As treatment options grow, consensus shrinks. Experts disagree on wet AMD.
Once upon a time, not so very long ago, a distraught patient would come to her ophthalmologist with the frustrating symptoms of wet age-related macular degeneration. She would complain of a rapid loss of central vision, increasing difficulty recognizing faces at a distance, and straight lines appearing wavy. And all her doctor could offer was argon laser photocoagulation, which didn’t help much at all.
Fortunately, the story has begun to change with the recent introduction of several treatment alternatives that promise to revolutionize the way retina specialists confront macular degeneration.
There is a problem, however. Even though the new alternatives are under evaluation in clinical studies, they are not currently being compared with each other—making it extremely challenging for ophthalmologists to determine which is truly the best option. Indeed, if you ask six ophthalmologists their opinion on treating wet AMD, you will get
six different answers.
That is exactly what we did, and here are the results.
Case One: Classic CNV
Patient: A 75-year-old man.
Presents: New-onset classic CNV due to macular degeneration in left eye, with visual acuity of 20/80. Optical coherence tomography shows subretinal fluid with cystic intraretinal fluid. Right eye 20/20 with high-risk drusen.
Problem: His only insurance is Medicare, and he would have trouble paying an additional 20 percent for treatment.
Dr. Saperstein: In my experience over the last two years, using PDT in combination with intravitreal triamcinolone acetonide has been superior to using PDT alone. PDT alone increases inflammation in the eye, which can lead to neovascularization. By adding the steroids, we can combat the inflammation. Plus, steroids can also decrease vascular permeability, giving us a double effect so we don’t have to treat as often.
Macugen (pegaptanib sodium) is a newly approved treatment that slows vision loss but only occasionally improves visual acuity. PDT plus intravitreal steroids results in improved vision in many patients. From a cost perspective, the combination of PDT and steroids is probably 60 percent of the cost of Macugen therapy.
Dr. Mieler: The controlled clinical trials of PDT have been done without steroids, yet the use of intravitreal triamcinolone has become commonplace. However, there are limited data showing the long-term effects of PDT and triamcinolone. There is also a small risk of infection with this approach.
This patient could be treated with Macugen, but I would still recommend PDT with Visudyne (verteporfin) because the Visudyne trial was driven by the classic forms of CNV, and the outcomes are really quite favorable. While we don’t know the size of the lesions in this case, under these parameters I would go with PDT and Visudyne.
Dr. Sternberg: The first thing I would do is refer the patient to the VERTACL study1 (which is comparing intravitreal triamcinolone acetonide and PDT with verteporfin to PDT with verteporfin alone). Then I would consider PDT with triamcinolone because with Macugen there is an increased number of visits and a slightly increased risk of complications.
Case Two: Minimally Classic CNV
Patient: A 79-year-old woman.
Presents: History of macular degeneration. Left eye has disciform scar after four sessions of PDT, with visual acuity of 20/400. Right eye has minimally classic CNV with visual acuity of 20/50.
Problem: This woman has transportation difficulties and cannot get to her doctor on a regular basis.
Dr. Mieler: Treatment choices depend on the size of the lesion. If the lesion is large—and there is documentation of worsening vision—I would treat with Macugen. And if the lesion is small, I would treat it with PDT. Without a doubt, however, the patient would question the PDT alternative because if it didn’t work in one eye, why should it work in the other eye?
Although she does have transportation difficulties, I would still recommend Macugen given a large lesion size and documentation of progression of the area of neovascularization.
Dr. Sabates: I wouldn’t let the woman’s transportation concerns get in the way of the best treatment. I would treat her with Macugen and then arrange the transportation. Hopefully that could be worked out. And if transportation is absolutely impossible, then I would recommend PDT and intravitreal triamcinolone, and follow her every three months. However, the PDT could be problematic given that the other eye did not respond to PDT treatment.
