There has been a number of reports of adverse reactions associated with off-label intravitreal injection of Avastin (bevacizumab) for the treatment of neovascular age-related macular degeneration (AMD). These include elevation of intraocular pressure (IOP) and toxic anterior segment syndrome (TASS). Similar adverse reactions have also been reported for Lucentis (ranibizumab), but reactions appear to occur much more frequently following Avastin.

Dr Malik Kahook of the University of Colorado has reported that elevation of IOP following intravitreal Avastin may be secondary to particulate matter that forms within plastic syringes during storage. The particles can clog channels within the eye after injection and lead to acute and chronic elevation of IOP.

Because Avastin is not designed for use within the eye, pharmacists must reformulate it for intraocular injection, a process known as compounding. It is during the compounding process, and subsequent storage in the doctor's office, that the chemical and physical properties of the drug and it's vehicle can change in ways that may lead to adverse reactions following intraocular injection.

Off-label use of any drug introduces variables that can increase the risk of adverse events. In many case there is no viable FDA-approved alternative, but with Avastin there is (eg. Lucentis). Because Avastin is so much less expensive than Lucentis, insurance carriers, health plans, or other payers weigh the pros and cons and decide whether the risk is worth the savings.

As long as we have to rely upon compounding pharmacies to prepare the drug, and the handling and storage practices are not standardized, then problems like this will continue. While the cost savings of off-label Avastin compared to Lucentis can be substantial, there ain't no such thing as a free lunch.

Print version

A case of bilateral central serous chorioretinopathy (CSC) that rapidly resolved with treatment of obstructive sleep apnea (OSA) is reported.

OSA is a condition characterized by repeated episodes of partial or complete obstruction of the airways resulting in the cessation of breathing for 10 seconds or longer during sleep. Between the ages of 30 and 60 years, 9% of women and 24% of men are afflicted with this sleep disorder. The incidence of sleep apnea is highest in men who are overweight and middle-aged or older. Several optic nerve disorders have been associated with OSA, including nonarteritic ischemic optic neuropathy, glaucoma, and papilledema. Among retinal disorders, OSA has been associated with a higher risk of retinal vein occlusion, central serous chorioretinopathy, and diabetic retinopathy.

In this case report, the patient suffered bilateral decreased vision to 20/30 right eye and 20/40 left eye due to typical CSC lesions. Systemic evaluation led to a diagnosis of OSA, which was treated and resulted in rapid resolution of the CSC and improvement of visual acuity in both eyes.

The authors state that this case is the first reported case of rapidly resolving bilateral CSC due to the treatment of OSA.

WHAT IT MEANS TO YOU: Sleep apnea has been associated with CSC, and now it has been reported that treatment of sleep apnea can speed resolution of CSC. Although this is just a single case report, and needs to be confirmed by additional research, it does indicate a need to consider sleep apnea in the management of patients with CSC.

Print version

Among persons with low vision, degree of vision impairment was not associated with risk of falling, but those who regularly participate in physical activity have a lower risk of experiencing a fall than those who are physically inactive, according to a new study.

Falls are a major cause of injury among the elderly. The healthcare cost associated with falls is considerable. Visual acuity has inconsistently been found to be an independent risk factor for falls.

In this study participants were mobile, aged 60 years or above, and had low vision. Details about falls in the previous 12 months and other information were collected, and patients completed a questionnaire about activities of daily living. The duration and main causes of visual impairment, visual acuity, contrast sensitivity, depth perception, and visual field were assessed.

One hundred and twenty seven patients (53%; 67 males) with a mean age of 76.3 years were recruited. Thirty seven percent of the participants had mild, 50% moderate and 13% severe visual impairment. The frequencies of single and multiple falls were 42.5% and 12.6% respectively. Visual acuity, contrast sensitivity, depth perception, visual field, main cause, and duration of visual impairment were not significantly associated with falls. In multiple regression analyses, physical inactivity remained the only variable independently associated with falls in all models except for visual field. Overall, visually impaired people were three times more likely to fall if they were physically inactive.

The investigators conclude that visual function, duration and main causes of visual impairment are not independently associated with falls in people with low vision. However, a significant relationship between non-participation in physical activity and falls was found.

WHAT IT MEANS TO YOU: This study found that the risk of a visually impaired person falling was associated with how physically active the person was, not the degree of vision loss. It is well established that vision loss increases the risk of falling, but among the vision impaired, degree of loss may not further increase risk. Indeed, recent research has found that the act of getting new eyeglasses increases the fall rate in older people; so although vision is presumably better with new eyeglasses, changes in visual magnification or other factors increases the risk of falling while wearing new eyeglasses. Less physically active seniors may have other medical problems that contribute to risk of falling, such as arthritis, obesity, and cognitive decline. This research suggests that visually impaired seniors have a lower risk of falling if they remain physically active.

