Now a MyVisionTest tradition, below are my picks for the ten most influential research papers of the past year.

Research in AMD is progressing at a feverish pace, with dozens of research papers being published every month. We cannot hope to cover each and every one, but we strive to cover those publications of greatest relevance to patients and their families. In 2009 we reviewed a total of 355 research papers covering every aspect of AMD, from basic research to low vision rehabilitation.

Of the 355 research papers that we reviewed on MyVisionTest last year, we have selected 10 as our choice for the year's most important. Two of the papers on this list are genuine breakthroughs in the treatment or prevention of AMD. The others are important advances in understanding or managing the disease. While no list can fully capture the progress that has been made in combating this disease, we hope that you will find our top 10 list an encouraging review of the progress made in 2009.

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Several studies published in 2009 provide evidence that the "as-needed" anti-VEGF dosing strategy currently in widespread clinical use results in inferior visual outcomes due to undertreatment of neovascular AMD.

One such study is a retrospective analysis of 131 eyes undergoing as-needed Lucentis monotherapy for wet AMD that found eyes receiving more frequent injections (on average less than 2 months between injections) gained more vision (+2.3 lines at 6 months) than eyes receiving injections less frequently (+0.46 lines at 6 months). At 6 months, 3% of those in the more frequent injection group lost more than 3 lines of vision compared with 16% in the greater than 2 months interval group. Those patients receiving the less frequent injections were, as you might expect, the patients that experienced few, if any, recurrences of macular fluid.

These results suggest that anatomic outcomes and functional outcomes may not coincide, and what would normally be considered treatment "failures" (e.g. refractory or recurrent fluid) may actually be associated with a more favorable visual outcome if these patients continue to receive frequent Lucentis injections.

WHAT IT MEANS TO YOU: While monthly dosing may not be a practical long term solution for most patients, it is clear that OCT-guided as-needed dosing regimen is an imperfect compromise. This study suggests that the most popular dosing strategy for Lucentis and Avastin leads to undertreatment, and vision outcomes would improve if more frequent injections were administered. In addition to inhibiting the growth and leakage of the choroidal neovascular membrane, it is possible that the anti-VEGF drugs are exerting other effects that improve the vision of patients with wet AMD. Advances in OCT imaging technology and more effective longer acting drugs may provide a means of improving outcomes without the need for fixed monthly injections.

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Because Avastin is approved by the FDA for the treatment of colorectal cancer, not macular degeneration, it must be specially prepared by a pharmacist before it can be injected into the eye. This process, known as compounding, is believed to be responsible for some of the adverse effects that are observed following intravitreal injection of the drug.

Although rare, intraocular inflammation (uveitis) occurs following about 2% of Avastin injections, and is reported to be the most common drug-related complication following intravitreal injection of either Avastin or Lucentis.

The researchers state that the characteristic features of Avastin-induced inflammation include an early onset with painless loss in vision mostly without conjunctival or ciliary injection. Patients respond to systemic or topical steroid treatment with slow recovery and no permanent damage.

Another problem associated with off-label intravitreal Avastin use is the presence of high molecular weight compounds that may plug outflow pathways or cause an immunologic response that leads to elevation of intraocular pressure (IOP).

Dr Malik Y. Kahook said during the 2009 joint meeting of the American Academy of Ophthalmology and Pan-American Association of Ophthalmology that 90 cases involving spikes in IOP after injection with anti-VEGF agents have surfaced recently. Among these cases is a series of 438 patients in which 12% developed persistent IOP spikes. Although elevation of IOP may also occur following Lucentis injection, "cases are overwhelmingly in the Avastin corner," Dr. Kahook said

WHAT IT MEANS TO YOU: The off-label intravitreal use of Avastin has been associated with a variety of adverse effects, including a cluster of toxic anterior segment syndrome cases that appeared in Canada in late 2008. Because Avastin is not specifically formulated for use within the eye, we may continue to see untoward effects associated with intravitreal injection of the drug.

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Folic acid may be able to lower the risk of developing AMD by 35-40%.

Recent studies indicate a direct association between homocysteine levels in the blood and the risk of AMD. Homocysteine is an amino acid formed during the metabolism of protein. Treatment with folic acid, vitamin B6, and vitamin B12 has been shown to lower serum homocysteine levels.

A total of 5205 women without AMD were included in the study. Participants were randomly assigned to receive a combination of folic acid (2.5 mg/d), vitamin B 6 (50 mg/d), and vitamin B 12 (1 mg/d) or a placebo.

After an average of 7.3 years, there were 55 cases of AMD in the treatment group and 82 in the placebo group (34% lower risk with treatment). Of these, a total of 70 cases were visually significant (visual acuity of 20/30 or worse). There were 26 visually significant cases in the treatment group, and 44 cases in the placebo group (40% lower risk with treatment).

This is the first randomized clinical trial to investigate use of folic acid and B vitamins in the prevention of AMD. The results indicate that the supplement resulted in a statistically significant decreased risk of developing early AMD.

