Cataract Surgery and Progression of AMD
There has been a concern that the removal of a cataract may hasten the progression of age-related macular degeneration. Ophthalmologists see a large number of patients who have severe AMD soon after cataract surgery. The combined data from two large studies, the Beaver Dam Eye Study and the Blue Mountain Eye Study, found that AMD developed more often in eyes that had cataract surgery compared to eyes that did not. Both of these studies however didn’t study the retina before the cataract surgery. Another explanation is that these patients already had AMD when they went to their doctor complaining of poor vision. They also had a cataract making it difficult for the doctor to examine the macula thoroughly. The doctor blamed the cataract for the poor vision and removed it only to find AMD in the retina. In these patients, the AMD caused the cataract surgery, so to speak, not the other way around. Frederick Ferris reported the results of an analysis of patients in the Age-Related Eye Disease Study (AREDS) at a retinal subspecialty meeting before the American Academy of Ophthalmology Meeting in Chicago. The advantage of AREDS was that the macula was closely examined and photographed before the cataract surgery. During a follow-up of six years, 19% of the patients in AREDS had cataract surgery. There was not an increased risk of developing severe AMD in the patients who had cataract surgery compared to those who did not. Therefore it appears that cataract surgery does not increase the progression of AMD. So, for patients with AMD, if your doctor feels that removing your cataract would improve your visual function, you can go ahead with the surgery if you wish without the fear that it will make your AMD worse. References: 1. Wang, JJ, Klein R, Smith W, et al. “Cataract Surgery and the 5-Year Incidence of Late-Stage Age-Related Maculopathy: Pooled Findings from the Beaver Dam and Blue Mountains Eye Studies.” Ophthalmology. 2003; 110:1960-1967. 2. Ferris, FL, Chew, EY, Gensler G, Milton R, and the Age-Related Eye Disease Study Research Group: Controversy of Cataract Extraction and AMD Progression.” Presentation, Retina 2005: Changing Concepts and Controversies, October 14, 2005, Chicago, Ill.
Follow-up Blog October 28th: More on the controversies in the treatment of wet AMD.
Let’s continue with the discussion concerning the treatment of wet AMD (see last blog). My colleague from Florida is correct that there were serious side effects when Avastin® was used in patients with metastatic colon cancer including hypertension, gastrointestinal perforations, and rarely pulmonary embolism and arterial thromboembolism. The dose in these patients was 5mg/kg. Someone who weighs a modest 154 pounds is 70 kilograms. That person would receive 350 mg of Avastin® intravenously every two weeks. An effective dose for AMD is 1.25 mg (280 times less) and is placed inside the eye. I believe that a systemic complication from this ocular dose would have to be exceedingly rare. I use the visual acuity, the fluorescein angiogram, and the OCT to determine whether I think a given treatment is working. In my experience:
When a patient returns with a two or three line loss of vision, that’s a bad sign, and usually means that the neovascularization is growing or, at the very least, is still active.
If the fluorescein angiogram shows that the neovascularization has grown after a treatment, that is a bad sign.
If the OCT shows fluid under or within the retina after treatment, that is a moderately bad sign.
In my experience, if patients return with sharply reduced vision or a larger membrane after treatment, they usually don’t do very well in the long-run, even if that treatment is continued. The patients who do well long-term, usually are doing well after the first or second treatment. They come back with stable or improved vision, an inactive neovascular membrane on FFA, and less fluid on OCT.
So when should you consider switching treatments? I said that I would try Visudyne® with intravitreal Kenalog® once or inject Macugen® two or three times and then reassess how the patient is doing. If the patient has reduced vision and a larger membrane, I probably would switch treatments. The exception to that rule is that many patients who are treated with Visudyne®, (especially if Kenalog® is not used), still have fluid at their three month visit. A little remaining fluid on OCT will not dissuade me from repeating the Visudyne® treatment so long as the vision and neovascularization is relatively stable.
Maybe I’m not waiting long enough for the Macugen® to kick in, but if a neovascular membrane is growing and the vision is going down after two or three injections, I just can’t see how the treatment is “working” and I don’t think the final visual acuity is going to be very good. In these cases, I’ll try something else.
That’s my opinion. Please write to express yours. Thanks!
