Pinnacle Medicare Services – A well intended but poor decision
Pinnacle Medicare Services is the carrier for the states of Arkansas, New Mexico, Oklahoma, Eastern Missouri, Rhode Island, and Louisiana.
The Medicare carrier decides whether a given treatment will be paid for by Medicare. Pinnacle decided that AMD patients must meet the following criteria before treatment with Avastin will be reimbursed:
The selected patient must have failed to improve or stabilize using other currently accepted ophthalmic therapies. This therapy may include Visudyne and/or Macugen. Given that the use of bevacizumab should only be attempted after other treatment failure(s), at least two fluorescein angiograms and OCT's should be performed, the first to evaluate the lesion type, location and size and the presence of subretinal fluid and the second or subsequent to document failure of the initial therapy(ies).
I don’t agree with their decision or their premise that bevacizumab should be used only after the failure of other treatments. They demand that the patient first be treated with Visudyne or Macugen. The results with Lucentis, which is derived from Avastin, are superior to Visudyne or Macugen. The early reports of the results of Avastin support that it’s better too and essentially the entire retinal community is switching to Avastin.
Visudyne is given every three months but the neovascularization can grow and a patient’s vision can decrease a lot in three months if the Visudyne is not effective. Macugen often shows a response only after four or more injections given at monthly intervals. So with either treatment there will be a delay before the ophthalmologist can give what he or she believes is the more effective treatment.
The second criterion discussing “lesion type” is probably based on the findings that Visudyne doesn’t work as well for occult neovascularization as it does for classic neovascularization. Macugen, Lucentis, and Avastin work for both types. Pinnacle wants a second fluorescein angiogram to document that the patient is getting worse. You really don’t need a second angiogram because the OCT, the vision, and the patient can tell you how they’re doing.
The main problem though is the delay in getting the Avastin. Wet AMD often progresses rapidly and once vision is lost, it usually doesn’t fully return. Larger neovascular membranes almost always mean worse vision. More scarring or bleeding means more loss of vision. That is why we tell patients over and over again to check their Amsler grids daily and to call us right away if they see any change. A day or two usually makes little difference but three months can determine whether a patient is able to read and drive a car.
I’m sure that Pinnacle has no ulterior motive. After all, Avastin is cheaper than Visudyne or Macugen. Pinnacles worries that Avastin is not approved by the FDA for the treatment of AMD. They worry that Avastin has some very nasty side-effects when it’s given intravenously to cancer patients in 800 times the dose that is used in the eye. So far we think these side-effects are extremely rare when it’s given intravitreally in AMD patients and maybe not be any different than in older patients who were not treated. We know though that Avastin. Lucentis, and Macugen get into the systemic circulation albeit in tiny amounts. We have no convincing evidence at this point that this tiny amount has deleterious effects. This may all be moot if the FDA approves Lucentis in the next few weeks but maybe, for now, Pinnacle should rethink their decision. References Spaide RF, et al. Intravitreal bevacizumab for choroidal neovascularization secondary to age-related macular degeneration. [ARVO 2006 poster 2962]. Available from http://tinyurl.com/gbqsp, program number 2962. Pieramici D, et al. Bevacizumab (Avastin) in the treatment of neovascular age-related macular degeneration. [ARVO 2006 poster 3540]. Available from http://tinyurl.com/gbqsp, program number 3540. Prabakaran SL, et al. Visual acuity response of patients with neovascular age-related macular degeneration treated with intraocular bevicazumab [sic] (Avastin) [ARVO 2006 poster 5224/B640]. Available from http://tinyurl.com/gbqsp, program number 5225. Brooks HL, et al. Safety and efficacy of intravitreal Avastin for neovascular age related macular degeneration. [ARVO 2006 poster 5212/B627]. Available from http://tinyurl.com/gbqsp, program number 5212. Shah AR, DelPriore LV. Comparing efficacy of AMD treatments using Lineweaver-Burke plots: A meta analysis. [ARVO 2006 poster 2190/B769]. Available from http://tinyurl.com/gbqsp, program number 2190.
