After the AREDS trial, people with moderate to severe age-related macular degeneration were advised to take dietary supplements to slow the progression of the disease. But some experts say the trial actually showed supplements don’t work, and might even make some patients worse.
Age-related macular degeneration (AMD) is a leading cause of blindness. Known risk factors include smoking, obesity, hypertension, high intake of vegetable fat, and low dietary intake of antioxidants and zinc. The AREDS (Age-Related Eye Disease Study) trial was designed to test whether supplementation with an antioxidant formula could slow the progression of the disease. In 2001 the results of the trial were published in the Archives of Ophthalmology. They found that a mixture of vitamin C, vitamin E, beta-carotene, zinc, and copper significantly slowed the progression of disease in patients with moderate to severe age-related macular degeneration. It was a large multicenter double-blind study.
There was concern about possible harm from certain ingredients in the original formulation (beta-carotene was associated with lung cancer in smokers, and zinc in high doses was known to cause adverse effects), so a subsequent study, AREDS2, was done. It tested the effects of various changes in the formulation: removing beta-carotene, reducing the amount of zinc, and adding lutein/zeaxanthin or omega-3 fatty acids. The results, published in 2013, found that there was no additional benefit from the changes.
Most clinicians accepted the results of AREDS and recommended that patients with moderate to advanced AMD take a supplement mixture. There was no evidence that patients with mild AMD would benefit, and there was nosuggestion that supplements could prevent the disease from developing in the first place. Not everyone followed the actual evidence. Eye vitamin preparations were taken by people who had no evidence-based justification for taking them. And many of the eye vitamins on the market were different from the AREDS mixtures.
A Cochrane review considered the strength of the evidence to be “moderate,” concluding:
People with AMD may experience delay in progression of the disease with antioxidant vitamin and mineral supplementation. This finding is drawn from one large trial conducted in a relatively well-nourished American population. The generalisability of these findings to other populations is not known. Although generally regarded as safe, vitamin supplements may have harmful effects.
Was the AREDS trial actually negative?
Dr. Daniel Seigel accused the AREDS investigators of distorting their findings. He said they promoted a nonsignificant result into a conclusive recommendation. The original study design called for 4 tests, none of which was statistically significant. “One, testing the effect of zinc on progression to advanced AMD, achieved a level of significance defined by the investigators as suggestive.” Essentially, the results were negative. They then restricted their analysis to a sub-group and “featured a combined treatment group which in secondary analysis broke the boundary of statistical significance, thereby disregarding the primary analysis in which neither treatment was significant.” They then made a conclusive recommendation based on these inconclusive findings. Dr. Seigel points out that a negative result would have been more in line with the majority of other studies in which antioxidant supplements have failed to prevent diseases.
In a letter to the editor in the Archives of Ophthalmology, Ambati and Ambati cautioned against “misplaced enthusiasm.” They said the benefit of these supplements is questionable, some of the ingredients may be harmful, and the study’s methodology is flawed. The researchers failed to correct for post hoc analysis. When the proper corrections are made, “The effect of the combination treatment on loss of visual acuity, the only endpoint that truly matters to patients…is even less compelling at a similarly corrected P=.24.”
Another professor of ophthalmology, Cynthia J. Mackay, published a devastating critique on her website She claims that the study results were actually negative, that the researchers went back and changed the research design after the study was completed, that they arbitrarily threw out all patients with mild AMD from the study, and the definition of “success” was changed from “preventing vision loss and progression” to “preventing AMD events.” She said:
The only people who supposedly “benefitted” from this drug are people who have intermediate AMD in one eye, and advanced AMD in the other. No other type of patients had any benefit. Even if a doctor accepts the results of this study, he should only recommend this drug to this small subgroup of patients.
She also pointed out that there were conflicts of interest, that there was no rationale for choosing the particular ingredients in AREDS, that all the ingredients were known to cause serious problems, and that the doses are far above recommended amounts.
The manipulation of the data amounts to what Norbert Kerr, writing in Personality and Social Psychology Review, called “HARKing: Hypothesizing After the Results are Known.”