Controversies in the treatment of wet AMD
A reader asked the following question: “My otherwise very healthy 80 year old father was just diagnosed with wet AMD in one eye. The doctor recommended the use of Macugen injections every 6 weeks starting in early Nov. My question is, is this the best way to treat this in terms of newest and most progressive? Or is there any other approved treatment that shows more promising results.”Here is what a retinal specialist from Florida wrote us: “Dr. Folk’s recent posting about the use of Avastin for treating wet age-related macular degeneration should not inspire the ophthalmology community to mass action. The physicians using Avastin are doing so based on anecdotal information, with neither significant evidence nor well-controlled studies to support its use for this indication. While I certainly understand how physicians could be intrigued by the Avastin experiments to date, it is surprising how quickly people seem to be jumping to use a drug that has been shown to cause serious adverse effects when used to treat colon and other cancers – and which is not recommended for use in elderly patients due to its side-effect profile. From a clinical viewpoint, our practice has performed more than 1,100 Macugen injections since January 2005. It is our impression that the majority of patients stabilize or significantly improve their vision over time. There are 2 caveats: the clinical effect may not be noted until the 4th through the 6th treatment (so don’t give up too soon); and there does not seem to be a great correlation between the visual response and the appearance of the fluorescein angiogram and/or OCT.Let’s re-think our approach here, and until we have more robust and well-controlled data, let’s use the very safe and effective therapies that have been FDA-approved to treat wet AMD.”So here’s what I think: Macugen® injections are given at six week intervals. The first injection is given at week zero, the second at week six, the third at week twelve, and so on. Therefore a doctor can’t evaluate the result of the fourth injection until 24 weeks, (six weeks after it was given), and the result of the sixth injection until 36 weeks. Macugen® was launched last January 20th, so it’s been available for only about forty weeks. Therefore most retinal docs haven’t yet seen a lot of patients who have had six or more injections. The company who makes Macugen® says the same thing as the doctor advised above, namely that you have to give the drug time to work. I don’t want to come across as the champion of Avastin®. I will tell you though, why many retinal specialists are not satisfied with Macugen®. The main study on Macugen® (see reference below) contained 1186 patients. After 54 weeks of follow-up, 70% of patients who received Macugen® lost fewer than three lines of vision compared to 55% of patients in the control group. 33% of the patients who received Macugen® had the same or improved vision after one year compared to 23% of the control group. That means that two-thirds of the patients in the Macugen® group lost vision. On average, the patients who received Macugen® lost about 1.5 lines of vision on the visual acuity chart. Patients come to us because they have already lost vision. They ask us if their vision will improve with treatment. We have to tell them that with Macugen® or with Visudyne®, that it is more likely that their vision will get worse, but that either treatment is still better than doing nothing. The patients don’t like that answer. I don’t like that answer either. We need a better treatment. My Florida colleague is right in stating that the evidence about Avastin is anecdotal. I concluded my October 19th Blog, ( http://www.medrounds.org/amd/2005/10/to-retinal-specialists-about.html), stating, “We have to be careful though, since we’ve not followed these patients for very long and we also have the proven treatments of Visudyne® and Macugen®.” It’s too long though, to have to wait until the fourth or sixth injection (24-36 weeks) for Macugen® to control the choroidal neovascularization. We know that neovascularization grows. I’ve seen it grow after Macugen® and Visudyne® and in general, the larger the area of neovascularization, the greater the area of scarring, and the poorer the visual acuity. Therefore it would be best to stop these vessels right away not six or seven months from now. A representative from Novartis, who makes Visudyne®, also objected to my statement that if a patient doesn’t respond to one Visudyne® treatment that I might consider Avastin. He said that often three or more treatments are needed before the neovascularization is controlled. So it’s a conundrum. Visudyne® and Macugen® take a while to work, yet meanwhile the neovascularization may be gobbling up more of the patient’s precious macula. I disagree with the retinal specialist from Florida that the fluorescein and OCT don’t correlate well with the vision. I use both of these tests to tell me whether a patient is responding to treatment. That’s probably enough for today. In the next blog, I’ll tell you what I do. It makes sense to me but I don’t know if it’s right or not. Meanwhile, I would invite any retinal specialist to write in and give us your experience. To be fair, also state whether you have any financial interest in any of these treatments. I don’t. 1. Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR, for the VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004; 351:2805-2816. 2. Klein M, Jorizzo P, Watzke R. Growth features of choroidal neovascular membranes in age-related macular degeneration. Ophthalmology 1989; 96:1416-1421. 3. Sletten KR, Folk JC, Russell SR. Shape and size of choroidal neovascularization in response to sequential photodynamic therapy. Retina 2005, in press.