Pain after Avastin Injection
We received the following question this week: "Has anyone other than myself suffered excruciating pain after an avastin shot?"Typically patients feel very little or no pain with the injection. I inject anesthetic beneath the conjunctiva in addition to topical drops and then wait at least three minutes before giving the intravitreal injection. Some physicians use only topical anesthetic drops. Patients who receive only topical drops often feel a very brief sharp pain as the needle pierces the sclera and choroid. Excruciating pain is rare. Perhaps the needle pierced one of the nerves in the choroid which are more commonly found in the horizontal meridians (three and nine if you look at the eye as a clock) although there is a lot of variation. Or perhaps this patient was very sensitive to the increased intraocular pressure of the injection. Injecting anything in the eye will increase the pressure temporarily as if you are over-inflating a tire. The eye adjusts quickly though by draining fluid through the normal channels in the front of the eye and the pressure usually returns to normal. The volume of Avastin injected is 0.05 ml so the pressure rise is usually modest. It’s unfortunate that this patient felt such pain but I doubt this means that anything went wrong. I also doubt that it was caused by the Avastin itself. Another cause of irritation of the outer surface of the eye can be due to the 5% Betadine that we use to sterilize the surface of the eye. I put a cotton tip applicator right on the conjunctiva in the area where I’m going to inject. I ask the nurse to irrigate the eye after I inject but some people still may get a mild chemical conjunctivitis. This typically lasts only a day or two and is treated with artificial tears and/or antibiotic eye drops. A more severe scratchy pain that can last two days can be due to a corneal abrasion. An abrasion means that the outer epithelium of the cornea is gone in a certain area. This exposes the underlying corneal nerves. This is due probably to the lid speculum rubbing the surface of the eye when it is put between the lids or removed. It may also be due to the speculum being in the eye too long. I take care not to rub the cornea with the speculum. I try to be ready to give the injection right after I put the speculum into the eye. I put the speculum in, touch the area gently with a Q-tip soaked in Betadine, measure the correct distance, give the injection, and then take the speculum out. The whole process should take about a minute. In patients who are prone to abrasions, I ask the nurse to put in a viscous liquid tear before I put in the speculum. This makes the surface of the cornea slippery which reduces the risk that the speculum will rub on it and cause an abrasion. Finally the pain ophthalmologists worry about is a severe dull pain that starts a day or a few days after the injection. This pain can mean an infection inside the eye. Not all intraocular infections (endophthalmitis) cause pain so we ask the patients to check their vision at least once a day for the first week after the injection. An intraocular infection will cause a lot of floaters and then a marked loss of vision. If you notice this, call your doctor right away. I thank this person for the question. I realize that he or she may not be too anxious to get another injection but remember that wet AMD typically causes severe central vision loss if left untreated so please don’t give up. Talk to your doctor about the risk of pain after another Avastin injection or maybe another type of treatment.
Update on the treatment of neovascular AMD
Hello again. Here are the numbers of the various AMD treatments done at the University of Iowa over the last six months. We also inject a few additional patients with Avastin and Macugen in an outreach clinic.
 It’s obvious that that number of treatments using Avastin is increasing steadily. There are two reasons for that. The first is that we are using Avastin in most new patients with wet AMD because we believe it gives the best results. This belief is based on the positive results of the Lucentis trials, recent papers and reports stating excellent results using Avastin, and mainly our positive clinical experience. The second reason that the numbers are increasing is that we’re now using Avastin in patients who have only mild vision loss small areas of occult choroidal neovascularization. We often didn’t treat these patients in the past because: their natural history was not too bad; PDT was not particularly good for treating them; and we hated to commit them to 24 months of Macugen which didn’t seem to help that much anyway. Avastin though works well for treating these patients so the overall number of Avastin injections is increasingt.
We now know that Avastin works very quickly. The fluid beneath the retina starts to decrease within twelve hours after the injection. It is clear that Avastin stops the neovascularization from leaking. It’s also becoming clear however, that Avastin often does not get rid of the neovascularization or cause it to involute into a dry scar. Partsch and colleagues looked at CNV that were removed surgically after treatment with intravitreal Avastin. The neovascular vessels were still open, proliferating, and inflamed. In a small study, Korotkin and colleagues found that neovascularization recurred in some patients even after they had monthly injections of Lucentis for two years. Rosenfield and colleagues reported preliminary results of the PrONTO study. In this study forty patients received three injections of Lucentis at monthly intervals. After seven months of follow-up, fifty percent of the patients needed retreatment.
I usually give three injections of Avastin at 4-6 week intervals in patients with AMD. I then watch them (do not inject them) if the have no fluid after the third injection. I ask them to see me again in three months but warn them to return if their vision decreases. So far, about 40% of the patients have returned but I expect that percentage to increase with longer follow-up. There are a few patients who have looked great after only one or two injections of Avastin and I elected to simply follow them.
