Journal Club

Recent Noteworthy studies to stimulate Discussion and Debate

■ Antibiotics in retinal disorders. The data are small at present, but two articles in the September 2010 issue of Ophthalmology indicate that antibiotics may play a role in combination or adjunct therapies for AMD and toxoplasmic retinochoroiditis.

The first study, a trial conducted in Venezuela, tested a combination of 1.5 mg/0.1 mL clindamycin and 400 µg/0.1 mL dexamethasone in patients with zone 1 toxoplasmic retinochoroiditis. All 12 patients given this combination therapy had resolution of their cases, with an average of 3.6 injections given over 15.5 days. There were no recurrences or serious adverse events, and two years out, 10 of the 12 patients had at least a two-letter improvement in best-corrected visual acuity. The finding could be important to patients who are HIV-positive or who have AIDS, as well as other immunocompromised patients, who tend to be more susceptible to and to develop the most problematic cases of toxoplasmosis.

The second article, a murine study conducted at the National Eye Institute, examined the in vivo effects of doxycycline on laser-induced choroidal neovascularization and directed in vivo angiogenesis assay (DIVAA) induced with human pterygium cells. Both conditions responded with statistical significance to doxycycline, which was added to drinking water, and while the study authors concede human studies are necessary, doxycycline may prove in the long term to be a successful adjunctive treatment for CNV and pterygia in humans.

■ Treat, yes; extend, no. Genentech's ranibizumab was approved by the FDA for treating exudative AMD four years ago, but one lingering question is whether a dosing schedule different from on-label monthly injections can be effective. Such a PRN protocol has become the standard in Germany, where decreases in visual acuity drive retreatment. A German study published online in October by Graefe's Archive for Clinical and Experimental Ophthalmology sought to compare this more flexible dosing schedule to the monthly protocol.

The study authors gave three monthly dosages of ranibizumab to 145 subjects (152 eyes); retreatment was given then only if visual acuity decreased by five ETDRS letters or central retinal thickness (CRT) increased by >100 µm.

While an initial mean increase in VA of 0.14 logMAR was detected at three months, this increase had disappeared by the one-year mark, with final mean visual acuity at the same level as at baseline. The worst losses occurred in patients with the worst VA at baseline. Given these results, the authors recommend that retreatment criteria be revisited, particularly in patients with poor baseline visual acuity.

■ Meanwhile, down under… Since bevacizumab continues to be used by retinal physicians to treat AMD as a more cost-effective alternative to ranibizumab, a study group in Adelaide, Australia, tested whether an as-needed dosing could be effective with that drug. They published their results in the October 2010 issue of Clinical and Experimental Ophthalmology.

The authors undertook a retrospective study of 231 eyes in 210 patients with choroidal neovascularization due to age-related macular degeneration. All patients received a 1.25-mg intravitreal injection of bevacizumab. After a first follow-up appointment at two to four weeks following treatment, patients were then seen monthly and reinjected based on preset criteria — a decrease in visual acuity or an increase in macular edema, subretinal fluid or intraretinal fluid on OCT.

One-month data were quite positive, with a logMAR improvement in mean visual acuity from 0.76 to 0.68 and a decrease in central retinal thickness from 306 µm to 244 µm.

The primary limitation of the study, however, was the poor adherence to follow-up by patients. Only 7.8% of the original cohort were able to provide data for the entire 12-month period. Thus, while the numbers are impressive, the study team concedes that further studies are necessary to come to the optimal dosing scheduling for bevacizumab.

■ Rethinking AMD protocols. An editorial in the September 2010 issue of Retina, signed by three ophthalmologists from Vitreous-Retina-Macula Consultants of New York, argues that the current classification scheme for AMD, which is based on fluorescein angiographic data and is now over 20 years old, needs to be updated. Newer imaging technologies — most importantly, spectral-domain OCT and indocyanine green angiography — and newer treatments, including but not limited to anti-VEGF, demand a change in the classification scheme.

The authors build on the types of choroidal neovascularization identified by Donald Gass, MD: type 1 refers to CNV below the retinal pigment epithelium; type 2 refers to CNV above the RPE; and type 3 refers to intraretinal neovascularization, or retinal angiomatous proliferation. They identify polypoidal choroidal vascularization as a variant of type 1 CNV, due in part to the location of the PCV lesions with regard to the RPE and Bruch's membrane.

