Age-related macular degeneration: What are the benefits and harms of drugs that are injected into the eyeball?

Regular injections of Lucentis or Macugen can slow down vision loss for some people with one form of age-related macular degeneration. Both the injection itself and the drug can cause adverse effects.

Age-related macular degeneration (AMD) is an eye disease in people over the age of 50. In developed countries it is the most common cause of sight loss. The macula is the part of the retina responsible seeing in fine detail.

The retina is the light-sensitive layer deep inside the eye. In AMD, people first lose what is called their central vision, but can eventually lose their sight completely. Central vision is important for things like driving and reading. People who have AMD can usually still see the outlines of objects they are looking at. It is not exactly known what causes it. There are two types of this disease: the most common form is called “dry” AMD, and a less common form is “wet” AMD. The medical terms for “wet” AMD are exudative or neovascular AMD (neovascular = related to new blood vessels). Wet AMD is where abnormal blood vessels start growing under the retina.

Treatment options

One of the treatments developed for wet AMD was thermal laser therapy, which nowadays is only used in certain cases. More recently, other treatments have been developed, including photodynamic therapy, surgery, and drug therapies. This summary discusses the existing scientific evidence on new drug therapies. You can read more about the eye, the disease and some other treatment options in our feature on AMD.

Relatively new drugs are also available that try to block the growth of the abnormal vessels in the eye by inhibiting the effect of a hormone (VEGF = vascular endothelial growth factor). In Europe, two of these drugs have been approved for treating wet AMD, ranibizumab (brand name: Lucentis) and pegaptanib (brand name: Macugen). These drugs are used as intravitreal injections, which means they are injected into the eyeball. There is also another drug called bevacizumab (brand name: Avastin). It is so similar to Lucentis that some specialists assume that it is practically identical, but Avastin is not approved for treating AMD.
 
Scientific research on Lucentis and Macugen

Researchers from the Southampton Health Technology Assessments Centre looked for clinical trials testing Lucentis or Macugen. The analysis of these trials was commissioned by the British National Institute of Health and Clinical Excellence (NICE).

The researchers found five reasonably well-designed trials: three tested Lucentis and two tested Macugen. The total number of people in the trials was just over 1,500. The people all had wet AMD, but the type of eye damage they had at the start was so different, there data cannot be compared exactly and many details remain unclear.

In three trials half of the participants in each trial were given the drug. The other half were given a fake injection – doctors pretended to give an injection, but did not stick the needle into the eye. As a result, the participants did not know if they had been given the drug or not. The two other trials looked at combinations of the drugs together with photodynamic therapy.

The trials showed that these drugs can slow down vision loss. But until there is more research, it is only possible to give a very rough estimate of the effects of these drugs and the injection.

One way to measure sight and vision loss is the eye chart. This is the common eye test where a person reads letters from a chart with a first row of very large letters, and each row of letters below gets smaller. The person reads the chart, and it is noted how many letters they can read correctly.

The participants had their vision tested several times during the trials in order to measure how much worse their sight was becoming. After one or two years, the researchers counted the number of people who could see 15 letters fewer (or more) than they had been able to see before. Losing 15 letters of sight is a moderate amount of vision loss. In some people, however, this loss can mean, for example, no longer being able to read the newspaper.

Both drugs were able to stop or at least slow down loss of vision in some people. Out of every 100 men and women who received the fake treatment, between 55 and 68 had practically the same level of vision or did not experience a substantial worsening of vision within one year (55 to 68%). Out of 100 men and women who were treated with one of the drugs between 70 and 96 (70 to 96%) had the same or not substantially worse vision. In other words, the drug was able to prevent sight from getting substantially worse in 15 to 32 people who received treatment (15 to 32 %). Some even experienced an improvement in vision. This advantage was still apparent after two years of therapy.

None of the trials compared the drugs directly against each other. This means that it cannot be said with certainty which drug works better. Nevertheless, from the research available, Lucentis appears to offer more benefit than any other treatment for AMD.

The risk of adverse effects

Adverse effects were common with both drugs, but most of the problems were temporary.

It was the injection itself that caused most of the adverse effects, pain, for example. About 1 to 2% of people who used the drug had endophthalmitis. This is a serious inflammation of the eyeball, which can damage the eye and even cause loss of sight. The risk of this adverse effect depended on dose and number of injections: if only one injection was given, the risk tended to be low, in higher doses or when the injections were given monthly, the number of cases of endophthalmitis rose to over 1%.

One of the adverse effects is “mouches volantes” (also commonly called “floaters”), where the person sees spots that move along with the eye’s movements. These could be caused in as many as 25% of people who take these drugs, but more research is needed to be sure.

The drugs themselves might also cause heart and circulation problems in some people. However, it is difficult to be sure about this until more follow-up results from the trials are reported in coming years. In the meantime, the manufacturers of Lucentis in America have warned doctors that there might be an increased risk of stroke with doses of 0.5 mg. Lower doses of 0.3 mg were effective at reducing loss of vision in the trials, and there has been no similar safety warning about this dose.

It is still being studied whether eye injections are suitable for people with increased intraocular pressure (glaucoma) or other kinds of damage to the eyes. According to preliminary data, the pressure inside the eyeball (intraocular pressure) rises as a result of the injection in about 10% of people who use Lucentis. For this reason, eye pressure is monitored after these injections are done, to see if this problem occurs and needs treatment.

These injections are usually used as the sole treatment for AMD, but they are also sometimes used together with other therapies, like photodynamic therapy. However, more research is needed to find out whether these combination treatments work better.

Off-label use: Avastin

Another drug used to treat wet age-related macular degeneration is Avastin (bevacizumab). Avastin is very similar to Lucentis. But Avastin is not approved for treating macular degeneration, and its safety and efficacy as an eye injection is just now being tested. It is on the market as a treatment for bowel cancer, but is also commonly used for treating AMD because many doctors suppose that it works like Lucentis. This is called “off-label use”, which is the use of a medicine for a purpose or indication for which it has not been licensed. You can read more about the off-label use of medicines here.

Avastin is used in AMD because it is much cheaper than the other drugs.
In May 2011 the results of one of the first trials comparing Avastin and Lucentis with each other were published. They showed that both drugs are in fact similarly effective. But Avastin led to adverse effects somewhat more frequently than did Lucentis. People who have AMD and doctors are now awaiting the results of further trials to see whether these results are confirmed. At the moment 5 more trials comparing Avastin with Lucentis are being done. This information will be updated as soon as the results are published.

Other drugs

Interferon-alpha is another drug that has been tried as an option for AMD. However, the only long-term trial of this drug found a high rate of harm and researchers from the Cochrane Collaboration report that further trials on this subject will probably not be done.

There is another drug that is sometimes used as an intravitreal injection for AMD, either alone or in combination with other treatments. This drug is called triamcinolone. It is a corticosteroid drug, which works to effectively reduce inflammation. Whether it is also effective in treating AMD has not been studied enough.

Other drugs for treating AMD are being tested. We will update this information as soon as more results become available.

Author: German Institute for Quality and Efficiency in Health Care (IQWiG)

Next planned update: May, 2014. You can read more about how we update our health information here.

© IQWiG (Institute for Quality and Efficiency in Health Care)