Dr. Mruthyunjaya: The fellow eye should serve as a guide. I would consider at least one setting of PDT with intravitreal triamcinolone, but she will likely progress with more vision loss.
If the vision continued to decline and if the total duration of vision loss has been less than six months, she would be an excellent candidate for a technique developed at Duke University Eye Center and advanced by Cynthia A. Toth, MD, called macular translocation 360-degree retinectomy (MT360). At Duke, we offer this procedure for the second eye of patients with advanced AMD.2
In a surgical setting, we create a 360-degree peripheral surgical retinectomy and reflect the retina, thereby gaining access to remove the causative CNV lesion. The retina is then rotated superiorly so the fovea is now repositioned over a relatively healthier bed of retinal pigment epithelium away from the bed of the CNV lesion. The retina is reattached under silicone oil. The retinal rotation results in tilting of images, but rarely significant diplopia as the fellow eye already has a central scotoma from AMD. Three months later, extraocular muscle surgery and silicone oil removal are performed to correct the ocular torsion.
In our prospective series of 64 patients, at 12 months after MT360, there was stabilization as well as statistically significant improvement in distance and near visual acuity and reading speed.3 It’s important to note that this group of patients not only had bilateral CNV but also had large lesions, with a median size of nine disc areas, in the treated eye.
This technique is the only treatment currently available for bilateral AMD to demonstrate statistically significant improvements in vision in the treated eye and an improved quality of life. MT360, however, has not been directly compared to current pharmacologic treatments in a clinical setting, so we carefully counsel eligible patients.
Case Three: Occult CNV
Patient: An 86-year-old woman.
Presents: Eight-week history of occult CNV due to macular degeneration in left eye, with vision of 20/100. Right eye has a disciform scar and count fingers vision.
Problem: She also has multiple medical problems.
Dr. Fekrat: This patient may be too old for MT360 surgery, although she would otherwise be a candidate. And I can’t see giving her Macugen every six weeks for two years because of her age and multiple medical problems. Additionally, I would not use transpupillary thermotherapy, which utilizes a low dose of infrared laser light without therapeutic drugs. I would treat her with PDT and intravitreal triamcinolone.
Dr. Sternberg: Before giving any treatment recommendation, I would first need to document the patient’s disease progression. Some eyes will improve spontaneously, and others may go through a dormant phase. If I am seeing patients for the first time, I may have them return in four to six weeks to determine what direction they are going. If they were stable or improving, I would watch them indefinitely.
In this case, if there is evidence of deterioration, Macugen may be slightly better than the other alternatives, so I would offer that to the patient.
Dr. Sabates: This patient has a long history of problems with AMD, having already lost her central vision in her other eye. She presents with progressive loss of vision in her remaining eye. With her age, our options are fairly limited. Placing an 86-year-old woman on a regimen of Macugen would be very difficult to sustain.
If there is a question of progression, then watching the patient closely would be reasonable. It appears that this patient has shown progression by her history. I would probably treat with PDT and an injection of triamcinolone. TTT could be another option for this patient.
Case Four: Predominantly Hemorrhagic CNV Lesion
Patient: A 68-year-old man.
Presents: Moderately thick subfoveal subretinal hemorrhage greater than 6 disc areas in size in left eye. Fluorescein angiography shows blocked fluorescence due to blood; no CNV is identified. Vision in the left eye is 20/400. Right eye has high-risk drusen with visual acuity of 20/30.
Dr. Saperstein: PDT wouldn’t work with this patient because you can’t get the light to activate the Visudyne through the blood. In this particular patient, you can’t see
any CNV, so there might not be any.
It is important to keep in mind, especially with patients on aspirin and warfarin, that spontaneous bleeding can occur due to a crack in Bruch’s membrane. So to determine the cause of the bleeding, I would do subfoveal hemorrhage displacement surgery.4 With this technique, we inject tPA (tissue plasminogen activator) under the retina. Using the cannula, we detach the inferior retina to allow the blood from underneath the macula to drain, and then do a partial fluid-air exchange and have the patient sit up after the surgery all night. In the morning, all the blood is in the inferior of the retina.
