Should Aspirin Be Prescribed to Prevent Recurrence in Nonarteritic Anterior Ischemic Optic Neuropathy

Nonarteritic anterior ischemic optic neuropathy (NAION) has no proven treatment and typically causes some degree of irreversible visual loss. Preventing second eye involvement is a worthy goal, but there is uncertainty regarding the benefit of any preventive therapy. Two experts debate the role of aspirin in preventing fellow eye involvement in NAION.

Point Counter-Point Section Editors: Andrew G. Lee, MD Gregory P. Van Stavern, MD Should Aspirin Be Prescribed to Prevent Recurrence in Nonarteritic Anterior Ischemic Optic Neuropathy? Robert A. Egan, MD, Anthony C. Arnold, MD, Andrew G. Lee, MD, Gregory P. Van Stavern, MD Nonarteritic anterior ischemic optic neuropathy (NAION) has no proven treatment and typically causes some degree of irreversible visual loss. Preventing second eye involvement is a worthy goal, but there is uncertainty regarding the benefit of any preventive therapy. Two experts debate the role of aspirin in preventing fellow eye involvement in NAION. Pro: Robert A. Egan, MD Nonarteritic anterior ischemic optic neuropathy (AION) is an idiopathic vasculopathy of the optic nerve and is the most common cause of acute optic neuropathy (1,2). Many studies have been conducted to determine causality, but none have been definitive. A link to certain systemic vascular risk factors has been suggested because there is an increased risk in AION of those factors including diabetes, hypertension, hypercholesterolemia, hypercoagulability, ischemic heart disease, and cerebrovascular disease (3-8). Because vision loss in the fellow eye can occur in up to 15% of patients with AION (9), a treatment to prevent second eye involvement has been sought. Given that vascular risk factors have been associated as noted above, aspirin has predictably been prescribed as this preventative measure. There is some evidence in the literature that supports this theory, although the number of published reports is sparse. Kupersmith et al (10) found in a retrospective trial that aspirin taken 2 or more times per week decreased the incidence and relative risk of second eye involvement (10). Beck et al found retrospectively that aspirin reduced the risk of second eye involvement and the effect was stronger in the first 2 years than at the first-year mark. The risk of second eye involvement was 7% in the aspirin group and 15% in the nonaspirin group at 2 years (11). The Ischemic Optic Neuropathy Decompression Trial (IONDT), a prospective study, enrolled 418 subjects and found that 14.7% developed second eye involvement during a follow-up period of MultiCare Rockwood Clinic (RE), Spokane, Washington; Department of Ophthalmology (ACA), Jules Stein Eye Institute, University of California Los Angeles, Los Angeles, California; Blanton Eye Institute (AGL), Houston Methodist Hospital, Houston, Texas; and Department of Ophthalmology and Visual Sciences (GVS), Washington University in St. Louis, St. Louis, Missouri. The authors report no conflicts of interest. Address correspondence to Gregory Van Stavern, MD, Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, 660 S. Euclid Avenue, St. Louis, MO 63130; E-mail: [e-mail] 428 5.1 years. They also found that increased incidence of second eye involvement was not associated with aspirin usage. Furthermore, another retrospective trial showed that aspirin not only reduced the rate of second eye involvement, it also had a dose effect and was more beneficial at higher doses and also prolonged onset of second eye involvement (12). There is also evidence that aspirin does not improve the visual outcome of patients suffering with NAION (13). It is generally believed that prospective studies are more important and consequential than retrospective studies. However retrospective studies have their merit and their place in the scientific milieu. Aspirin has also been used for secondary prevention in other disorders. If we take simply ischemic cerebrovascular disease, there are a myriad of reports in the scientific literature demonstrating clear benefit of risk reduction with aspirin usage. If we extrapolate from the possibility that AION is associated with vascular risk factors, then treating these risk factors may help patients in other ways besides attempting to prevent second eye recurrence. The data regarding the benefits of secondary prevention of ischemic stroke with aspirin monotherapy are huge; there are countless studies in the medical literature. Aspirin plus clopidogrel seems to show some heightened benefit over aspirin monotherapy. A meta-analysis of 11 randomized controlled trials revealed a significant reduction in recurrent ischemic stroke (14). Another analysis of 16 randomized controlled trials showed a significant stroke risk reduction with dual antiplatelet therapy over aspirin monotherapy (15). Long-term dual antiplatelet therapy is also associated with more bleeding side effects and typically not recommended. This author has had personal and professional experience in early recurrence