Highlights of the Canadian Ophthalmological Society 2006 Annual Meeting and Exposition

2006年6月21－24日

加拿大安大略省多伦多

June 21-24, 2006; Toronto, Ontario, Canada

David M. Brown, MD 
Medscape Ophthalmology.  2006;7(2) ©2006 Medscape

　
Introduction
On June 23, 2006, the Canadian Retina and Vitreous Society hosted the retina subspecialty day in Toronto, Ontario, Canada, at the 69th Annual Meeting of the Canadian Ophthalmological Society (COS). The morning and afternoon free paper sessions featured invited guest lectures on the value of retinal treatment from Gary Brown, MD, and Melissa Brown, MD, of the Wills Eye Hospital, Philadelphia, Pennsylvania, and the Center for Value-Based Medicine in Flourtown, Pennsylvania. Additional papers throughout the day concentrated on basic science and clinical issues in the treatment of neovascular age-related macular degeneration (AMD) and other retinal diseases.

Angiogenesis
The retina basic science free paper session focused on angiogenesis. The highlight was a presentation by Alexander Tan of Dalhousie University, Halifax, Nova Scotia, Canada, entitled "Analysis of Vitreous and Serum Leptin Levels in Diabetic Retinopathy.[1]" Leptin, a 167 amino acid protein that is known to be associated with obesity, has been shown to have angiogenic properties. Using a radioimmunoassay technique, Tan and colleagues[1] demonstrated that leptin concentrations were 10-fold higher in vitrectomy specimens of patients with diabetic retinopathy (2.2 ng/mL average in 30 patients) than in those without diabetes (0.2 ng/mL average in 25 control patients). Tan's paper was awarded second prize by the COS/Coherent-AMT award for excellence in ophthalmic research.

Additional papers by Mathalone and colleagues[2] and Zhang and colleagues[3] documented the potential role of erythropoietin (EPO) in retinal angiogenesis. Mathalone demonstrated increased EPO levels in proliferative diabetic retinopathy vitreous samples and EPO receptors in rat models of type 1 and type 2 diabetes, whereas Zhang's work showed upregulation and early appearance of EPO receptors by hypoxia. This research suggested a potential new angiogenic target for retinal therapy.

Controversies in Retinal Practice
The Retina Controversies Section moderated by Peter Kertes, MD, was a spirited forum pitting 2 retina surgeons with back-to-back opposing talks involving important controversies that practicing retina specialists face. The most spirited controversy revolved around the use of monotherapy vs combination therapy for AMD.[4,5]

The monotherapy data focused on the unprecedented visual acuity efficacy results from the 2-year MARINA trial results[6] and the 1-year ANCHOR results.[7] These trials demonstrated maintenance of visual acuity in nearly 95% of patients as well as visual acuity improvements in approximately one third of patients with AMD with monotherapy treatment with the antivascular endothelial growth factor (VEGF) agent ranibizumab. However, the protocol for these trials was monthly intravitreal injections for 24 months. Ideally, combination therapy could devise a treatment regimen that could duplicate the visual acuity gains seen in the ranibizumab trials while reducing the total number of intravitreal injections that are necessary to accomplish these gains. Dr. Sheidow argued that an ideal treatment for choroidal neovascularization (CNV) in AMD would address oxidative stress reduction, block the neovascular stimulus, inhibit the growth of abnormal blood vessels, cause maturation of the abnormal vessels in the CNV membrane, eliminate edema, and repair or reduce retinal scarring.[8] Effective monotherapy anti-VEGF agents are thought to block the neovascular stimulus, inhibit the growth of abnormal blood vessels, and eliminate edema. It is primarily the antipermeability effects of ranibizumab in eliminating retinal and subretinal edema that led to the improvements in visual acuity seen in the ANCHOR and MARINA trials. Combinations of other agents with such an anti-VEGF agent may reduce the number of treatments by addressing the components that are not affected by the anti-VEGF agent alone.

Quality-of-Life Issues
The Medical Retina section was highlighted by Dr. Gary Brown's[9] invited lecture on the value of retinal therapies that highlighted quality-of-life (QOL) issues and the importance of treatment for both economic and QOL reasons. Dr. Melissa Brown[10] had previously discussed the framework of value-based medicine, and Dr. Gary Brown specifically related these techniques to retinal surgery and the treatment of wet AMD. He noted that severe AMD cuts employment rates by 61% and thereby salary by 76% (by cutting employment rates and working wages). This accounts for $31 billion lost in the US economy alone, with $24 billion attributable to dry AMD and $5 billion to wet AMD. Dr. Brown discussed a QOL utility analysis that showed that with time-trade-off utilities (determined by questionnaires asking patients how much life they would give up to not have a particular medical condition), mild macular degeneration was equivalent to a leg amputation or chronic mild angina. Once vision was reduced to the 20/50 to 20/100 level, QOL measures placed the disability equivalent to chronic renal dialysis. Severe visual acuity loss from AMD (< 20/800) was equivalent to a Rankin class V cerebrovascular accident with hemiparesis and end-stage metastatic prostate cancer with severe pain. Of note, these surveys showed that most ophthalmologists greatly undervalued the QOL significance of visual declines from AMD.

Dr. Brown also reviewed cost analysis per quality of adjusted life years (QALY). His analysis demonstrated that ophthalmologic treatments have superior QALY improvements compared with many systemic interventions. It is generally accepted that procedures that cost $100,000 per QALY are reasonable. Statin therapy cost per QALY gained is approximately $40,000-$60,000, whereas treatments for osteoporosis are currently $100,000-$300,000/QALY. By comparison, photodynamic therapy (PDT) for classic CNV is $31,000 per QALY and pegaptanib is $66,865/QALY. The visual improvements seen in the ranibizumab trials will be used in these types of analysis once the average number of treatments necessary to achieve these good results becomes more apparent.