The authors also discuss mixed lesions, which straddle different classification types. In addition, there is a brief discussion of genotyping and composition, as well as extensive illustration of different pathologies using SD-OCT, ICGA and fundus photography.

Running a whopping 17 pages, the editorial may prove useful to retinal physicians seeking greater understanding of AMD or those having difficulty classifying patients. At the very least, it will be sure to stimulate debate.

■ The surgical option. Macular translocation remains an option for AMD patients with hemorrhagic pigment epithelial detachments or rips in the RPE, since these patients' lesions can cause complications arising from anti-VEGF treatment or photodynamic therapy that are not seen with other patients.

A study from the United Kingdom on the technique and its effect on visual acuity appears in the October 2010 issue of the British Journal of Ophthalmology. The London-based team looked at data from 40 macular translocation patients operated on from 2003 to 2008. Baseline best corrected visual acuity was compared to measurements taken at one year, as well as at the most recent follow-up appointment.

The mean length of time to most recent follow-up was 37.5 months, with some patients having histories as long as over five years. Mean BCVA decreased from 0.80 logMAR at baseline, to 0.70 at one year and 0.78 at most recent follow-up, although these differences were not statistically significant. Nevertheless, 30% of patients had achieved three-line increases in visual acuity at the one-year mark and one-quarter maintained that gain to the most recent follow-up examination.

The study authors conclude that close postoperative monitoring to aid in the detection and treatment of delayed complications accounted for their high success rate. Thus they recommend close follow-up for the first two years following macular translocation surgery, which, they argue, remains a valid surgical option in these patients.

■ Safety revisited. Since interim data collected during the SAILOR phase 3 study of ranibizumab, which indicated an increased risk of stroke in patients receiving 0.5 mg doses (vs 0.3 mg) of ranibizumab, there has been concern that anti-VEGF treatments elevate cardiovascular risk, even though the final SAILOR data did not indicate a greater risk of arteriothrombic events. To address this issue, a study group from Duke University published the results of a two-year study in the October 2010 issue of Archives of Ophthalmology.

In a retrospective cohort study of nearly 150,000 Medicare recipients who filed claims for AMD between January 2005 and December 2006, patients were first divided on what treatment they received. Patients who were treated using verteporfin/photodynamic therapy acted as a control group, while the active study cohorts consisted on whether the patients received ranibizumab, bevacizumab or pegaptanib sodium. Data on mortality, myocardial infarction, bleeding and incident stroke were collected and analyzed statistically.

Statistically significant differences in the rates of myocardial infarction and death were detected, with ranibizumab recipients having a lower rate of mortality than either the control group or the pegaptanib group and also having a lower rate of myocardial infarction than the controls. No significant relationships were identified between bevacizumab and the other treatments and no treatment group had a statistically significant rate of bleeding events or stroke.

Of course, because the study was not prospective, the study authors concede that the data are not authoritative. Furthermore, the data on comorbid conditions were limited, so the ability of the study authors to take such conditions into account during their statistical analysis was somewhat compromised. However, the sheer size of the study does argue in favor of its credibility. The authors entertain the notion that ranibizumab may actually have a protective effect on the cardiovascular system, although they concede that there are currently no studies to support the validity of this idea.

■ Recurrent retinal detachment. A review on surgical techniques used to manage recurrent retinal detachments (RRDs) in silicone oil-filled eyes appears in the September 2010 issue of Techniques in Ophthalmology. The study was conducted at the Vision Research Foundation in Tamil Nadu, India.

The authors set out to do four things: review the causes of RRD, provide a paradigm for treatment choice, provide tips on surgery, and furnish some data on outcomes from their clinic.

After identifying three types of proliferative vitreo-retinopathy and intrinsic retinal contraction as the chief causes of RRD, they make the case for removing silicone oil as a first step in most surgical procedures to treat RRD. They do comment that they tend to retain silicone oil in the eye in cases of large and multiple retinal breaks with PVR, arguing that the oil can provide useful countertraction in some cases.

The authors posted success rates of 76.8% completely attached cases, with 66.3% achieving final visual acuity of 4/200 or better. They conclude that additional surgery should be reserved for posterior or progressive retinal detachments. RP