Ophthalmology Volume 121, Number 10, October 2014 into a single category. Overall, 64% of patients had the same lesion type in each eye (Cohen kappa ¼ 0.48), indicating fair to good concordance of lesion type between first and second affected eyes. This study evaluated characteristics and outcomes in a large cohort of patients in whom both eyes were diagnosed and treated for nAMD with intravitreal ranibizumab. The within-patient, paired data allow a close examination of characteristics at diagnosis and 12-month outcomes without extraneous variation as both eyes belonged to the same patient and were treated in the same practice. Second affected eyes had smaller lesions and better vision when they started treatment. They had slightly more injections than first affected eyes over the first 12 months of their treatment (mean of 7.3 vs 6.3) and had better VA after 12 months of treatment than first affected eyes, even though first affected eyes had a greater mean VA improvement. This provides strong evidence that earlier diagnosis and treatment of nAMD leads to better outcomes.4 The fact that the mean VA of the first affected eye group was 11 logMAR letters lower than the second affected group at the index visit was expected. A recent analysis of approximately 1200 eyes with nAMD from patients treated in the United Kingdom found a 10-letter difference at presentation between first and second affected eyes.5 A slow decline in VA in 1 eye may go unnoticed if the other eye still has good vision and that patients are likely to seek help more quickly when the better (second) eye is affected. It is also likely that second eye involvement would be detected earlier during the regular visits required for treatment of the first affected eye. This is reflected by the better vision and smaller lesion size of second affected eyes that we observed. The better VA at the index visit seems to be the main reason for better outcomes after 12 months of treatment because mean VA improvement of the first affected eye group was significantly greater than that of the second affected group. The relatively greater improvement in first eyes is most likely owing to ceiling effects in the second affected eye which had higher starting VA. We also observed concordance of choroidal neovascular lesion types developing in the first and second affected eyes. This may be attributed to various factors, most likely genetic, although some discordance observed suggests that environmental factors may also contribute to lesion type. Although not addressed in randomized, controlled trials, second eye involvement is common. Hence, patient education that second eye involvement may occur and regular checks of the second eye during busy clinics in which the first affected eye is being treated are strongly recommended to identify changes early and institute treatments promptly.
DANIEL BARTHELMES, MD, PHD1,2 RICHARD J. WALTON, MSC1 JENNIFER J. ARNOLD, MBBS3 IAN L. MCALLISTER, MBBS4 JUDY M. SIMPSON, BSC, PHD5 ANNA CAMPAIN, PHD1 ALEX P. HUNYOR, MBBS1,6 ROBYN GUYMER, MBBS, PHD7 ROHAN W. ESSEX, MBBS8 NIGEL MORLET, MBBS9 MARK C. GILLIES, MBBS, PHD1, FOR BLINDNESS! PROJECT INVESTIGATORS
2074
THE
FIGHT RETINAL
1 The Save Sight Institute, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia; 2Department of Ophthalmology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; 3Marsden Eye Specialists, Parramatta, Australia; 4 The Lions Eye Institute, Center for Ophthalmology and Vision Science, University of Western Australia, Perth, Western Australia, Australia; 5 Sydney School of Public Health, University of Sydney, Sydney, New South Wales, Australia; 6Retina Associates, Chatswood, New South Wales, Australia; 7Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Victoria, Australia; 8Department of Ophthalmology, Canberra Hospital, Garran, Australian Capital Territory, Australia; 9Department of Population Health, University of Western Australia, Perth, Western Australia, Australia
Financial Disclosure(s): Supported by a grant from the Royal Australian NZ College of Ophthalmologists Eye Foundation (2007e2009) and a grant from the National Health and Medical Research Council, Australia (NHRMC 2010-1012). The authors state they have no conflicts of interest to declare. Mark Gillies is a Sydney Medical Foundation Fellow and is supported by an NHMRC practitioner fellowship. Robyn Guymer is also supported by an NHMRC practitioner fellowship (#529905), Daniel Barthelmes was supported by the Walter and Gertrud Siegenthaler Foundation Zurich, Switzerland, and the Swiss National Foundation.