of second eye involvement. Steve Feldon was also quoted previously (9) as having a similar experience and has relayed that he found that this occurs within 18 months (personal communication). Because current Egan et al: J Neuro-Ophthalmol 2020; 40: 428-433 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point medical thought is directed toward using dual antiplatelet therapy to reduce early ischemic stroke recurrence (14-16), it is possible that using combinations of the drugs aspirin plus clopidogrel for 6-12 months after onset of first eye involvement of AION may more significantly reduce the rate of second eye involvement. This of course has not been studied yet, but could be a direction for future research. Although the data in favor or prevention of second eye involvement with aspirin are based on only a few retrospective clinical trials, the potential benefits are great with low bleeding risk. The possible benefit of preventing other cerebrovascular accidents can also not be ignored. This author is in favor of treating patients with first or second eye involvement with aspirin therapy. Con: Anthony C. Arnold, MD The discussion of the use of ASA in patients with NAION includes 2 major aspects: 1) reduction of risk of subsequent cardiovascular events, and 2) reduction of risk of fellow eye NAION events. Basis for ASA use to reduce risk of cardiovascular events Aspirin (ASA) may have a 2-fold effect in reducing the risk of cardiovascular events: antithrombotic and antiinflammatory. Aspirin inhibits platelet aggregation by its action to block thromboxane A2, which is effective at a low dose of 100 mg (17); it also has been shown to reduce the levels of proinflammatory cytokines and c-reactive protein (18). Multiple studies have demonstrated that ASA is effective in reducing the risk of myocardial infarction (MI), stroke, and vascular death in both men and women with pre-existing cardiovascular disease (secondary prevention) (17-19). For primary prevention (socalled "healthy" patients, without prior cardiovascular events, not eliminating patients with so called "vasculopathic risk factors" such as diabetes, hypertension, hyperlipidemia, or smoking), the Physicians' Health Study (20) concluded that low dose ASA therapy reduced the risk of MI in healthy men $50 years. Subsequent studies and meta-analyses (21) found that the benefit of low dose ASA in the reduction of combined risk of cardiovascular events extended to healthy men (MI) and women (ischemic stroke). However, the study of healthy British male doctors published contemporaneously did not find a significant benefit. Large scale recent studies have cast further doubt on the risk-benefit ratio for ASA for primary prevention. The Aspirin in Reducing Events in the Elderly (ASPREE) Study (22-24) in healthy men and women $70 years recently demonstrated an increased risk of major hemorrhagic events with no significant reduction in cardiovascular events or survival with the use of low dose ASA. Risk of cardiovascular events in patients with NAION NAION is often associated with vasculopathic risk factors, including hypertension, diabetes, hyperlipidemia, and obstructive sleep apnea, which may be expected to result Egan et al: J Neuro-Ophthalmol 2020; 40: 428-433 in a higher risk of cardiovascular events in this patient group. The data, however, are mixed. Although Guyer et al (3), Sawle et al (25), and Hayreh et al (4) reported increased occurrence of MI or stroke, other large series by Ellenberger et al (26), Boghen et al (27), and Repka et al (28) did not. Studies assessing for carotid stenosis in patients with NAION (29,30) have not revealed an association. Recent papers from Asia remain mixed. Lee et al (31) reported an increased risk of ischemic stroke after NAION, whereas Park et al (32) did not. An issue in all of these studies is the distinction between NAION with and without the vasculopathic risk factors known to increase risk of stroke and MI. Although most studies were not powered to distinguish between groups with and without risk factors regarding cardiovascular events, Hayreh et al (4) did so and found that NAION alone was not associated with an increased risk. Moreover, as shown by studies listed in the previous section, the use of ASA for primary prevention, even in those with vasculopathic risk factors, is unproven. Basis for ASA use to reduce risk of NAION If we assume that there is a component of thrombosis in the pathogenesis of NAION, then antiplatelet therapy may be a logical approach to prevention. However, there is limited evidence for this. The pathogenesis of NAION and specifically the role of thrombosis has not been established. There has been a scattering of reports of NAION occurring in patients with the Factor V Leiden mutation and activated Protein C resistance, antithrombin III deficiency, antiphospholipid antibodies, and other disorders of the coagulation system (33,34), but only one systematic study has been performed. Salomon et al (12) examined the association of prothrombotic risk factors and NAION, finding none. A later study by the same group (35) found a platelet polymorphism in 16 of 92 patients with NAION, suggesting it as a possible risk factor, but there has been no corroboration by further study, and the clinical implications remain unclear. These disorders typically potentiate venous thrombosis and are treated with anticoagulant rather than antiplatelet therapy. Hyperhomocysteinemia has also been proposed as a risk factor for NAION, particularly in younger patients. 