To Retinal Specialists About Compounding Pharmacies and Avastin
Retinal specialists have asked me about compounding pharmacies around the country that have offered Avastin® in small doses for intraocular injection. I asked the Director of the Pharmacy here at The University of Iowa Hospitals and Clinics how one can tell if these pharmacies are any good. There have been problems with bacterial contamination, including Pseudomonas, in some compounded drugs. The director said the waters are muddy but offered these tips: - The pharmacy should be licensed in the state where it is located, say Texas. If the pharmacy sends drugs into another state, most states require that it also be licensed in that state, say, California. The director said however, that most licensing procedures involve only paperwork and aren’t a guarantee of quality.
- He said that the doctor should ask, and get in writing, that the compounding pharmacy follows USP 797 Standards. 797 is a chapter dealing with the sterile technique and handling of drugs. If they won’t give you that in writing, I would avoid that pharmacy.
- Life of Avastin®. I read 797, a summary of which is available on the net; Avastin® is considered a low risk drug. The standard in 797 states that even a low risk drug that is refrigerated should be used within 14 days. If the drug is frozen, it can be used up to 45 days. Therefore, if a compounding pharmacy says that their refrigerated Avastin® can be used after 14 days, they are not following the 797 standards.
- Finally the director said that he would call the Board of Pharmacy in the state where the compounding pharmacy is located. That number is easy to get on the internet by combining the state with Board of Pharmacy in the search or by checking the National Association of Boards of Pharmacy's website.
If any compounding pharmacies read this blog and comply with these standards, they can send an e-mail or letter to that effect and I’ll publish their name, address, and telephone number. For convenience, I ask them to include the number of their state’s Board of Pharmacy.
I’ve talked a lot about Avastin® on this blog. We have to be careful though, since we’ve not followed these patients for very long and we also have the proven treatments of Visudyne® and Macugen®.
Once again, I am not paid by any company.
Avastin: Update to last Blog
Update to last blog: 1. To doctors: I received an e-mail from a retinal surgeon who said that the pharmacies he uses keep Avastin® for only two weeks after it has been divided into smaller doses for intraocular use. Their concern is that it will become inactive. I checked with our pharmacy at The University of Iowa Hospitals and Clinics and they also keep the drug for only two weeks at 4◦ C. So the two-week limit on Avastin® is probably a good idea until we learn otherwise. To keep the price low, you may need to come up with a plan to bunch your patients so they can be injected within a two week period. 2. We received the following question (paraphrased) from a reader: “ My mom was just diagnosed with wet AMD in one eye, and dry AMD in the other. She is scheduled to have her first Visudyne® treatment tomorrow but I was wondering if she should have Avastin® instead?” Answer: Your mother’s eye doctor should be able to tell you if the new blood vessels are of the “classic” type and if they are, I think it is appropriate to try Visudyne®. Visudyne® is FDA approved and has been shown in clinical trials to be better than no treatment. Visudyne® also works best in eyes with classic neovascularization. I use intraocular Kenalog® with Visudyne® because I think the visual results are better but this is still unproven. Patients who have Visudyne® often have decreased vision for a week or so after treatment because of inflammation and increased fluid within and under the retina. If your mother has continued loss of vision after that, I would ask her ophthalmologist to re-evaluate her. If the neovascularization is enlarging, say after six weeks, or there still is a lot of fluid beneath the retina, I would ask him or her about intraocular Avastin®. 2. We received the following question from a reader: “ Can you inform me if there are any studies indicating a connection [or lack of one] between Macular Degeneration and cardiac ‘blood thinners?’”Answer: This is a good question. There is no evidence that aspirin, any other platelet inhibitor, or Coumadin® increases the progression of AMD. There is a lot of evidence however that Coumadin® increases the risk of severe bleeding in eyes of patients with the wet or neovascular form of AMD. The bleeding can be so severe that all vision is lost. Therefore, if you have the wet form of AMD, you should ask your doctor if you really need Coumadin®. Your doctor may or may not be able to take you off the drug, if for instance, you have an artificial heart valve, atrial fibrillation, or a history of strokes. If this is the case, then ask your doctor to keep the dose and the INR (a measure of how much you are anticoagulated) as low as possible. One would think that aspirin or other platelet inhibitors would also increase the risk of bleeding in AMD but that hasn’t seemed to be the case. References: 1. Rosenfeld PJ, Moshfeghi, AA, Puliafito CA. “Optical Coherence Tomography Findings after Intravitreal Injection of Bevacizumab (Avastin) for Neovascular Age-Related Macular Degeneration.” Opthalmic Surg Lasers Imag 2005;36:331-335.