My best guess is that over fifty percent of patients will need additional injections periodically because the neovascularization will reactivate with leakage. Perhaps that’s not a bad tradeoff: a patient with AMD gets three injections initially and then has maybe a 60% chance of needing more injections four months down the line. Each time the neovascularization recurs though, there is always the risk of bleeding, scarring, and more visual loss.
We need a treatment that combines the rapid effect of Lucentis or Avastin with another drug that causes involution of the neovascularization. Visudyne combined with Avastin does this but some doctors believe that Visudyne can cause scarring with a drop of vision. It makes no sense to combine Macugen with Lucentis or Avastin since the both act on vascular endothelial growth factor (VEGF) and both need repeated injections.
An intriguing possibility would be combining Lucentis or Avastin with anecortave acetate (Retaane). Retaane is an anti-angiogenic steroid and works at multiple sites to block a variety of enzymes and growth factors involved in neovascularization. It is injected beneath the conjunctiva and Tenon’s capsule superiorly. Retaane lasts six months and has been shown to be as good as Visudyne or Macugen for the treatment of wet AMD. So a treatment involving the injection of either Lucentis or Avastin intraviteally combined with Retaane might achieve long-term involution of the neovascularization. Alcon manufactures Retaane and has been reluctant to permit the intravitreal injection of this drug. The combination of Lucentis or Avastin with Retaane (maybe even intravitreally) could be a real winner. Retaane has been approved in Australia and I’m hoping that some of our colleagues “Down Under” are trying this combination. If you have, please let us know how it worked.
We’ll talk more next week about the toxicity of Lucentis and Avastin.
References:
1. Partsch MC, et al. Immunohistopathologic evaluation of choroidal neovascular membranes following intravitreal bevacizumab (Avastin®) therapy. [ARVO 2006 poster 864/B785]. Available from http://tinyurl.com/gbqsp, program number 864.
2 Korotkin A, et al. An emerging problem: Recurrence of CNV in AMD is common after cessation of 24 month treatment with ranibizuman (Lucentis®). [ARVO 2006 poster 2961]. Available from http://tinyurl.com/gbqsp, program number 2961.
3. Visual acuity outcomes following a variable-dosing regimen for ranibizumab (Lucentis™) in neovascular AMD: The PrONTO Study. [ARVO 2006 poster 2958]. Available from http://tinyurl.com/gbqsp, program number 2958.
Update from ARVO 200
ARVO is the acronym for the Association for Research in Vision and Ophthalmology. Most of the world’s best researchers in eye disease attend the annual ARVO meeting which was recently held in Fort Lauderdale, Florida. There were a number of reports that dealt with diet and the risk of AMD. Most of us had thought that omega-6 fatty acids (linoleic acidor LA) was bad for AMD and that omega-3 (linolenic or ALA) fatty acids might reduce the risk of AMD (see blogs 8/4,8/12, 8/22-3 and 11/9). Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are the omega-3 acids that are normally found in the body. AREDS II is testing whether one gram a day of DHA retards the rate of progression of AMD. ARED II is also testing whether supplementation with lutein and zeaxanthin reduces the progression of AMD.
Here is the latest from ARVO:
Fletcher and associates found that higher levels of either LA (supposedly the bad one) or ALA were associated with less risk of AMD. They basically found no association with DHA or EPA.
SanGiovanni and associates found that AMD patients with the highest dietary intake of DHA and EPA were 20-25% less likely to progress to severe AMD.
Robman and associates found that higher dietary intake of omega-3 fatty acids or lutein/zexanthin actually increased the rate of AMD progression.
Hodge and associates reviewed published studies and found the results concerning the protective effect of omega-3 fatty acids varied greatly. The effect varied from being protective to neutral to actually harmful in preventing AMD.
Souied and colleagues found that patients with wet AMD had low serum of DHA.
Chong and associates found no association between late AMD and dietary intake of LA, ALA, lutein or zexanthin. They found that fried fish increased the risk of late AMD but steamed, grilled, or baked fish decreased the risk. They also found that olive oil decreased the risk.
Rosenthal and associates found that high dietary intake of lutein/zeaxanthin reduced the risk of wet AMD.
As you can see the results of the studies were varied. These studies point to the need of a randomized controlled trial testing whether supplementation with DHA and or lutein/zexanthin reduces the risk of progression to severe AMD. That is exactly what AREDS II will do and recruitment into the trial will start soon.