References 1. Davis MD, Gangnon RE, Lee LY, et al. The Age-Related Eye Disease Study severity scale for age-related macular degeneration: AREDS Report No. 17. Arch Ophthalmol 2005;123:1484–98. 2. Gillies MC, Walton R, Liong J, et al. Efficient capture of high-quality data on outcomes of treatment for macular diseases: The Fight Retinal Blindness! Project. Retina 2014;34: 188–95. 3. Five-year follow-up of fellow eyes of patients with age-related macular degeneration and unilateral extrafoveal choroidal neovascularization. Macular Photocoagulation Study Group. Arch Ophthalmol 1993;111:1189–99. 4. Lim JH, Wickremasinghe SS, Xie J, et al. Delay to treatment and visual outcomes in patients treated with anti-vascular endothelial growth factor for age-related macular degeneration. Am J Ophthalmol 2012;153:678–86. 5. Keenan TD, Kelly SP, Sallam A, et al. Incidence and baseline clinical characteristics of treated neovascular age-related macular degeneration in a well-defined region of the UK. Br J Ophthalmol 2013;97:1168–72.
Absence of Amiodarone-Associated Optic Neuropathy In 2008, the present author published an editorial in the American Heart Journal1 dealing with optic neuropathies (ON) associated with amiodarone use. Cited were data of amiodarone sales and US Food and Drug Administration (FDA) reports of amiodaroneassociated ON for 2001 through 2006 (6 years). The IMS National Prescription Audit captured approximately 70% of all US retail prescription sales and projected the number to 100%. The IMS Integrated Patient Claims Database provided an estimate of the number of patients treated. From 2001 to 2006, >16 million prescriptions were filled for generic amiodarone plus the 2 existing brands, Cordarone (Pfizer, New York, NY) and Pacerone (Upsher-Smith Laboratories, Maple Grove, MN). The number of patients treated during
Reports this period was >3.6 million. The FDA requires drug manufacturers to report all toxicities, including those in the literature. In addition, the FDA independently collects reports submitted to it; these are not limited to health care professionals; for example, patients and lawyers can submit reports. The total number of amiodarone-associated ON reported to the FDA from 2001 to 2006 was 38. Using these data, the calculated average annual incidence of amiodarone-associated ON was 0.0009%, or approximately 1 in 100 000 in amiodaronetreated patients. The lowest estimate in the literature for nonarteritic anterior ischemic ON (NAION) in those 50 is 2.3 in 100 000.2 This is greater than was calculated above for amiodarone-associated ON. Several explanations can be offered: One is that amiodarone’s abilities to stabilize the cardiac rhythm and increase the cardiac ejection fraction improve the circulation and help protect against ischemia. (This explanation would also challenge the concept, found in the case report literature, that delayed toxicity is the cause of ON that occurs after amiodarone is discontinued3). A second is that the literature estimates of NAION are falsely high. A third is that amiodarone-associated ON is underreported in both the literature and to the FDA owing to a lack of interest or awareness by health care providers. It is unquestioned that underreporting of side effects and toxicities occurs. Hopefully, large-scale underreporting of blindness would occur less often than with other, less devastating, adverse effects such as skin rashes. However, no matter what the degree of underreporting, what does seem apparent is that the incidence estimates of amiodarone-associated ON in the case report literature are unrealistically high. The lowest estimate is 0.36% (360/100 000) annually (1.79% incidence during a 5-year period).4 Based on this estimate, and using the IMS amiodarone retail sales data, there should have been 13 000 patients with ON during 2001 through 2006 (plus an additional number of those spontaneously developing NAION). There would have been >300 patients developing amiodaroneassociated ON for every 1 reported to the FDA. This report provides information for a 5-year period (2008e2012). The IMS National Prescription Audit projected there were >14.7 million amiodarone prescriptions filled. The FDA data were handled in a different manner than in the past report because that agency now pools all amiodarone adverse event reports. The Division of Anti-infective and Ophthalmologic Products was no longer able to provide only the ON data. The FDA received 4948 reports of amiodarone adverse events during 2008 through 2012. These were coded by the FDA using the MedDRA Medical Dictionary. All 4948 reports were reviewed by the present author, looking for newly reported cases coded: Optic Nerve Neuropathy, Blindness, Optic Nerve Disorder, Optic Nerve Neuritis, Optic Nerve Infarction, Optic Nerve Ischemic Neuropathy, Optic Nerve Unilateral Neuropathy, Optic Nerve Injury, Optic Nerve Disc Disorder, Amaurosis and Optic Nerve Unilateral Neuropathy. When a single report had more than one of these codes, only 1 diagnosis was used per patient. Multiple reports of the same patient were treated as one report. “Blindness Unilateral” was also included in the search, but 2 patients had a simultaneous diagnosis of “Retinal Vein Occlusion” and were excluded. The search yielded 53 new FDA reports of amiodarone-associated ON from 2008 through 2012. Of these, 19 were submitted by health professionals, 23 by nonprofessionals, and 11 by sources whose background could not be determined. The calculated annual incidence of amiodarone-associated ON, using the IMS and FDA