2. Tilanus MA, et al. “Relationship between Anticoagulant Medication and Massive Intraocular Hemorrhage in Age-Related Macular Degeneration.” Graefes Arch Clin Exp Ophthalmol, 238:482-485, 2000.
3. Lewis H, Sloan, SH, Foos RY, “Massive Intraocular Hemorrhage Associated with Anticoagulation and Age-Related Macular Degeneration.” Graefes Arch Clin Exp Ophthalmol. 226:59-64, 1988.
4. el Baba F et al. “Massive Hemorrhage Complicating Age-Related Macular Degeneration. Clinicopathologic Correlation and Role of Anticoagulants.” Ophthalmology 93:1581-92, 1986.
Avastin
A number of ophthalmologists who specialize in retinal disease have been writing and asking about Avastin® (bevacizumab), which was covered in the Sept 19th blog. A number of retinal specialists have begun using Avastin® for the treatment of patients with the wet or neovascular form AMD. Most of these patients are those who have not responded well to treatment with Visudyne® or Macugen®. The early results reported at The Retina Society meeting and from a polling of my colleagues, indicate that Avastin® usually controls the abnormal blood vessels in AMD and can result in increased vision. We still don’t know if there are any long-term side-effects from intraocular Avastin®. Most of us believe however that this treatment should be safe because the risks were low with the long-term use of Lucentis®, which is a smaller fragment made from Avastin®. In addition some patients need only two or three injections of Avastin® (at monthly intervals) to control the neovascularization which is probably safer than the multiple injections used with Lucentis® or Macugen®. A good discussion for both patients and physicians about the possible risks and benefits of this drug can be found on http://www.omic.com/. Click on the informed consent tab on the right and then scroll down to Avastin®. The remaining part of this blog is directed to retinal specialists and is therefore rather technical. It still may be of interest to the layperson especially if they have AMD. To the retina doctors: the dose is 1.25mg per 0.05ml given intraocularly, like Macugen®. A reputable and approved pharmacy should prepare doses from a large bottle of Avastin® under sterile conditions and then keep them at 4◦ centigrade. We ask our pharmacy to place about 0.2cc in a 1mm (TB) syringe. We then order it from the pharmacy when we need it for a patient, let it thaw, place a 30 gauge needle on the end of the syringe, expel the extra along with any bubbles until we get to 0.05 ml, and then inject it through the pars plana like Macugen®. The small volume delivered into the eye through the sharp fine needle is usually well tolerated even with topical anesthesia but a small bleb of subconjunctival anesthetic can also be used. Our pharmacy charges us around $125 per dose, which is reasonable. I wouldn’t worry as much about the price as I would about the quality of the pharmacy preparing the doses. Medicare should pay for the drug and the injection. Some docs worry about the off-label use of Avastin™ but I don’t think this is a big issue if you are using it in the best interests of your patient. Remember we use Kenalog®, intravitreal antibiotics, and tissue plasminogen activator in an off-label manner also. There are several articles in PubMed that discuss this use of Avastin® [Pubmed Search Results].
This field is evolving rapidly but here is what I currently do (most of the time): I start with the FDA approved treatments that have been proven in large trials, namely Visudyne® or Macugen™. I usually recommend Visudyne® immediately followed with 4mg of Kenalog® intravitreally to a patient who has a small to medium size CNV that has a classic component (does not necessarily have to be over 50% classic because I also use Kenalog®). I usually recommend Macugen® to a patient who has a large CNV, a medium or large occult CNV, an indiscrete CNV, or a CNV associated with blood. I use either Visudyne® with Kenalog® or Macugen® for a patient with a symptomatic small occult CNV. At the first three-month visit after the Visudyne® plus Kenalog® treatment or after 2-3 Macugen® injections, I re-evaluate with fluorescein angiography and optic coherence tomography. If the fluid is mostly gone and the CNV is about the same size, I continue the same treatment. If the CNV is larger or there still is subretinal fluid, I’ll usually recommend Avastin®. The patient’s opinion as to whether the sight and distortion is improving or not can also be very helpful in making your decision as to which treatment to use. In general, I have not had good luck with switching from Visudyne® to Macugen® or from Macugen® to Visudyne®. The clinical conundrum we all face is to wait long enough to see if the treatment is working but not wait too long until it is too late to try something else. This seems a reasonable compromise to me at this time. If we find that Avastin® is as good as we hope it is, we may switch treatments sooner. Good luck and please write with any opinions or questions. Jim More blogs on Avastin:
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