Print version

Anticoagulants and antiplatelet agents are strongly associated with the development of large subretinal hemorrhages in AMD patients, according to a new study.

Patients with submacular hemorrhage complicating AMD typically have a poor visual prognosis. The question whether antithrombotic therapy (including aspirin and Coumadin) increase the risk of subretinal hemorrhages in patients with AMD remains controversial.

This study retrospectively reviewed the medical and photographic records of 71 consecutive patients with acute subretinal hemorrhages complicating AMD. The size of the subretinal hemorrhage was measured. Data on the use of medications and medical indications for anticoagulation and antiplatelet therapy were obtained.

Overall, patients receiving antithrombotic therapy had a significantly larger subretinal hemorrhage size than patients not receiving anticoagulant or antiplatelet therapy. Moreover, subgroup analysis among patients with arterial hypertension revealed that individuals receiving antithrombotic therapy had a statistically significantly larger hemorrhage size than hypertensive patients who did not receive anticoagulants or antiplatelet agents.

The investigators conclude that patients receiving long-term antithrombotic therapy had statistically significantly larger subretinal hemorrhages than patients without such medications.

A striking feature of the present study was an increased risk of large subretinal hemorrhages among patients with arterial hypertension receiving antithrombotic agents. Interestingly, arterial hypertension without antithrombotic therapy was not associated with an increased risk of subretinal bleeding complications.

WHAT IT MEANS TO YOU: There is no evidence that patients taking blood thinners suffer subretinal hemorrhage more frequently than patients that do not take these medications. However, if a hemorrhage does occur, then it will be larger in patients taking blood thinners. This study also found that high blood pressure is an important risk factor for subretinal hemorrhage in patients taking blood thinning medication. Because it is vitally important that patients taking blood thinners continue on their medication, they may be able to decrease their risk of developing subretinal hemorrhage by better controlling their blood pressure.

Print version

Alcohol consumption was significantly associated with increased risk of incident early AMD in older women after adjusting for confounding factors, a study found.

In addition, the study found that female subjects aged 80 years or older who smoked had a higher risk of early AMD than subjects who were younger than 80 years and did not smoke.

"The magnitude of the greater-than-additive effect of smoking on the age-adjusted risk of AMD reinforces recommendations to quit smoking even for older individuals," the study authors said.

The prospective cohort study looked at 1,958 women in the Study of Osteoporotic Fractures who had 10 years and 15 years of follow-up. Of those patients, 245 were black and 1,713 were white. The mean age was 78.2 years at the 10-year follow-up visit.

Subjects had fundus photographs taken at each follow-up visit. Photographs were graded for AMD, and logistic regression measured risk factors associated with incident AMD.

The study found that overall 5-year incidence was 24.1% for early AMD and 5.7% for late AMD.

WHAT IT MEANS TO YOU: Smoking is strongly associated with AMD, but alcohol has only inconsistently been associated with the condition. Alcohol consumption hypothetically may have both harmful and protective effects on AMD. Alcohol is a known neurotoxin that can result in oxidative brain damage and thus in heavy amounts may be expected to have an adverse effect on the retina, and has been reported to increase the risk of AMD. However, moderate consumption is associated with decreased platelet aggregation, lower serum fibrinogen levels, lower C-reactive protein concentrations, and higher high-density lipoprotein levels, all of which may be protective for AMD.

Print version

A prospective, multicenter, nonrandomized clinical trial finds that low-fluence photodynamic therapy (PDT) is as effective as standard-fluence PDT in treating patients with chronic central serous chorioretinopathy (CSC) and carries a lower risk of inducing choroidal hypoperfusion.

Active CSC is characterized by detachment of the neurosensory retina caused by accumulation of serous fluid between the photoreceptor outer segments and the retinal pigment epithelium (RPE). The disease often resolves spontaneously, but occasionally the neurosensory detachment persists and leads to damage to the RPE and photoreceptors, with visual impairment.

PDT with verteporfin has been shown to be effective in chronic CSC by improving visual acuity and reducing subretinal fluid. However, complications such as persistent choriocapillaris hypoperfusion have been reported. It has been suggested that modified PDT protocols may improve the safety of PDT.

Forty-two eyes (42 patients) with chronic CSC were enrolled; 19 eyes received standard-fluence PDT (50 J/cm(2)) and 23 eyes received low-fluence PDT (25 J/cm(2)).

