels.29 

Another option is Alcon’s ICaps Eye Vitamin AREDS Formula.30 The recommended dose is two soft gels or four tablets daily. At that regimen, the patient would ingest the same nutrients in amounts equal to the PreserVision AREDS Formula. This product is also roughly equivalent to what patients received in the AREDS study. 

Risk to Vitamin E Ingestion

In early 2005, the AREDS Coordinating Center sent a letter to patients who had participated in the original AREDS.31 The Center explained that a research paper of interest was being published in the January 2005 issue of the Annals of Internal Medicine. This paper combined data from 19 clinical trials that tested vitamin E for different diseases. One of the trials used in the 2005 paper was the original AREDS. The authors of the 2005 paper looked at risk of death from vitamin E ingestion, concluding that doses of vitamin E equal to or in excess of 400 IU may increase the risk of mortality from all causes. The Center provided a deeper analysis demonstrating that the 400 IU dose used in the AREDS did not increase risk of dying in a large number of patients. Finally, the Center concluded that the AREDS-associated 25% reduction in risk of developing AMD might outweigh the negligible or nonexistent risk of early death, and suggested that patients discuss the issue with their physicians. 

AREDS 2

A second study on the effects of various supplements on the eye is ongoing. Known as AREDS2, it has several objectives. One is to determine whether high supplemental doses of lutein, zeaxanthin, and/or omega-3 long-chain polyunsaturated fatty acids (e.g., docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) affect the development of advanced AMD, cataracts, and moderate vision loss. Another is to examine the impact on the development and progression of AMD of eliminating the beta-carotene or reducing the amount of zinc in the original AREDS formula.32 Enrollment of 4,000 patients aged 50 to 85 years was concluded in June 2008, and the patients will be followed for 5 to 6 years. 

Bausch & Lomb initially supplied PreserVision AREDS2 Formula, to be taken in a dose of one soft gel twice daily; however, due to incidents of patients aged 70 years and above who reported difficulty in swallowing or a sensation of choking, this product was voluntarily recalled.33 It was reintroduced as a smaller soft gel, with patients being directed to take two soft gels twice daily. At that dose, patients would ingest 226 mg of vitamin C, 200 IU of vitamin E, 34.8 mg of zinc, 0.8 mg of copper, 325 mg of EPA, 175 mg of DHA, 5 mg of lutein, and 1 mg of zeaxanthin daily.34 As AREDS2 is ongoing, the exact benefits of this altered formula remain to be seen. 

Conclusion

When patients ask about AMD and the use of supplements, pharmacists must explain that only those with intermediate AMD in one or both eyes, or advanced AMD (dry or wet) in only one eye, are proven to benefit from the AREDS formula. Products such as Preser-Vision AREDS Formula Tablets and ICaps AREDS Formula provide levels of the supplements that are extremely close to the original AREDS formula and can be recommended to concerned patients for whom they are appropriate. 

REFERENCES

1. A randomized, 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.
2. Prasad PS, Schwartz SD, Hubschman JP. Age-related macular degeneration: current and novel therapies. Maturitas. 2010;66:46-50.
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21. Willis MS, Monaghan SA, Miller SL, et al. Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination. Am J Clin Pathol. 2005;123:125-131.
22. Patterson WP, Winkelmann M, Perry MC. Zinc-induced copper deficiency: megamineral sideroblastic anemia. Ann Intern Med. 1985;103:385-386.
23. Nations SP, Boyer PJ, Love LA. Denture cream: an unusual source of excess zinc, leading to hypocupremia and neurologic disease. Neurology. 2008;71:639-643.
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. Accessed December 25, 2010.
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dietarysupplementdatabase. usda.nih.gov/ingredient_ calculator/help.php#q10. Accessed December 25, 2010.
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visioncare/product/vitamins/ ocuvite_preservision.aspx. Accessed December 25, 2010.
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visioncare/product/vitamins/ preservision_softgel.aspx. Accessed December 25, 2010.
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corporate/corpcomm/news/media_ advisory_7_22_2010.aspx. Accessed December 25, 2010.
34. PreserVision Eye Vitamin AREDS 2 Formula, Soft Gels. www.drugstore.com:80/
qxp319034/preservision/eye_ vitamin_areds_2_formula_soft_ gels.htm?fromsrch=preservision . Accessed December 25, 2010. 

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