Because these findings apply to the onset of AMD in persons without a prior diagnosis of AMD, they appear to represent the first identified means, other than avoidance of cigarette smoking, of reducing the risk of developing AMD.

WHAT IT MEANS TO YOU: This study represents a potential breakthrough in the prevention of AMD. It is the first time ever that a randomized controlled trial has demonstrated an effective means of preventing the onset of AMD. It does, however, raise more questions than it answers. How does the supplement prevent AMD? Is the supplement effective in men? Is the supplement safe? No doubt these and other questions will be the focus of numerous forthcoming studies. But in the meanwhile, we now have something to offer those patients without AMD who, because of family history or other reasons, wish to take steps to reduce their risk of developing the disease.

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Two studies published last year offer good news for persons with cataract. The first study finds that cataract surgery does not accelerate the progression of AMD, and the second study finds that cataract surgery provides meaningful visual benefits for persons with AMD regardless of the severity of the macular degeneration, from mild to advanced.

In the first study, visual acuity results were analyzed for 1939 eyes that had cataract surgery during the AREDS study. The mean change in visual acuity at the next study visit after the cataract surgery was as follows: eyes without AMD gained 8.4 letters of acuity, eyes with mild AMD gained 6.1 letters of visual acuity, eyes with moderate AMD gained 3.9 letters, and eyes with advanced AMD gained 1.9 letters. The gain in visual acuity after cataract surgery was maintained an average of 1.4 years after cataract surgery.

In the second study, 65 subjects with confirmed non-neovascular AMD underwent cataract surgery and were followed for 1 year. Neovascular AMD developed in 3 eyes (4.6%). This compares favorably to an expected rate of 5% for this population.

WHAT IT MEANS TO YOU: Persons with AMD benefited from cataract surgery regardless of severity of AMD. Furthermore, there appears to be a normal rate of AMD progression during the first year after cataract surgery. These findings suggest that previous reports of an accelerated rate of progression of AMD after cataract surgery were inaccurate, and indicate that the presence of AMD should not be a deterrent to cataract surgery.

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Last year we learned that a person's genetics will determine their response to the AREDS vitamin/mineral supplement - persons homozygous for the compliment factor H (CFH) high-risk allele (CC genotype) have a smaller treatment response to the supplement than persons homozygous for the low-risk allele (TT genotype). Last year saw two additional studies that confirm that genetics play a major role in determining the effectiveness of AMD therapy

The first study finds that response to Lucentis differs according to CFH genotype. Persons homozygous for the CFH Y402H high risk allele (CC) required more Lucentis injections over a 9 month follow-up period than persons without the high risk genotype.

In this retrospective review of 156 patients treated with Lucentis for exudative AMD and followed for at least 9 months, patients with the CC genotype had a 37% higher risk of requiring additional injections compared to persons with the low-risk TT genotype. Patients with only one risk allele (TC genotype) had a 25% increased risk, suggesting a possible genotype-dose dependent pharamacogenetic effect.

In the second paper, researchers found that weekly fish consumption decreases the risk of late AMD only in persons with the high risk CC genotype, not in persons with the CT or TT genotypes. The researchers conclude that joint contributions from genetic and systemic factors are involved in determining the progression of AMD.

WHAT IT MEANS TO YOU: It is clear that genetics plays a major role in determining who will develop AMD. Now there is growing evidence that one's genotype can have a significant effect on response to therapy as well. In 2007, it was reported that patients with the high-risk CC genotype demonstrated less visual acuity improvement with intravitreal injections of Avastin than patients with the lower risk genotypes. It is clear that genetics not only governs the risk of developing AMD, but also how aggressively it needs to be treated.

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A meta-analysis of data from three large clinical studies finds that intravitreal injection of Lucentis is associated with increased risk of stroke.

To date, no single study has been large enough to determine whether intravitreal Lucentis injections increase the risk of adverse systemic effects. Therefore, the researchers pooled data from several large studies to investigate the relationship between the intravitreal injection of Lucentis and systemic arterial thromboembolic events.

Data from the MARINA, ANCHOR, and FOCUS studies were pooled and analyzed. The frequencies of stroke and nonfatal heart attack between those who received monthly intravitreal injections of Lucentis and those who received placebo treatment were compared.

According to the current meta-analysis, intravitreal Lucentis was associated with an increased incidence of stroke (odds ratio: 3.24), whereas there was no apparent association between intravitreal Lucentis and heart attack.

WHAT IT MEANS TO YOU: A previous meta-analysis of Lucentis therapy found an increased risk of stroke, but the trend failed to achieve statistical significance. It is unclear why this study found a significant risk while the earlier study did not. Nonetheless, it is clear that intravitreal Lucentis increases the risk of stroke.

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Yet another study finds that fish oil decreases the risk of progression to advanced stages of both wet and dry AMD.