AMD Treatment
The PIER study 1-year efficacy and safety results were also presented at COS.[11] The PIER study was a phase 2, randomized, double-blind study comparing sham therapy with a rationed injection protocol with ranibizumab. Patients in the treatment arms received 3 monthly injections of ranibizumab followed by mandatory quarterly dosing with intravitreal ranibizumab. The safety data were similar to the MARINA and ANCHOR trials, as was the initial efficacy, whereas the intravitreal injections were administered monthly. Patients had improved vision analogous to the MARINA study by month 3, but then returned (on average) to baseline visual acuities during the period of quarterly injections. Despite this decline, however, treatment with this regimen still demonstrated a highly statistically significant improvement over the standard-of-care arm. The obvious comparisons between these results and the ANCHOR and MARINA results (with monthly injections) imply that many patients may require more than 6 injections per year to achieve the improvements in visual acuity seen in the ANCHOR and MARINA trials. It was hoped by many that the PIER trial would demonstrate that ranibizumab could be used much less frequently than in the ANCHOR and MARINA trials.

Additional papers of interest included the first-prize winner COS/Coherent-AMT award for excellence in ophthalmologic research presented by Rajeev Muni.[12] In his talk focusing on the use of PDT in Canada, Dr. Muni showed that there was minimal agreement in the determination of classic, minimally classic, and occult lesions when a cohort of 60 Canadian retinal specialists graded similar angiograms. Fortunately, these differentiations will be less important with the transition of AMD therapy from PDT, which is much more effective with classic lesions, to the anti-VEGF therapies, which seem to have equal efficacy with all lesion types.

Behn and colleagues[13] also presented preliminary results testing blueberries (in a dehydrated placebo-controlled trial) and blueberry juice in visual acuity function in AMD patients and non-AMD patients. This study aimed to validate the use of bilberries (European blueberries) by many North American AMD patients. Behn's initial results implied that blueberry juice improves dark adaptation, but these results were not seen with the dried preparation used in the placebo-controlled trial.

References
Tan A, O'Brien D, Dickinson J, Imran A, Wilkinson M, Samad A. Analysis of vitreous and serum leptin levels in diabetic retinopathy. Program and abstracts of the Canadian Ophthalmological Society 2006 Annual Meeting and Exposition; June 21-24, 2006; Toronto, Ontario, Canada.
Mathalone N, Altomare F, Sit S, et al. Erythropoietin (Epo) and its receptors in a rat model of type I and II diabetic retinopathy. Program and abstracts of the Canadian Ophthalmological Society 2006 Annual Meeting and Exposition; June 21-24, 2006; Toronto, Ontario, Canada.
Zhang L, Zhao X, Boyd S. Erythropoietin (Epo) receptors are upregulated by hypoxia in retinal stem cells. Program and abstracts of the Canadian Ophthalmological Society 2006 Annual Meeting and Exposition; June 21-24, 2006; Toronto, Ontario, Canada.
Brown D. The future of macular degeneration therapy: monotherapy. Program and abstracts of the Canadian Ophthalmological Society 2006 Annual Meeting and Exposition; June 21-24, 2006; Toronto, Ontario, Canada.
Sheidow T. The future of macular degeneration therapy: combination therapy. Program and abstracts of the Canadian Ophthalmological Society 2006 Annual Meeting and Exposition; June 21-24, 2006; Toronto, Ontario, Canada.
Heier JS, Shapiro H, Singh AA Sr; MARINA Study Group. Randomized, controlled phase III study of ranibizumab (Lucentis) for minimally classic or occult neovascular age-related macular degeneration: two-year efficacy results of the MARINA study. Program and abstracts of the Association for Research in Vision and Ophthalmology; April 30-May 4, 2006; Fort Lauderdale, Florida. Abstract 2959.
Kaiser P. Anchor data. Program and abstracts of Macula 2006; January 13-14, 2006; New York, NY.
Konerding MA. Ocular angiogenesis: translating preclinical indications to successful clinical development. Expert Opin Ther Targets. 2004;8:255-258.
Brown G. Value based medicine and macular degeneration therapies. Program and abstracts of the Canadian Ophthalmological Society 2006 Annual Meeting and Exposition; June 21-24, 2006; Toronto, Ontario, Canada.
Brown M. Value-based medicine, basic principles. Program and abstracts of the Canadian Ophthalmological Society 2006 Annual Meeting and Exposition; June 21-24, 2006; Toronto, Ontario, Canada.
Brown DM, Ianchelev T, Yue H, Shams N. Phase IIIb, multicenter, randomized, double-masked, sham injection-controlled study of the efficacy and safety of ranibizumab in patients with choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD): first-year results of the PIER study. Program and abstracts of the Canadian Ophthalmological Society 2006 Annual Meeting and Exposition; June 21-24, 2006; Toronto, Ontario, Canada.
Muni R, Altaweel M, Tennant MTS, Weaver B, Kertes PJ. Agreement among Canadian Retina Specialists in the determination of treatment eligibility for photodynamic therapy in age-related macular degeneration. Program and abstracts of the Canadian Ophthalmological Society 2006 Annual Meeting and Exposition; June 21-24, 2006; Toronto, Ontario, Canada.
Behn D, Tremblay F, McDonald J, et al. Can a diet rich in blueberries improve vision? Program and abstracts of the Canadian Ophthalmological Society 2006 Annual Meeting and Exposition; June 21-24, 2006; Toronto, Ontario, Canada.