JOURNAL CLUB

RECENT NOTEWORTHY STUDIES TO STIMULATE DISCUSSION AND DEBATE

■ Biweekly anti-VEGF dosing. Many questions about the optimal dosing regimens for various anti-VEGF drugs remain unanswered. To increase our knowledge about these regimes, retinal physicians from Florida, in collaboration with ophthalmologists in China, undertook a study of dosing regimens for Avastin, Lucentis and Eylea. They report their findings in the March 2012 issue of Retina.

The authors used a mathematical model to compare the pharmacokinetic properties of the three drugs and determine the theoretical peak and trough binding activities of the drugs when injected either every 14 days or every 28 days for Avastin and Lucentis and every 28 days for Eylea.

Using the known pharmacokinetic intravitreal half-lives and relative molar binding activities of the drugs, expected peak and trough binding activity measurements were calculated from the three drugs. Finally, biweekly dosing was performed on those patients who responded poorly to monthly dosing.

The data revealed that biweekly dosing of all three drugs resulted in significantly greater trough binding activity but had only a slight impact on peak binding activity at day 28. Furthermore, biweekly dosing of Avastin resulted in superior binding levels to monthly dosed Lucentis, and Eylea dosed monthly outperformed biweekly Lucentis for both peak and trough binding activity. Avastin also outperformed high-dose (2.0 mg) Lucentis dosed monthly.

The authors also included two case studies with the Retina article of patients with refractory subretinal fluid that resolved with biweekly dosing of anti-VEGF agents. These cases, as well as the data from the study at large, provide evidence that biweekly dosing of anti-VEGF drugs can be beneficial in patients who do not respond to monthly dosing. Eylea should eventually eliminate the need for bi-weekly dosing of either Avastin or Lucentis, they note.

■ NSAID combo therapy for AMD. The quest continues for a combination therapy employing an anti-VEGF drug and some agent that can boost the efficacy of intravitreal anti-VEGF injections, particularly for those patients with suboptimal responses to anti-VEGF agents. A study in the March 2012 issue of Retina examined Lucentis in combination with Xibrom, a topical nonsteroidal, in patients with wet AMD.

Doctors at the Casey Eye Institute in Portland, OR, prospectively enrolled 30 eyes into a single-site, multi-investigator, open-label phase 2 study, with 20 eyes randomized to combination therapy and the remaining 10 patients receiving Lucentis alone. Lucentis was administered monthly for four months and then on an as-needed basis. Xibrom was administered in the combo therapy group as one drop twice per day for the 12-month follow-up period.

The study authors found no statistically significant differences in visual acuity between the two groups or in the number of injections required. The mean 12-month change in central retinal thickness was -81.56 µm in the combo therapy group vs -42.50 µm in the Lucentis group. There was also a greater proportion of patients experiencing a decrease in CRT of 50 µm or more in the combo therapy group.

Although further studies that are blinded are necessary to confirm their findings, the study authors state that theirs is the first to identify a biologic signal (CRT) to indicate a well-tolerated eye drop as a combination therapy for Lucentis.

■ Sustained IOP elevation with Avastin. IOP always rises temporarily after intravitreal injections, but what about sustained elevations? Ophthalmologists in Israel investigated this question, and their results were published online recently by Graefe's Archive for Clinical and Experimental Ophthalmology.

The study authors undertook a retrospective cohort study of 201 eyes in 174 consecutive patients with neovascular AMD (Figure 1). Studying the records from these patients, the authors collected demographic data, as well as IOP levels, length of follow-up, total number of injections and other variables. They defined sustained IOP elevation as elevation to ≥22 mm Hg and a change from baseline IOP of ≥6 mm Hg for at least 30 days.

Figure 1. In AMD, as here, Avastin injections caused sustained IOP elevation in 11% of patients.

Twenty-two of 201 (11%) eyes demonstrated sustained IOP elevation. In all of these cases, increased IOP was controlled with topical medication. Male gender and an interval between injections of less than eight weeks were noted as risk factors for sustained IOP elevation, although sustained IOP elevation was significantly more prevalent when the interval was less than eight weeks, regardless of the gender of the patient. The authors conclude that patients being treated with Avastin for AMD should be monitored closely for sustained IOP elevation, particularly if their dosing interval is ≤8 weeks.

■ Antiviral implant for CMV retinitis. Increased longevity among patients with AIDS has resulted in a greater number of these patients being treated for cytomegalovirus (CMV) retinitis (Figure 2) over the long term. Retinal physicians at the Johns Hopkins University in Baltimore undertook a study of the outcomes with an intraocular implant of the antiviral drug ganciclovir. They report their findings in the April 2012 issue of the American Journal of Ophthalmology.

Figure 2. The Vitrasert ganciclovir insert showed efficacy against cytomegalovirus retinitis, seen in this fundus photo.

In this retrospective cohort study, the authors studied the charts of 166 eyes from 115 patients treated with the Vitrasert ganciclovir insert (Bausch + Lomb) between April 1996 and November 2009. The authors analyzed data on visual acuity, side effects and immune recovery. They also noted whether the patients had been previously administered highly active antiretroviral therapy (HAART).

Fifty-five percent of the patients were on HAART at implantation with Vitrasert vs 21% formerly prescribed HAART and 24% who were HAART-naïve. A total of 257 inserts were implanted in the 166 eyes that were studied, and there were 126 adverse events in 57 eyes, with the most common complications including cataracts, vitreous hemorrhage, retinal detachment. Patients who experienced immune recovery during treatment with Vitrasert were less likely to experience complications.

Despite a relatively high rate of complications in the studied patients, severe vision loss (≥6 lines lost) was rare, occurring at a rate of only 0.005 per eye per year of treatment. As a result, the authors suggest that close monitoring for adverse events is crucial and that treatment with Vitrasert is most likely to have a positive outcome if administered along with HAART.

■ Retina and heart health. The March 2012 issue of the British Journal of Ophthalmology features the results of a cohort study of participants in the Cardiovascular Health Study (CHS), which ran for most of the last decade, which indicate having two or more retinal microvascular signs was correlated with higher rates of disability than having one or zero signs.

A total of 1,487 participants in the CHS who were free of disabilities in activities of daily living (ADLs) and who had available data for both retinal microvascular signs and intima-media thickness at doctors' visits in 1998 and 1999 were included in a prospective cohort study. The principal outcomes measured were disabilities in ADLs, the presence of retinal signs, and several outcomes based on cerebral microvascular disease, including slow gait and depression.

Over an average follow-up of 3.1 years, participants with two or more retinal microvascular signs had a higher rate of disability than those with one or zero signs. However, there was no association between retinal microvascular signs and advanced atherosclerosis. As a result, the authors conclude that their study has provided greater evidence of a correlation between retinal micro vascular signs and age-related disabilities, but the proper role of retinal imaging in clinical risk prediction remains unclear.

■ Intravitreal chemo for retinoblastoma. An editorial in the April 2012 issue of the British Journal of Ophthalmology, a collaborative effort between ocular oncologists at the Cole Eye Institute in Cleveland and St. Erik's Eye Hospital in Stockholm, addresses delivery of chemotherapy for retinoblastoma directly into the vitreous cavity. The editorial addresses concerns about extraocular spread of tumor cells caused by fine-needle aspiration biopsy and repeat intravitreal injections of chemo drugs. This issue also includes data from two case series of children with advanced intraocular retinoblastoma managed with intravitreal chemo. It is must reading for all ocular oncologists. RP