data, was 1.6 per 100 000 patients. Once again, this incidence is below that estimated for NAION in the general population. Perhaps a larger number of amiodarone-associated ON could be found by mining the legal records. Searches were performed on Lexis Nexis Court House Searches (LNCHS) and Courthouse News Service (CNS). The LNCHS covers 32 of the 50 states and 1081 state courts. The CNS covers all federal courts and 2200 state courts in all 50 states. The LNCHS searches were for complaints containing the primary words “amiodarone,” “Cordarone” or “Pacerone,” and one of the secondary words: “Vision,” “Blind,” or “Optic.” The CNS search engine limited screening to only the primary words, “amiodarone,” “Cordarone,” and “Pacerone.” From January 1, 2007, to March 26, 2014, the LNCHS search provided 29 new complaints, some of which were duplicates, for example, selected under “amiodarone” and “Cordarone.” The CNS search for January 1, 2007, to March 12, 2014, yielded 52 cases. Review of these combined 81 cases resulted in finding only 4 instances during 2008 through 2012 where amiodarone was claimed to have caused ON: Plaintiffs Randall (Jacksonville, FL, Duval County Circuit Court 11ca9705), Plaintiff Westerlund (Central New Jersey Middlesex County Superior Court MID-L-8311-10), Plaintiff Bryant (US Eastern District Court of Oklahoma 6:10-cv-410), and Plaintiffs Arters (Central Ohio Delaware County Court 10 cv b 01 57). It seems unlikely that a large reservoir of non-FDA reported cases of amiodarone-associated ON exists in the court system. Amiodarone remains an important medication, effective for controlling atrial fibrillation and ventricular arrhythmias. Implantable defibrillators are superior to amiodarone in preventing sudden death, but there is a subgroup that receives so many shocks that it requests, and receives, concomitant amiodarone.5 If not justified, fear of loss of vision should not curtail the use of amiodarone. Acknowledgments. The statements, findings, conclusions, views and opinions contained and expressed in this report are based in part on data obtained under license from the following IMS Health Incorporated information service(s): National Prescription Audit tm (2008-2012), IMS Incorporated. All Rights Reserved. The statements, findings, conclusions, views and opinions contained and expressed herein are not necessarily those of IMS Health Incorporated or any of its affiliated or subsidiary entities.
JOEL S. MINDEL, MD, PHD The Mount Sinai Hospital, New York, New York
References 1. Mindel JS. Amiodarone and optic neuropathy. Am Heart J 2008;156:411–3. 2. Johnson LN, Arnold AC. Incidence of nonarteritic and arteritic anterior ischemic optic neuropathy: population based study in the state of Missouri and Los Angeles County, California. J Neuroophthalmol 1994;14:38–44. 3. Johnson LN, Krohel GB, Thomas ER. The clinical spectrum of amiodarone-associated optic neuropathy. J Natl Med Assoc 2004;96:1477–91. 4. Feiner LA, Younge BR, Kazmier FJ, et al. Optic neuropathy and amiodarone therapy. Mayo Clin Proc 1987;62:702–17. 5. Vassallo P, Trohman RC. Prescribing amiodarone. An evidence-based review of clinical indications. JAMA 2007;298: 1312–22.
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DANIEL BARTHELMES, MD, PHD1,2 RICHARD J. WALTON, MSC1 JENNIFER J. ARNOLD, MBBS3 IAN L. MCALLISTER, MBBS4 JUDY M. SIMPSON, BSC, PHD5 ANNA CAMPAIN, PHD1 ALEX P. HUNYOR, MBBS1,6 ROBYN GUYMER, MBBS, PHD7 ROHAN W. ESSEX, MBBS8 NIGEL MORLET, MBBS9 MARK C. GILLIES, MBBS, PHD1, FOR BLINDNESS! PROJECT INVESTIGATORS
2074
THE
FIGHT RETINAL
1 The Save Sight Institute, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia; 2Department of Ophthalmology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; 3Marsden Eye Specialists, Parramatta, Australia; 4 The Lions Eye Institute, Center for Ophthalmology and Vision Science, University of Western Australia, Perth, Western Australia, Australia; 5 Sydney School of Public Health, University of Sydney, Sydney, New South Wales, Australia; 6Retina Associates, Chatswood, New South Wales, Australia; 7Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Victoria, Australia; 8Department of Ophthalmology, Canberra Hospital, Garran, Australian Capital Territory, Australia; 9Department of Population Health, University of Western Australia, Perth, Western Australia, Australia
Financial Disclosure(s): Supported by a grant from the Royal Australian NZ College of Ophthalmologists Eye Foundation (2007e2009) and a grant from the National Health and Medical Research Council, Australia (NHRMC 2010-1012). The authors state they have no conflicts of interest to declare. Mark Gillies is a Sydney Medical Foundation Fellow and is supported by an NHMRC practitioner fellowship. Robyn Guymer is also supported by an NHMRC practitioner fellowship (#529905), Daniel Barthelmes was supported by the Walter and Gertrud Siegenthaler Foundation Zurich, Switzerland, and the Swiss National Foundation.