Mean best-corrected visual acuity improved significantly at all time points (P < .01), in the standard-fluence group from 0.43 to 0.24 logMAR at 12 months and in the low-fluence-group from 0.46 to 0.16 logMAR, without significant difference between the 2 groups. At 12 months, a complete subretinal fluid reabsorption was seen in 15 standard-fluence-treated and 21 low-fluence-treated eyes (79% vs 91%; P = .5). A moderate-significant choriocapillaris nonperfusion was seen in 8 standard-fluence-treated and 0 low-fluence-treated eyes (44% vs 0%; P = .002).

In conclusion, standard-fluence and low-fluence PDT both reduce subretinal fluid and improve visual acuity in chronic CSC. Low-fluence PDT induces less choriocapillaris damage. The results of this study show that modulation of PDT parameters may result in an improved clinical effect.

WHAT IT MEANS TO YOU: Most patients with CSC recover spontaneously without need for treatment, but patients with chronic CSC have faced a dilemma: treatment could speed recovery, but carried a risk of causing permanent vision impairment. Now it appears that safety-enhanced PDT may offer a low-risk alternative that is nearly as effective as standard PDT.

Print version

Radiation therapy, when used to treat patients requiring chronic anti-VEGF therapy, may reduce the burden of treatment for neovascular AMD.

According to results from a study presented by Dr Pravin Dugel at the joint meeting of the American Academy of Ophthalmology and Pan-American Association of Ophthalmology, a single procedure of epimacular brachytherapy (radiation therapy) can further improve visual acuity in a majority of this patient population while decreasing the number of injections required.

"The problem is not really giving an injection twice or thrice. The problem is giving this injection 15 times or 20 times," Dr. Dugel said. "Most of the injections I do, most of the injections that most of my colleagues do, are not in treatment-naive patients. They are in patients who have significant disease with persistent fluid. And that's where the treatment burden is."

The interim study results were from the MERITAGE I trial, which enrolled 50 patients. The study enrolled patients who had as many as 23 injections of anti-VEGF therapy before receiving radiation therapy.

During the study period, 88% of patients maintained visual acuity. However, in an unexpected finding, 63% of patients gained visual acuity, with 50% gaining five or more letters (one line).

The application of epimacular brachytherapy may be beneficial because it disrupts secondary and tertiary chemical pathways that lead to angiogenesis, including those inducing fibrosis.

The results reported at the AAO/PAAO meeting from the MERITAGE I trial are a 6-month interim analysis of an ongoing 1-year trial, and while encouraging, "it's way too early to make any conclusions," Dr. Dugel said.

WHAT IT MEANS TO YOU: Radiation therapy has an established record of positive results for patients with CNV. The primary reason it is not more widely used is the difficulty associated with delivering the radiation to the macula. Epimacular brachytherapy, as used in the MERITAGE study, requires a vitrectomy and surgically positioning the radiation source directly over the macula. Invasive surgery makes this an unattractive option for many patients. Now a new delivery vehicle is being studied. The IRay system (Oraya Therapeutics) delivers radiation beams passed through the eye held stationary with a suction contact lens and followed with eye-tracking software. This non-invasive system is currently being studied in Phase 2 clinical trials.

Print version

A flexible, individualized visual acuity-guided regimen after the three initial injections may sustain vision improvement with Lucentis and could improve cost-effectiveness and convenience and reduce drug administration-associated risks, according to a new study published in Investigative Ophthalmology and Vision Science. Using available clinical trial data, the researchers constructed a drug and disease model of neovascular AMD treated with intravitreal Lucentis. A flexible VA-guided regimen (after the three initial injections) in which treatment is initiated by loss of >5 letters from best previously observed VA scores was simulated. The model predicted that, on average, to maintain initial VA gains, an estimated 5.1 Lucentis injections are needed during the 9 months after the three initial monthly injections, which amounts to a total of 8.1 injections during the first year. In conclusion, VA outcomes data from Lucentis phase 3 clinical trials support an individualized Lucentis treatment regimen of three initial once-monthly injections of Lucentis followed by monthly monitoring of VA, and retreatment if a VA loss of more than 5 letters occurs.

Print version

RXi Pharmaceuticals Corporation, a biopharmaceutical company pursuing the development and commercialization of proprietary therapeutics based on RNA interference (RNAi), has announced a collaboration with that will be focus on the application of RXi's self-delivering RNAi (sd-rxRNA) compounds for ocular diseases such as AMD. RNA interference (RNAi) is a naturally occurring mechanism whereby short, double-stranded RNA molecules interfere with the expression of genes in living cells. This mechanism has the potential to be harnessed to "silence" or specifically block the production of disease-causing proteins before they are made. sd-rxRNA is a proprietary technology developed at RXi which has the potential to enable the efficient delivery of RNAi compounds without the requirement of an additional delivery vehicle, such as a virus.

