AREDS is changing the minds of general ophthalmologists

The study is out, dietary supplements are available, but will physicians encourage their patients to begin antioxidant and zinc loading?

In November, the National Eye Institute released data from its Age-Related Eye Disease Study showing that a combination of antioxidant and zinc supplementation may play a significant role in slowing the progression of age-related macular degeneration.

What will this new information mean for general ophthalmologists? For years, supplements aimed at staving off age-related eye disease have been available, but there have been little or no scientific data to document their effectiveness. Finally there are data. Will sales of eye health supplements go through the roof in coming months? Are physicians ready to recommend these supplements to their patients?

To answer these questions, Ocular Surgery News asked ophthalmologists in both private practice and academic settings about their reaction to the new information – their awareness of it, their opinions of it, how it will affect their practices. The responses, from practitioners on three continents, show that many ophthalmologists were eagerly awaiting confirmation of the benefits of supplements that they have suspected for some time.

The Age-Related Eye Disease Study (AREDS) data suggests that a daily supplement of 500 mg of vitamin C, 400 IU of vitamin E and 15 mg of beta carotene, along with 80 mg of zinc as zinc oxide and 2 mg of copper as cupric oxide to prevent potential anemia will slow the progression of age-related macular degeneration (AMD).

While the formulations do not all match the AREDS supplements’ makeup exactly, several eye health supplements have been on the market for some time. Bausch & Lomb has offered the vitamin supplement Ocuvite for more than 5 years, and Alcon’s Icaps have been available for about that amount of time. ScienceBased Health’s MaculaRx and OculaRx have been available for at least 2 years. See the accompanying chart on page 38 for a comparison of the supplements’ contents.

AREDS results

At the 2001 American Academy of Ophthalmology meeting in New Orleans, AREDS investigator Frederick L. Ferris, MD, presented data on the 10-year study of 3,640 AMD patients.

AREDS involved 11 centers across the United States, concentrated most heavily in the Northeast. The study evaluated persons aged 55 to 80 years who had visual acuity of 20/32 or better in both eyes, or who had 20/32 or better in one eye but had AMD and vision loss or advanced AMD in the fellow eye.

Participants in this study were divided into four categories. Category 1 consisted of cataract patients with various levels of lens opacity. These 1,117 participants had few or no drusen. Category 2 had 1,063 patients with some small drusen, which had to be less than 125 µm in size.

Category 3 patients had extensive intermediate drusen, large drusen, which could be as few as just one large drusen. Category 4 was comprised of two different groups, a group with neovascularization and a group that had central geographic atrophy.

Patients in each category received one of four formulations. One formulation contained only antioxidants, including vitamin C, vitamin E and beta carotene. A second formulation contained zinc oxide and cupric oxide.

“The cupric oxide is important be cause persons taking elevated levels of zinc may be at risk of copper deficiency anemia because of the competition in uptake with copper by zinc,” Dr. Ferris said.

A third formulation contained a combination of both the zinc and antioxidant formulations. The fourth was a placebo.

The final study design included 3,640 patients in categories 2, 3 and 4. They were divided into four roughly equally size groups at random. The category 1 patients were excluded because it was felt they had little or no likelihood of developing advanced AMD.

Over 6.3 years AREDS successfully followed 97.5% of these participants. In addition, as reported by the patients’ own pill counts, 75% of patients complied with the dosing regimen.

According to Dr. Ferris, AREDS could find no effect of the supplements on cataract or visual acuity loss.

The antioxidant group showed few, if any, effects that could be directly linked to the treatment. In the zinc group there were slightly more hospitalizations for mild to moderate symptoms.

“The hospitalizations may be in large part due to an increase in genitourinary complications and specifically, I think, increase in prostatic hypertrophy,” said Dr. Ferris. “We were also concerned about anemia, but when we measured hematocrits at yearly intervals we found no difference between the zinc and non-zinc groups.”

Emily Y. Chew, MD, also an AREDS investigator, showed that in category 2, early AMD with few intermediate drusen and no large drusen, only 1.3% of patients progressed to advanced AMD within 5 years.

