Update on Avastin® vs Lucentis®

I thought that Lucentis would be a little better than Avastin for treating wet AMD. I thought this because Lucentis is a smaller molecule and has a higher binding affinity for VEGF. I’ve used both drugs many, many times for wet AMD and I can’t really tell a difference between them. That’s why we need to do the Comparisons of AMD Treatments Trial (CATT) which will compare Avastin to Lucentis. With the latest worry that Lucentis may increase the risk of stroke, the CATT becomes doubly important. Now we not only want to find out if one of the drugs works better but also if one has a lower risk of side-effects.

I read recently that one expert on the treatment of AMD was quoted as saying that he thought that Lucentis lasted about long as Avastin. I disagree with this. I think that patients who need repeated injections will often start to develop fluid again at four weeks after a Lucentis injection. These patients won’t need repeated injections of Avastin however, for six or seven weeks. I think, on average, and there is a lot of variability among different patients, that Avastin last two weeks longer than Lucentis.

Daily Vitamins for People with AMD

Many people with AMD wonder whether they should take a daily vitamin in addition to the vitamins recommended by the age-related eye disease study. They worry that they might be getting too much of a good thing. Most daily vitamins contain 100% of the daily recommended dose. The daily doses recommended by the AREDS study are much higher: about 7 times the daily recommended dose of vitamin C, 6 times the daily dose of beta-carotene, 13 times the daily dose of vitamin E and 5 times the daily dose of zinc. I tell most people to them to go ahead and take the daily vitamin and then not take the AREDS vitamins one day of the week. People who are on Coumadin should ask their doctor before taking a multivitamin because it may contain vitamin K which will interfere with its blooding thinning effect.

A recent study showed that elevated homocysteine and low serum vitamin B12 were associated with an increased risk of AMD. High levels of homocysteine increase the risk of thrombosis and cardiovascular disease. Vitamin B12 and folic acid are needed to metabolize homocysteine so a lack of these vitamins can lead to elevated levels.

B12 and folic acid are typically found in a daily vitamin supplement. Therefore this study perhaps indicates a need for the daily vitamin in addition to the ARED’s vitamins. As always, the best way to get these and other nutrients is to eat the right foods. Foods rich in B12 are mostly meats but fish and clams are also excellent sources. Foods rich in folic acid include dark leafy vegetables, whole wheat bread, nuts and beans. You shouldn’t count on vitamin supplements making up for a bad diet (highly processed foods, lots of animal fats, no vegetables). Do both, eat right and take the supplements.

Reference

1. Rochtchina E, Wang JJ, Flood VM, Mitchell P. Elevated serum homocysteine, low serum vitamin B12, folate, and age-related macular degeneration: the Blue Mountains Eye Study. Am J Ophthalmol. 2007 Feb;143(2):344-6. Epub 2006 Sep 29.
   

Ouch!

We received the following comment anonymously:

What say you now, Dr. Folk? I would hope that the Dear Doctor letter that Genentech sent opened your eyes. I am bewildered at what my colleagues, yourself included, are willing to do and say to fulfill their own agenda. Also, the ignorance about clinical trials and the interpretation of data that the retina community shares is staggering.
(Anonymous) 2/20/07

The Dear Doctor, actually the “Dear Health Care Provider,” letter was sent by Genentech on January 24, 2007. It stated that a planned interim analysis of the accruing data in the SAILOR study showed a higher risk of strokes, (1.2%) in the group receiving 0.5mg of Lucentis than in the group receiving 0.3mg (0.3%). People with a history of a previous stroke were at higher risk. There were no differences between groups in the risk of heart attacks or vascular death. Both groups of patients had been followed an average of 230 days or a little less than eight months.

Most retinal doctors thought that, since the percentages were small and since there are often fluctuations in data especially as it is acquired, that they would continue to use Lucentis and/or Avastin. We are concerned about this of course and anxiously await more data.