Conflicts of interest
The AREDS study was funded in part by Bausch + Lomb, and many of the investigators had ties to the company. One of the AREDS study authors, Dr. Ferris, holds a patent for the AREDS formulation with Bausch + Lomb and earns royalties, and he did disclose this conflict of interest in a few published papers; yet in many of the papers he co-authored reporting AREDS data, he neglected to report it. Out of 48 AREDS reports, only 8 include any mention of conflicts of interest. While this doesn’t necessarily mean the studies are biased, a conflict of interest statement is standard practice, and one can only wonder why it was selectively omitted from most of these reports. One article explains that Dr. Ferris invented the patent, but it is owned by Bausch + Lomb, and he has assigned his interest in the patent to the United States Government and received government compensation. A Freedom of Information request disclosed that Dr. Ferris has personally earned $1.8 million from the Bausch + Lomb patent. Such payments to federal employees are allowed under a U.S. law designed to encourage transfer of technology from government to industry. Isn’t $1.8 million worth mentioning in a financial disclosure? An article on Medscape criticized this and similar conflicts of interest.
Do genotypes matter?
In the original AREDS study, only patients who had category 2 through 4 disease (minimal, intermediate, and advanced) were enrolled in the trial. Category 1 patients who were thought to be at low risk of AMD were enrolled in a separate study to evaluate the effect of antioxidant supplements on cataract progression. In a Jan 26, 2017 article in the Journal of Vitreoretinal Diseases, 3 doctors (Awh, Zanke, and Kustra) re-analyzed data from that trial and genotyped the subjects.
Here’s what they concluded:
On average, antioxidant treatment has no impact on the development of intermediate AMD in patients without AMD. However, antioxidant treatment may increase the risk of developing intermediate AMD in patients with low genetic risk and may reduce the risk of developing intermediate AMD in patients with high genetic risk.
This would seem to support the idea of selectively prescribing eye vitamins for patients without AMD based on genetic testing, but the authors cautioned:
Pending validation studies, physicians, and patients should be mindful of the unproven benefit, and the potential risk, of antioxidant supplementation for most patients without AMD.
It should be noted that two of the authors disclosed a conflict of interest: they both own shares in a company that markets genetic tests for AMD.
Should prescription be guided by genotype?
It’s probably too early to say. The American Academy of Ophthalmology does not support the routine use of genetic testing, citing bias in the data analysis. The validity of the genotype studies was questioned in an editorial in Ophthalmology .
A 2015 study examined 11 of the top-selling ocular nutritional supplements in the US and found that the majority of products were not identical to the formulations tested in the AREDS or AREDS2 trials. Only 4 out of the 11 contained equivalent dosages. They found evidence of misleading marketing. All the individual supplements claimed to “support,” “protect,” “help,” or “promote” vision and eye health, but none specified that there is no proven benefit in using nutritional supplements for primary prevention of eye disease.
In an abstract presented at the ARVO Annual Meeting in September 2016, Ellingson and Ambati reported that 73.5% of patients taking eye vitamins did not meet AREDS criteria, and only 29.6% of those taking eye vitamins were taking a preparation identical to the AREDS formulation. They calculated an adjusted NNT (number needed to treat) of 220, and they calculated the direct cost of inappropriate vitamin use as between $218,000 and $657,000 per quality adjusted life year. They also noted that 86% of patients who were active smokers were unaware that beta-carotene might increase their risk of lung cancer.
Standard of care?
Many ophthalmologists, and the manufacturers of eye vitamins, would have us believe the standard of care is to recommend AREDS formulas for patients with moderate to severe AMD. In my opinion, there is good reason to question that recommendation. The evidence is from a single flawed study.
The AAO Preferred Practice Pattern Guidelines say supplements “should be considered,” rather than employed routinely. They rate it as “discretionary,” a category they use when there is low-quality evidence or when the evidence suggests that desirable and undesirable effects are closely balanced. The Veterans Administration noted the poor-quality analysis, pointing out that the 6% absolute risk reduction comes from a post-hoc analysis.
Conclusion: Questions remain
With all the questions that have been raised about the evidence, and the fact that it hinges on a single study, I don’t think we can strongly recommend AREDS-type supplements for anyone. Patients who meet the AREDS study criteria can be offered the supplements with acknowledgement of the uncertainty, and they can work with their ophthalmologists to arrive at a shared informed decision. Patients who do not meet the AREDS criteria should not take the supplements, and there is no justification for taking supplements that do not match the AREDS formulations. There is an intriguing possibility that genetic analysis might identify some patients without AMD who could prevent or delay the development of the disease by taking an AREDS-type formula, but it’s too early to base clinical recommendations on that yet.
This article was originally published in the Science-Based Medicine Blog.