A few days after surgery we perform a fluorescein angiogram. This technique is helpful in most of my patients. We often don’t see CNV in patients who are on blood thinners. In patients with CNV, we will go ahead and treat them with an appropriate therapy depending on the size and type of their lesion. Many times they will rebleed up to a year after treatment. They are always complex patients to treat.
Dr. Fekrat: At the American Society of Retina Specialists meeting in Montreal this past July, we presented data from our series treating these types of eyes with PDT alone. We had a series of 21 eyes with pretreatment average visual acuity of 20/160 with a mean subretinal hemorrhage size of 13 disc areas. At 10-month follow-up, the median time for it to resolve was 4.9 months and the mean change in visual acuity was less than when compared with the natural history in 41 eyes.5
In cases of predominantly hemorrhagic CNV lesions, I have done vitrectomy with tPA infusion and a gas bubble, but postoperatively the patients have a disciform scar. Given these results, I think that there is much more rapid clearing with PDT than in patients who are untreated.
Dr. Mruthyunjaya: First, I would be sure this patient is on AREDS vitamins to protect the other eye. Also, if appropriate, I would definitely counsel on smoking cessation. And then I would do pneumatic displacement with subretinal tPA to better image the underlying lesion. I would also recommend using PDT alone.
The Bottom Line of This Discussion?
To date, there is no clear consensus among vitreoretinal experts on the best way to treat various presentations of macular degeneration. And if there were, it could change overnight with the introduction of newer agents (See “AMD Drugs: A Promising Pipeline?”.)
As Dr. Fekrat pointed out, “At this point, with the availability of such diverse treatment options, we are truly practicing the art of medicine.”
1 VERTACL stands for VERteporfin, Triamcinolone ACetonide, Laser. The full name of the study is Photodynamic Therapy and Triamcinolone-Acetonide Preservative-Free in Patients with Neovascular Age-Related Macular Degeneration.
2 Mruthyunjaya, P. et al. Ophthalmology 2004;111:1715–1724.
3 Cahill, M.T. et al. Ophthalmology 2005;112:144–151.
4 Boada, R. et al. Poster #B505 presented at the Association for Research in Vision and Ophthalmology, Wednesday, May 8, 2002.
5 Ahmad, S. Presentation at the American Society of Retina Specialists, Tuesday, July 19, 2005.
Dr. Fekrat is an investigator for Alcon, Genentech, Eyetech, Iridex, Novartis and VisionCare. Dr. Mieler is an advisory board member for Alcon, Eyetech, Novartis and Genentech. Dr. Sabates has been an investigator for Eyetech, Genera, Acuity Pharmaceuticals and Novartis. Dr. Saperstein’s research has been funded by QLT, Genvec and Novartis; he is a consultant/advisor for Eyetech, Pfizer, Light Sciences, Amgen and Genentech. Dr. Sternberg is a consultant for Genentech and Alcon. Dr. Mruthyunjaya has no financial interests.
Special thanks to Dr. Fekrat for her help with this article.
|AMD Drugs: A Promising Pipeline?|
Lucentis. We also asked the discussants: If ranibizumab (Lucentis) were available today, would it change the way you treat these patients? “If the company’s preliminary data are accurate, I would consider Lucentis for the first three cases we discussed,” said Dr. Fekrat. “In fact, the introduction of new pharmaceuticals in the next few years could make this discussion a bit obsolete.”
Ranibizumab is a humanized antibody fragment designed to find and inhibit vascular endothelial growth factor A (VEGF-A), thus blocking new blood vessel growth and leakiness.