References 1. Davis MD, Gangnon RE, Lee LY, et al. The Age-Related Eye Disease Study severity scale for age-related macular degeneration: AREDS Report No. 17. Arch Ophthalmol 2005;123:1484–98. 2. Gillies MC, Walton R, Liong J, et al. Efficient capture of high-quality data on outcomes of treatment for macular diseases: The Fight Retinal Blindness! Project. Retina 2014;34: 188–95. 3. Five-year follow-up of fellow eyes of patients with age-related macular degeneration and unilateral extrafoveal choroidal neovascularization. Macular Photocoagulation Study Group. Arch Ophthalmol 1993;111:1189–99. 4. Lim JH, Wickremasinghe SS, Xie J, et al. Delay to treatment and visual outcomes in patients treated with anti-vascular endothelial growth factor for age-related macular degeneration. Am J Ophthalmol 2012;153:678–86. 5. Keenan TD, Kelly SP, Sallam A, et al. Incidence and baseline clinical characteristics of treated neovascular age-related macular degeneration in a well-defined region of the UK. Br J Ophthalmol 2013;97:1168–72.
Absence of Amiodarone-Associated Optic Neuropathy In 2008, the present author published an editorial in the American Heart Journal1 dealing with optic neuropathies (ON) associated with amiodarone use. Cited were data of amiodarone sales and US Food and Drug Administration (FDA) reports of amiodaroneassociated ON for 2001 through 2006 (6 years). The IMS National Prescription Audit captured approximately 70% of all US retail prescription sales and projected the number to 100%. The IMS Integrated Patient Claims Database provided an estimate of the number of patients treated. From 2001 to 2006, >16 million prescriptions were filled for generic amiodarone plus the 2 existing brands, Cordarone (Pfizer, New York, NY) and Pacerone (Upsher-Smith Laboratories, Maple Grove, MN). The number of patients treated during
Reports this period was >3.6 million. The FDA requires drug manufacturers to report all toxicities, including those in the literature. In addition, the FDA independently collects reports submitted to it; these are not limited to health care professionals; for example, patients and lawyers can submit reports. The total number of amiodarone-associated ON reported to the FDA from 2001 to 2006 was 38. Using these data, the calculated average annual incidence of amiodarone-associated ON was 0.0009%, or approximately 1 in 100 000 in amiodaronetreated patients. The lowest estimate in the literature for nonarteritic anterior ischemic ON (NAION) in those 50 is 2.3 in 100 000.2 This is greater than was calculated above for amiodarone-associated ON. Several explanations can be offered: One is that amiodarone’s abilities to stabilize the cardiac rhythm and increase the cardiac ejection fraction improve the circulation and help protect against ischemia. (This explanation would also challenge the concept, found in the case report literature, that delayed toxicity is the cause of ON that occurs after amiodarone is discontinued3). A second is that the literature estimates of NAION are falsely high. A third is that amiodarone-associated ON is underreported in both the literature and to the FDA owing to a lack of interest or awareness by health care providers. It is unquestioned that underreporting of side effects and toxicities occurs. Hopefully, large-scale underreporting of blindness would occur less often than with other, less devastating, adverse effects such as skin rashes. However, no matter what the degree of underreporting, what does seem apparent is that the incidence estimates of amiodarone-associated ON in the case report literature are unrealistically high. The lowest estimate is 0.36% (360/100 000) annually (1.79% incidence during a 5-year period).4 Based on this estimate, and using the IMS amiodarone retail sales data, there should have been 13 000 patients with ON during 2001 through 2006 (plus an additional number of those spontaneously developing NAION). There would have been >300 patients developing amiodaroneassociated ON for every 1 reported to the FDA. This report provides information for a 5-year period (2008e2012). The IMS National Prescription Audit projected there were >14.7 million amiodarone prescriptions filled. The FDA data were handled in a different manner than in the past report because that agency now pools all amiodarone adverse event reports. The Division of Anti-infective and Ophthalmologic