I thought it would be worthwhile to review the risk of side effects in various trials using Macugen and Lucentis. This is somewhat difficult because these trials did not list the same side-effects but here goes:

Pegaptanib (Macugen)

1. In the original Macugen study(1), the risk of thromboembolic events was 6% in both the treated and sham (placebo) groups and the death rate was 2% in both.
2. In a follow-up study(2), the risk of serious thromoboembolic events was 4% in both the Macugen and sham groups during the first year. During the second year of the study, the risk of thromboembolic events was 10% in the sham group and 5% in the Macugen treated group.

Ranibizumab (Lucentis)

1. In the MARINA trial(3), at twenty-four months the following risks were seen:
   Death: 2.5% in the sham group; 2.1% in the group receiving monthly injections of 0.3mg Lucentis; 2.5% in the 0.5mg group
   Myocardial Infarction, (Heart Attack): 1.7% in sham group; 2.5% in the 0.3mg group; 1.3% in the 0.5mg group
   Stroke: 0.8% in the sham group; 1.3% in the .3mg group; 2.5% in .5mg group
2. In The ANCHOR Trial that compared Lucentis to Verteporfin the following risks were seen at twelve months(4):
   Death: 1.4% in Verteporfin group; 2.2% in the group receiving monthly injections of 0.3mg Lucentis; 1.4% in the 0.5mg group.
   M-I: 0.7% in Verteporfin group; 0.7% 0.3mg group; 2.1% in the .5mg group
   Stroke: 0 .7% in the Verteporfin group; 0% in the 0.3mg group; 0.7% in the 0.5mg group
3. In the FOCUS trial, which compared Lucentis with Verteporfin to Verteporfin alone at twelve months the risks were(5):
   Myocardial infarction: 3.6% in the Verteporfin group; 0.0% in the group receiving Verteporfin plus monthly injection of 0.5mg Lucentis.
   Stroke: 0.0% in the Verteporfin alone group; 3.8% in the Verteporfin plus 0.5mg Lucentis group

I can’t be sure of the intent of the anonymous author’s e-mail. I think the author meant that the “Dear Health Care Provider” letter showed that Lucentis is risky. I don’t know if the author advocated Macugen, verteporfin, Avastin, or observation as alternative treatments. We can interpret the results that are listed above in two main ways. We could say that the second Macugen results showed that Macugen actually protected against thromboembolic events. We could also say that Verteporfin caused heart attacks or Lucentis prevented them. Obviously these conclusions don’t make sense and border on the absurd.

It makes more sense to me to say that the results show that about 2% of patients with wet AMD die each year and that treatment with verteporfin, Macugen, or Lucentis doesn’t really increase this risk. In the MARINA and the ANCHOR studies though, the risk of stroke was higher in the 0.5mg dose group. These results, coupled with the recent letter, concern me about strokes but not enough to change my care at this time. Genentech has promised to keep as informed as more results are accrued in the SAILOR trial.

The anonymous author also states: “I am bewildered at what my colleagues, yourself included, are willing to do and say to fulfill their own agenda.” I want to repeat that I receive no money from the companies that market verteporfin, Macugen, or Lucentis. Neither I nor any of my extended family own stock in these companies. I have no agenda. I just try to call ‘em as I see them.

1: Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR; VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004 Dec 30;351(27):2805-16.

2: VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group; D'Amico DJ, Masonson HN, Patel M, Adamis AP, Cunningham ET Jr, Guyer DR, Katz B. Pegaptanib sodium for neovascular age-related macular degeneration: two-year safety results of the two prospective, multicenter, controlled clinical trials. Ophthalmology. 2006 Jun;113(6):992-1001.

3: Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006 Oct 5;355(14):1419-31.

4: Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, Sy JP, Schneider S; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006 Oct 5;355(14):1432-44.

5: Heier JS, Boyer DS, Ciulla TA, Ferrone PJ, Jumper JM, Gentile RC, Kotlovker D, Chung CY, Kim RY; FOCUS Study Group. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration: year 1 results of the FOCUS Study. Arch Ophthalmol. 2006 Nov;124(11):1532-42.

Related posting: Avastin and Hypertension