So what should you do? I would participate in the AREDS II if possible. If you cannot I would take the vitamins recommend from the AREDS trial (see blog June 29, 2006). I would also limit my intake of animal fat and I would eat baked, steamed, or grilled fish at least once a week. I would also use olive oil instead of other oils such as soy, sunflower, peanut, and corn oils all of which have a high content of LA and little ALA. And of course, eat colorful fruits and vegetables.
You can also purchase our book if you wish which, among many other things, discusses diet, vitamins, and other supplements in detail.
References
Treatment of AMD in Stroke Patient
I received this question recently:My 75 year old father has wet AMD in one eye and has lost vision in this.eye. He has had two treatments of Visudyne with poor results. He has been anxiously awaiting Avastin treatment (as we're from Canada, it has not been available here) and has recently traveled to the U.S. to seek advice.Two weeks ago, he had a minor stroke and is now taking Coumadin. His new doctor has told him he is no longer a candidate for either Lucentis or Avastin because of his stroke. This doctor says that Visudyne is "overkill" in his case and recommends Macugen treatments. My dad is very nervous about bleeding within the eye with the Macugen. Could you please confirm that a) the Macugen treatment is safe for a patient taking Coumadin; and b) that a stroke definitely rules out Avastin or Lucentis as treatment for wetAMD. Any other thoughts on the matter would be appreciated.I would recommend Macugen. When Macugen, or anything for that matter, is injected into the eye, the pressure inside the eye increases. The pressure increase slows or even stops the flow of blood into the eye so there is little risk of hemorrhage from the injection. Macugen doesn’t increase the risk of hemorrhage from the neovascular membrane either. As the neovascularization atrophies, the risk of hemorrhage should decrease not increase. My biggest concern with your father is that Coumadin® increases the risk of intraocular hemorrhage in eyes with wet AMD. Therefore the doctor who monitors his protime (a measure of Coumadin’s anticoagulant effect) should be told to keep the protime as low as possible yet still have the desired effect of decreasing the risk of a stroke. That usually means an INR (International Normalized Ratio) of around 2.0-2.5. Why not Avastin or Lucentis since in studies they appear to result in better vision than Macugen? These drugs inhibit all forms of vascular growth factor whereas Macugen inhibits only one. There is concern that a small amount of Avastin and/or Lucentis can get out of the eye into the systemic circulation. In the large studies on Lucentis, the groups treated with the drug had a slightly higher, albeit overall very low, risk of heart attack than the control group. One eye doctor noted an effect of Avastin in the opposite eye of the one injected. The only way the Avastin could have gotten into the fellow eye is through the bloodstream. Eyetech has also reported a patient who had a life-threatening allergic reaction after an injection of Macugen and we’ve seen severe skin rashes after injection. Avastin. Lucentis, and Macugen are very safe but we are becoming suspicious that they may have rare side-effects. So we have to weigh the possible benefits of these drugs with the risk. That begs the question as to the visual potential of your father’s eye? If he has done poorly after two Visudyne treatments maybe there is already scarring and the vision won’t get better with any treatment. If he has another good eye and he’s not well, maybe it would be best just to watch the better eye. Or maybe he could be treated again with Visudyne, (which he appears to tolerate well), to make sure the neovascularization dries up into an inactive scar. Please tell all of this to your father and in the end, he should be the one to make the decision. Good luck! References: 1. Gragoudas ES, Adamis AP, Cunningham ET, Feinsod M, Guyer DR, VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for Neovascular Age-Related Macular Degeneration. New Engl J Med 2004; 351(27):2805-2816. 2. Avery RL, Pearlman J, Castellarin AA, Nasir MA, Patel A, Wendel RT, Reed B. Regression of retinal and iris neovascularization from diabetes following intravitreal bevacizumab (Avastin®). [ARVO 2006 poster 3860/B900]. Available from http://tinyurl.com/gbqsp, program number 3860. 3. Rosenfeld PJ, Heier JS, Hantsbarger G, Shams N.Tolerability and efficacy of multiple escalating doses of ranibizumab (Lucentis) for neovascular age-related macular degeneration. Ophthalmology 2006; 113(4):623-632. ================ Reply from reader: Thank you to both Dr. Folk and Dr. Doan for responding to my question. I can't tell you how much it is appreciated. We feel like we have had a lot of conflicting advice, and you have really helped us to make a more informed decision on my dad's next treatment.
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