Products was no longer able to provide only the ON data. The FDA received 4948 reports of amiodarone adverse events during 2008 through 2012. These were coded by the FDA using the MedDRA Medical Dictionary. All 4948 reports were reviewed by the present author, looking for newly reported cases coded: Optic Nerve Neuropathy, Blindness, Optic Nerve Disorder, Optic Nerve Neuritis, Optic Nerve Infarction, Optic Nerve Ischemic Neuropathy, Optic Nerve Unilateral Neuropathy, Optic Nerve Injury, Optic Nerve Disc Disorder, Amaurosis and Optic Nerve Unilateral Neuropathy. When a single report had more than one of these codes, only 1 diagnosis was used per patient. Multiple reports of the same patient were treated as one report. “Blindness Unilateral” was also included in the search, but 2 patients had a simultaneous diagnosis of “Retinal Vein Occlusion” and were excluded. The search yielded 53 new FDA reports of amiodarone-associated ON from 2008 through 2012. Of these, 19 were submitted by health professionals, 23 by nonprofessionals, and 11 by sources whose background could not be determined. The calculated annual incidence of amiodarone-associated ON, using the IMS and FDA
data, was 1.6 per 100 000 patients. Once again, this incidence is below that estimated for NAION in the general population. Perhaps a larger number of amiodarone-associated ON could be found by mining the legal records. Searches were performed on Lexis Nexis Court House Searches (LNCHS) and Courthouse News Service (CNS). The LNCHS covers 32 of the 50 states and 1081 state courts. The CNS covers all federal courts and 2200 state courts in all 50 states. The LNCHS searches were for complaints containing the primary words “amiodarone,” “Cordarone” or “Pacerone,” and one of the secondary words: “Vision,” “Blind,” or “Optic.” The CNS search engine limited screening to only the primary words, “amiodarone,” “Cordarone,” and “Pacerone.” From January 1, 2007, to March 26, 2014, the LNCHS search provided 29 new complaints, some of which were duplicates, for example, selected under “amiodarone” and “Cordarone.” The CNS search for January 1, 2007, to March 12, 2014, yielded 52 cases. Review of these combined 81 cases resulted in finding only 4 instances during 2008 through 2012 where amiodarone was claimed to have caused ON: Plaintiffs Randall (Jacksonville, FL, Duval County Circuit Court 11ca9705), Plaintiff Westerlund (Central New Jersey Middlesex County Superior Court MID-L-8311-10), Plaintiff Bryant (US Eastern District Court of Oklahoma 6:10-cv-410), and Plaintiffs Arters (Central Ohio Delaware County Court 10 cv b 01 57). It seems unlikely that a large reservoir of non-FDA reported cases of amiodarone-associated ON exists in the court system. Amiodarone remains an important medication, effective for controlling atrial fibrillation and ventricular arrhythmias. Implantable defibrillators are superior to amiodarone in preventing sudden death, but there is a subgroup that receives so many shocks that it requests, and receives, concomitant amiodarone.5 If not justified, fear of loss of vision should not curtail the use of amiodarone. Acknowledgments. The statements, findings, conclusions, views and opinions contained and expressed in this report are based in part on data obtained under license from the following IMS Health Incorporated information service(s): National Prescription Audit tm (2008-2012), IMS Incorporated. All Rights Reserved. The statements, findings, conclusions, views and opinions contained and expressed herein are not necessarily those of IMS Health Incorporated or any of its affiliated or subsidiary entities.
JOEL S. MINDEL, MD, PHD The Mount Sinai Hospital, New York, New York
References 1. Mindel JS. Amiodarone and optic neuropathy. Am Heart J 2008;156:411–3. 2. Johnson LN, Arnold AC. Incidence of nonarteritic and arteritic anterior ischemic optic neuropathy: population based study in the state of Missouri and Los Angeles County, California. J Neuroophthalmol 1994;14:38–44. 3. Johnson LN, Krohel GB, Thomas ER. The clinical spectrum of amiodarone-associated optic neuropathy. J Natl Med Assoc 2004;96:1477–91. 4. Feiner LA, Younge BR, Kazmier FJ, et al. Optic neuropathy and amiodarone therapy. Mayo Clin Proc 1987;62:702–17. 5. Vassallo P, Trohman RC. Prescribing amiodarone. An evidence-based review of clinical indications. JAMA 2007;298: 1312–22.
2075
