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