AREDS examined the relationship of dietary intake of omega-3 long-chain polyunsaturated fatty acids (fish oil) with progression to advanced AMD in 1837 participants. Dietary intake was estimated using a questionnaire.

Those participants reporting the highest consumption of fish oil were approximately 30% less likely than their peers reporting the lowest fish oil consumption to progress to advanced AMD. Results for geographic atrophy and neovascular AMD were similar.

The researchers conclude that omega-3 fatty acids represent an effective means to decrease the risk of AMD progression.

WHAT IT MEANS TO YOU: This is additional evidence indicating that fish oil is a safe and effective means of decreasing the risk of progression of AMD. Unlike the AREDS vitamin/mineral supplement - which is only effective for a narrow range of patients with AMD, has the potential for undesirable side effects, and is contraindicated in smokers - fish oil has no serious adverse effects and appears to be effective in slowing the progression of AMD for a broad range of persons with the disease.

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A series of three patients with neovascular AMD have been successfully treated off-label with Remicade (infliximab), an anti-tumor necrosis factor (TNF) monoclonal antibody.

Remicade has been approved by the FDA for the treatment of psoriasis, rheumatoid arthritis, sarcoid and other chronic inflammatory conditions. It works by blocking tumor necrosis factor alpha (TNFa). TNFa is a key component of inflammatory reactions.

In this study 3 patients previously treated unsuccessfully with Lucentis received 2 intravitreal injections of Remicade spaced 2 to 3 months apart. Best corrected visual acuity and central macular thickness improved in all three patients.

The researchers conclude that TNF plays a role in neovascular AMD and speculate that Remicade might prove a useful adjunct treatment, especially in cases refractory to anti-VEGF agents, or when anti-VEGF agents are contraindicated.

WHAT IT MEANS TO YOU: Although too small a study to permit any firm conclusions to be drawn, this series of three patients offers a tantalizing glimpse at the potential anti-TNF agents may hold in treating AMD. It is described as a potential “breakthrough treatment” in an editorial accompanying this research paper. Anti-TNF therapy could decrease the need for reinjection with anti-VEGF drugs, and possibly even improve visual outcomes beyond what is possible with anti-VEGF therapy alone.

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Investigators have shown that there is no difference in efficacy between Avastin and Lucentis for the treatment of AMD. The study is the first to report early outcomes of a prospective, double-masked, randomized, controlled trial comparing Avastin to Lucentis for the treatment of exudative AMD.

Twenty patients were enrolled by a 2:1 randomization to either the Avastin (13 patients) or Lucentis (7 patients) arm of the study. Patients were given intravitreal injection of Avastin or Lucentis every month for the first three months. Following the third injection, patients returned for monthly examination and testing and received further injections on an as needed basis for one year.

"Early results of this trial suggest that at 6 months, visual outcomes of bevacizumab appear to be no different from ranibizumab," said principal investigator Manju Subramanian.

WHAT IT MEANS TO YOU: Double-masked, randomized, controlled clinical trials are the gold standard of clinical research. This is the first such study comparing Avastin to Lucentis for the treatment of exudative AMD to reach publication. It, like the smaller clinical case series that have preceded it, finds no significant difference between Avastin and Lucentis in terms of visual acuity and foveal thickness after 6 months of therapy.

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A study examining the relationship between the choriocapillaris (CC) and retinal pigment epithelial changes in AMD finds that the primary insult in geographic atrophy (GA) appears to be at the level of the retinal pigment epithelium (RPE), whereas the primary insult in wet AMD appears to be CC degeneration.

The researchers dissected and analyzed the CC and RPE in eyes with wet and dry AMD. What they found was that although the CC and RPE will both degenerate in either form of the disease, which one goes first will determine whether the AMD is wet or dry. RPE atrophy occurs first in dry AMD and CC degeneration occurs first in wet AMD.

It seems that the CC and RPE need each other - if one dies the other will eventually die also. The RPE secretes VEGF and other survival factors that help to keep the CC healthy. In the absence of these survival factors following RPE death, the CC will atrophy and the AMD remains dry. If, on the other hand, the CC atrophies first the RPE will become ischemic. It will secrete a large amounts of VEGF in an attempt to recruit a new blood supply, and the AMD becomes wet.

We know that certain factors contributes to RPE atrophy (oxidative stress) and other factors contributes to CC degeneration (atherosclerotic disease). It may turn out that which succumbs first (or when there is atrophy of both, which is more severe) will determine whether the AMD stays dry, or becomes wet.

WHAT IT MEANS TO YOU: This study helps to advance our understanding of what causes AMD. It makes clear that atrophy of the RPE may be primary (eg due to oxidative damage) or it may occur secondary to CC degeneration. Likewise, CC atrophy may be primary (impaired perfusion) or secondary to RPE atrophy. According to this model, AMD in both its wet and dry forms is fundamentally the breakdown of the relationship between these two tissues.

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