According to a press release issued by Genentech in July, in a Phase 3 clinical study approximately 95 percent of patients maintained or improved vision (defined as a loss of fewer than 15 letters in visual acuity) at one year when treated with intravitreal Lucentis injections compared with approximately 62 percent of controls given a sham injection. (One-year data from the study was presented at the American Society of Retina Specialists.1)
For Dr. Fekrat, these data are interesting but preliminary. Dr. Mieler said he would need more information about what is referred to as the MARINA study.2 And Dr. Sternberg noted that while Genentech “suggested that Lucentis may have more efficacy than Macugen or Visudyne, I am hesitant to make treatment recommendations based on a press release until I have had an opportunity to examine the data more closely.”
Avastin. Another promising therapy for wet AMD is bevacizumab, known by the trade name Avastin. This is an intravenous anti-VEGF monoclonal antibody originally used to treat colorectal cancer. An uncontrolled clinical study published in the June Ophthalmology3 showed a significant increase in visual acuity within one week of treatment. At 12 weeks, the median and mean visual acuity letter scores increased by eight letters and 12 letters, respectively. The authors of this study called for a randomized, controlled clinical trial to determine the efficacy of this approach.
Another report, in Ophthalmic Surgery, Lasers & Imaging, described the response to 1 milligram of intravitreal bevacizumab in a woman with neovascular AMD who had responded poorly to pegaptanib. Within one week, subretinal fluid had resolved and no inflammation was noted. Visual acuity was stable and a normal macular appearance was maintained for at least four weeks. The authors surmise that bevacizumab may be a safe and effective treatment for vision loss caused by neovascularization.4
Some experienced physicians are already using bevacizumab in their practice. “A compounding pharmacy can prepare this drug for intravitreal use,” said Dr. Fekrat. “I have been using it for eyes with CNV from neovascular AMD and have had impressive results after a single injection.”
In the near future, these drugs may show even wider promise for more effective AMD treatments.
1 Heier, J. Presented at the American Society of Retina Specialists, Monday, July 18, 2005.
2 Minimally classic/occult trial of the Anti-VEGF antibody Ranibizumab In the treatment of Neovascular AMD.
3 Michels, S. et al. Ophthalmology 2005;112:1035–1047.
4 Rosenfeld, P. J. et al. Ophthalmic Surg Lasers Imaging 2005;36: 331-335.
|MEET THE EXPERTS|
|Sharon Fekrat, MD, associate professor of ophthalmology, Duke University. “Since none of the available treatments has been compared to the others in a standardized way, we have come to the point where the treatment offered to patients with macular degeneration depends on the physician the patient sees.”|
William F. Mieler, MD, professor and chairman of ophthalmology, University of Chicago. “The tough part [of treating AMD] is comparing which of the new alternatives is the best option. And as more products reach the market, it will become even more complex and more confusing. It is a rapidly changing area of ophthalmology.”
Prithvi Mruthyunjaya, MD, assistant professor of ophthalmology, Duke University. “We are moving toward a combination pharmacologic treatment that would use timing of different treatments to affect the various components and mediators of these lesions. Until these treatments are proven, there will be a role for the vitreoretinal surgeon—especially in treating advanced bilateral disease.”
Nelson R. Sabates, MD, professor and chairman of ophthalmology, University of Missouri, Kansas City. “Without a doubt, the treatments for macular degeneration are better than what we had, but they are not where we want to be. However, I predict treatment results are going to improve over time, and I am very excited about the future.”
David A. Saperstein, MD, associate professor of ophthalmology, University of Washington, Seattle. “Before, we could only offer these patients low vision rehabilitation and very little hope. Today, newer treatments at least allow us to slow down the progression of the disease and in some cases improve vision. Now the challenge is managing patient expectations in a realistic manner.”
Paul Sternberg Jr., MD, professor and chairman of ophthalmology and visual sciences, Vanderbilt University, and director, Vanderbilt Eye Institute. “I have been practicing for 20 years and am certainly excited about the current intense interest among researchers to develop new alternatives in the treatment of macular degeneration. I think there is definitely a cause for optimism.”