Eighteen percent of category 3, the intermediate risks patients with at least one large drusen or extensive intermediate drusen, went on at 5 years to have advanced AMD. And 43% of the highest risk patients in category 4, who already had advanced AMD in one eye, advanced to AMD by 5 years.

The placebo group had the largest event rate with 28% of patients developing advanced AMD by 5 years.

“When we looked at the estimate of the risk reduction of developing any advanced AMD in categories 3 and 4, patients with intermediate risk and patients with advanced AMD, we saw that the biggest reduction is with the combination treatment of antioxidant and zinc with a 25% reduction compared to placebo,” Dr. Chew said.

The study found no beneficial effect in patients with early AMD but statistically reduced risk of developing advanced AMD with both zinc alone and antioxidant and zinc together in patients with intermediate AMD or advanced AMD in one eye.

“We recommend that patients have to come in for a dilated eye exam to determine whether there’s a risk for advanced AMD progression. That includes patients with extensive intermediate drusen, at least one large drusen, non-central geographic atrophy or a patient having advanced AMD or vision loss due to AMD in one eye. These are the high-risk patients that we like to identify. We recommend the treatment that we’ve given. Consider supplements of antioxidant plus zinc in these patients,” Dr. Chew said.

Real-world commentary

The AREDS is the first of its kind to show that nutritional supplements may have a direct and significant effect on a particular eye disease. But the study results and the long-term effects of supplementation are still the subject of debate among ophthalmologists.

“Yes, it has influenced doctor’s opinions,” said Albert J. Augustin, MD, of Karlsruhe, Germany, in an interview with Ocular Surgery News. “However, the side effects show that we have to be careful. We need additional studies. I personally believe that the side effects can be explained by the mechanism of an ‘oxidative deficit.’ The most important issue of the study is that we will have additional studies and information, which will give us more insight into the pathogenesis of diseases such as AMD or diabetic retinopathy. I believe that oxidative mechanisms play an important role in the pathogenesis of these diseases.”

From Udine, Italy, Paolo Lanzetta, MD, added, “It is now known that oxidative damage to the retina may be involved in the pathogenesis of AMD. Of course this is only one of probably multiple events that are at the basis of the disease. Unfortunately, previous data from a number of epidemiological or randomized studies did not really show strong definitive evidence of association between intake or deficiency of antioxidants and zinc and risk of AMD. New data from the AREDS study are helpful, because they define better the role of supplements and the risk of progression of the disease. Therefore, through the modality of application of what we have learned from the AREDS study, we must discuss this with our patients. I will take into serious consideration modifying our preventive approach to avoid the advanced stages of AMD.”

Dr. Augustin said he also believes the rationale of giving high dose supplements has to be further discussed. He said he also wonders why car otenoids were used in the study and not lutein and zeaxanthin. Before recommending that patients take these supplements, he said, physicians should evaluate patients for additional signs or symptoms of diseases that indicate an oxidative deficit.

He is also somewhat fearful of all the metals being ingested. “It makes no sense to take so much copper in civilized countries,” Dr. Augustin said.

Dr. Lanzetta said he is less concerned with the heavy concentration of metals in the AREDS regimen. “In cases where it is clear that supplements would be helpful, the study is unremarkable (design of the study, statistical methodology, results), and long term supplement intake is safe, it is the duty of the physician to educate the patient to an effective preventive regimen.”

Dr. Lanzetta said it is still too early to form one’s own practical enthusiastic or negative opinions on the results of the study. “Surprisingly, I have been updating many people working in companies that produce supplements who were still unaware of the results of the AREDS,” he said.

“My personal behavior will be to discuss extensively with the patient about her or his disease, depending on the stage of AMD. I always underline the high incidence of bilaterality and the multifactorial pathogenesis that is still poorly understood. With regard to prevention, I suggest a healthy lifestyle with no smoking (a known risk factor), blood pressure monitoring and a dietary style that may be identified in the Mediterranean diet, rich in fresh vegetables and fruit, pasta and olive oil. Considering that patients in the AREDS study received supplements 5 to 15 times the RDA, I also mention the opportunity to take adjunctive antioxidants and zinc in selected cases,” Dr. Lanzetta said.