Print version

Acucela announced the launch of its ENVISION Clarity Trial, a Phase 2 clinical trial of ACU-4429, an investigational oral treatment for dry AMD. ACU-4429 utilizes visual cycle modulation (VCM) technology. Preclinical data indicate that ACU-4429 slows the rod visual cycle, resulting in decreased accumulation of a toxic by-product that is the precursor of lipofuscin. The chronic accumulation of lipofuscin has been implicated in degenerative retinal diseases. ACU-4429 is administered to patients as an oral, daily pill rather than by injection into the eye. The ENVISION Clarity Trial is a randomized, double-masked, placebo-controlled study of three planned escalating dose levels of ACU-4429 and up to two additional dose levels in subjects with dry AMD. Patients will receive either ACU-4429 or placebo orally once daily for three months. The trial will be conducted at multiple sites throughout the U.S. It is anticipated that a minimum of 56 patients with dry AMD will be enrolled.

Print version

The first major clinical trial to compare Avastin and Lucentis in a head-to-head fashion has completed enrollment, and the first data analysis is expected in about 1 year. Although the head-to-head comparison of Avastin and Lucentis in CATT (Comparisons of age-related macular degeneration treatments trials) has generated the most interest, other findings from the trial may ultimately prove more useful, Dr Daniel Martin said at the Retina 2010 meeting. "The actual Lucentis vs. Avastin comparison is the one that has garnered the most attention in the press, and yet the aspect of CATT that I find most interesting is the comparison of fixed vs. variable dosing, and the hope that we can identify subgroups within the variable dosing that can predict how to better treat these patients," Dr. Martin said. The first results from CATT are expected in January 2011, Dr. Martin said. Four additional multicenter clinical trials are ongoing around the world evaluating Avastin and Lucentis in a head-to-head comparison.

Print version

A series of computer-generated photographs simulating vision loss secondary to macular disease was recently published in the journal Archives of Ophthalmology. The photographs attempt to portray the normal drop-off of visual acuity away from the macula and the impact of various types of macular disease upon central vision. Copies of several of these photographs are available at myvisiontest.com. Click on "Simulating vision with macular disease" under Recommended.

Print version

Avastin decreases survival of cultured retinal pigment epithelial (RPE) cells stressed by hydrogen peroxide, according to a study published in Investigative Ophthalmology and Vision Science. This study found high doses of Avastin significantly induced RPE cell death under conditions of high oxidative stress, which may be attributable to Avastin blocking the VEGF survival signal. However, the dose of Avastin used in this study was greater than is used clinically, and RPE cell death was induced only at higher levels of oxidative stress. This study provides evidence that VEGF assists in RPE cell survival. The results imply that neutralization of VEGF with an agent such as Avastin influences RPE cell survival. The high level of VEGF secreted from RPE cells under oxidative stress conditions may participate in the pathogenesis of exudative AMD (by stimulating CNV); however, VEGF may also have a beneficial effect in assisting RPE resistance against oxidative stress. Thus, the extent or specificity of VEGF blockade, and the level of oxidative stress, may affect treatment outcomes when anti-VEGF treatment is used in patients with neovascular AMD.

Print version

A novel platelet-derived growth factor (PDGF) currently being studied in clinical trials may boost the effect of anti-VEGF therapy and provide a benefit in patients with wet AMD, according to a speaker at the at Retina 2010 meeting. In the study, combination therapy with E10030 (Ophthotech), a PDGF-B inhibitor, and three doses of Lucentis produced a mean change in visual acuity of 12.3 letters at 4 weeks in 22 patients, which increased to a mean change of 16.5 letters in 20 patients by 12 weeks of follow-up. Overall, 32% of patients gained three lines of visual acuity at 4 weeks and 60% at 12 weeks. PDGF was targeted, Dr. Kaiser said, because it recruits pericytes to newly formed lesions. Theoretically, the novel agent stops pericyte recruitment and may also be effective in eliminating pericytes in recently formed lesions.

Print version

Notal Vision has received FDA approval for the firm's ForeseeHome AMD analysis device. The ForeseeHome AMD Monitor is the first device of its kind in the eye care industry that allows patients with the dry form of AMD to monitor themselves for signs of an oncoming choroidal neovascularization in the convenience and comfort of their own home with data transmitted to the patient's eye care physician and the Notal Vision Data Monitoring Center. Notal Vision plans to introduce the ForeseeHome AMD Monitor to the market in the first quarter of 2010.

Print version