Compliance issues

Annabelle A. Okada, MD, of Tokyo, said while she has been impressed by the AREDS study. Physicians must consider if patients will actually take the required amounts of antioxidants and zinc.

“The studies taken alone would warrant taking these supplements; however, actual use also depends on cost, availability in each country, etc. For example, supplements are not currently covered by Japanese national health insurance,” Dr. Okada said.

She said easy-to-use multivitamin supplements from the pharmaceutical companies will help with compliance.

“I was very pleased that the AREDS study confirmed what a lot of peripheral studies have said in the past,” said Richard B. Rosen, MD, of New York. “I’ve always believed that nutritional supplements could have an effect.”

Dr. Rosen said the real bonus of the study is that it has raised the awareness and confidence of patients who may be helped by these supplements. He noted that many patients wish to take control in their lives and their health, and supplements offer them that opportunity.

While the AREDS study has raised the general level of awareness of supplements, Dr. Rosen said, it has also led to confusion among patients as well. He said physicians need to inform their patients of exactly what has been proven by the studies.

“I think physicians are interested in keeping their minds open about new things,” said Ralph C. Lanciano, MD, of Pennsauken, N.J. “In most cases, if patients come to us and ask us about new ideas, we need to make sure we’re telling them that this is our opinion. However, in the case of AREDS, this is now backed up by good science.”

He said even with the results of AREDS, physicians must weigh the benefits of the supplements with what is in the best interests of their patients and of their patients’ wallets.

“Supplements aren’t regulated by the FDA. There could be problems with megadosing on these like we’ve seen with vitamin E and vitamin C. Vitamin E has been shown to increase bleeding and vitamin C has been implicated in kidney stones. Since these supplements are unregulated, we need to let patients know this.” Dr. Lanciano said.

Dr. Lanciano said he checked with the retina specialists he works with to gauge their opinions. He said it would not do for patients to hear one thing from a general ophthalmologist and another from a retina specialist. He said his retina specialists informed him that patients in category 1 or 2 are probably best served by taking a supplement such as Centrum Silver once a day. Category 3 and 4 patients should most likely be taking the recommended AREDS dosages.

Dr. Lanciano says he also gives his patients a consumer copy of the AREDS study so they can understand the basic science of the study and what kind of results they can expect.

Dr. Lanzetta said that before starting patients on supplements a physician must consider what population among his patients is as similar as possible to the population in the AREDS study and how long supplements should be taken to have a clinical benefit. He believes physicians must consider potential risks due to the long-term intake of supplements that are in some cases 5 to 15 times the recommended daily allowance.

Michael J. Cooney, MD, of Duke University, said he also believes the results of AREDS will influence doctors’ opinions on supplements.

“Many physicians had been recommending supplements for years without any scientific data to support that recommendation. Physicians want to be able to recommend something for their patients, and AREDS now allows us to do so for previously untreatable eye diseases,” he said.

Dr. Cooney is now proactively recommending supplements that meet the treatment guidelines for AMD patients. Prior to AREDS, he did not recommend supplements because of a lack of scientific data. He left it up to the patients to decide for themselves on the merits of supplementation.

“I recommend these supplements to AMD patients, but make certain that they are informed of the findings, understand the expectations and understand the potential side effects,” he said. “I tell all my patients to see their internists before seeing their ophthalmologist. I don’t think a physician should make the decision for the patient. Patients need to be told of the findings in lay terms and make decisions for themselves. Most patients with AMD are motivated to do anything to help their vision.”

Dr. Rosen said the study is far from perfect. He noted that the removal of the non-AMD patients and the lack of any information showing that the supplements could stop AMD from progressing means that more studies are still necessary.

“It’s not the answer, but it’s still good. If you can slow the progression you’re giving patients more time with vision and more time to wait for a cure,” Dr. Rosen said.

Dr. Lanciano added, “The AAO has done a wonderful job promoting this study. The AAO has recognized that familiarizing yourself with complementary medicine is an important part of a physician’s job.” He pointed out that a recent study showed that 66% of medical schools now offer courses in alternative medicine.

For Your Information:

• Frederick L. Ferris, MD, can be reached at 31 Center Dr., MSC 2510 Bldg. 31, Room 6A52, Bethesda, MD, 20892-2510; (301) 496-6583; fax: (301) 496-2297; e-mail: rickferris@nei.nih.gov. Ocular Surgery News could not confirm whether Dr. Ferris has a financial interest in any of the products mentioned or if he is a paid consultant.
• Emily Y. Chew, MD, can be reached at 31 Center Dr., MSC 2510 Bldg. 31, Room 6A52, Bethesda, MD, 20892-2510; (301) 496-6583; fax: (301) 496-2297; e-mail: echew@nei.nih.gov. Dr. Chew has no direct financial interest in any of the products mentioned, nor is she a paid consultant for any companies mentioned.
• Albert J. Augustin, MD, can be reached at Department of Ophthalmology, Moltke strasse 90, 76133 Karlsruhe, Germany; (49) 721-974-2000; fax: (49) 721-974-2009; e-mail: 106020.560@compuserve.com. Dr. Augustine has no direct financial interest in any of the products mentioned in this article, nor is he a paid consultant for any company mentioned.
• Annabelle A. Okada, MD, can be reached at Kyorin University School of Medicine Ophthalmology Department, 6-20-2 Shinkawa Mitaka, Tokyo, 181-8611 Japan; (81) 4-22-47-55-11; fax: (81) 4-22-71-68-36; e-mail: aokada@po.iijnet.or.jp. Dr. Okada has no direct financial interest in any of the products mentioned, nor is she a paid consultant for any companies mentioned.
• Richard B. Rosen, MD, can be reached at the New York Ear and Eye Infirmary, 310 E 14th St. 6th Floor, South Building, New York, NY 10003; (212) 979-4181; fax: (212) 979-4268; e-mail: rrosen@nyee.edu; Web site: www.richardrosen.eyemd.org. Dr. Rosen has no direct financial interest in any of the products mentioned in this article, nor is he a paid consultant for any company mentioned.
• Ralph C. Lanciano, MD, can be reached at 7703 Maple Ave., Pennsauken, NJ 08109; (856) 665-5533; fax: (856) 665-5055; e-mail: rclanciano@mindspring.com. Ocular Surgery News could not confirm whether Dr. Lanciano has a financial interest in any of the products mentioned or if he is a paid consultant.
• Paolo Lanzetta, MD, can be reached at Department of Ophthalmology, University of Udine, 33100 Udine, Italy; (39) 0432-239-268; fax: (39) 0432-239-313; e-mail: paolo.lanzetta@dsc.uniud.it. Dr. Lanzetta has no direct financial interest in any of the products mentioned in this article, nor is he a paid consultant for any company mentioned.
• Michael J. Cooney, MD, can be reached at Duke University Medical Center, Box 3802, Durham, NC 27710; (919) 684-1000; fax: (919) 681-6474; e-mail: coone004@mc.duke.edu; Web site: www.dukeeye.org. Dr. Cooney has no direct financial interest in any of the products mentioned in this article, nor is he a paid consultant for any company mentioned.
• n Alcon Laboratories Inc., manufacturer of Icaps, can be reached at 6201 South Freeway, Fort Worth, TX 76134; (800) 862-5266; fax: (817) 241-0677; Web site: www.alconlabs.com.
• Bausch & Lomb Pharmaceuticals, manufacturer of Ocuvite PreserVision, can be reached at 8500 Hidden River Pkwy., Tampa FL 33637; (800) 323-0000; fax: (888) 386-1222; Web site: www.bausch.com.
• ScienceBased Health, manufacturer of MaculaRx and OculaRx, can be reached at 3579 Highway 50 East, Carson City, NV 89701; (888) 433-6726; fax: (888) 433-4726; Web site: www.sciencebasedhealth.com.
• Whitehall-Robins, manufacturer of Centrum Silver, can be reached at 5 Giralda Farms, Madison, NJ 07940; (888) 797-5638; Web site: www.centrum.com.