429 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point Although it may have implications for platelet activity in addition to direct endothelial damage, the studies assessing the link to NAION have produced conflicting results. Kawasaki et al (36), Pianka et al (37), Weger et al (38), and Glueck et al (39) suggested an association, but Biousse et al (40) and Salomon et al (7), in a much larger controlled study, did not. Moreover, the treatment of hyperhomocysteinemia, whether related to the methylenetetrahydrofolate reductase (MTHFR) C677T mutation or not, involves folate supplementation. No studies have assessed the benefit of ASA use in reducing fellow eye involvement in patients with platelet polymorphisms or hyperhomocysteinemia. Risk of fellow eye involvement in NAION Does the risk of fellow eye involvement after NAION justify intervention? Early studies of the frequency of second eye occurrence ranged from 24% to 48% (26,28), with variance of methodology and length of follow-up confounding the results. In planning for a prospective study of ASA for fellow eye prophylaxis after unilateral NAION, Beck et al reviewed data from 431 patients with NAION, finding a 2-year risk for fellow eye involvement of 9%- 12%, with 5-year risk of 12%-19% (11) The subsequent follow-up data from the IONDT suggested a similar 5-year fellow eye involvement rate of 15% (9). Evidence that ASA reduces fellow eye involvement in NAION The data from Beck et al revealed that a viable prospective study would require enrollment of 4,000 patients, an infeasible goal; the study was not pursued, and no prospective data are available regarding the benefit of ASA in reducing fellow eye involvement after NAION. Beck et al did review the question retrospectively in their review of 431 patients, finding that the 5-year risk was 10%-17% with ASA and 13%-20% without, not significantly different. The IONDT (9), although not designed to study the effect of ASA, did not reveal a difference in fellow eye involvement rate between those patients using vs those not using ASA. Two subsequent smaller retrospective studies proposed a substantial benefit from the use of ASA. Salomon et al (12) reviewed 52 patients for the development of fellow eye involvement, finding 8 of 16 (50%) without ASA use vs 5/28 (18%) with ASA $325 mg/day use, with follow-up up to 13 years. Although the differences were not statistically significant, the findings were felt to strongly suggest a benefit from ASA. The study has been criticized (41) for the unusually high fellow eye involvement rate in the very small sample of nontreated patients, inconsistent with other larger studies of fellow eye involvement. Kupersmith et al (10) reviewed the data from 100 patients with NAION, with 23/43 (53.5%) without ASA use developing fellow eye involvement vs 10/57 (17.5%) with ASA use, with follow-up up to 16 years. This study has been criticized for the same reasons. Two more recent metaanalyses have concluded that the evidence for ASA as an agent to reduce fellow eye involvement after NAION is either "weak" (42) or nonsupportive (43). The use of ASA in patients with NAION, to reduce either the risk of subsequent cardiovascular events or the development of fellow eye NAION, is not supported by the evidence. Although ASA has been shown to be effective for secondary prevention of cardiovascular events, the evidence for benefit in primary prevention, (in the population of NAION patients with no prior cardiovascular events), has been recently refuted. The role of thrombosis in NAION has not been established, and most data regarding the effect of ASA on fellow eye involvement do not support its use. Rebuttal: Robert A. Egan, MD I appreciate the scholarly article written by my colleague Dr. Arnold in coordination with mine. We have discussed a number of factors regarding second eye recurrence of AION and the paucity of data associated in favor and against those factors. I do not believe that the data that he has provided really differ from mine. The interpretation is slightly different. I will therefore not speak further on the issue of using aspirin to reduce the risk of second eye involvement, because the data is just too weak to prove either way and therefore not constructive. What I would like to address is the fear of intracerebral hemorrhage when using low dose aspirin. Many studies have been performed showing the positive effectiveness of aspirin in secondary prevention of ischemic stroke. However, there is also evidence that there is little if any benefit of low-dose aspirin in primary prevention of ischemic stroke in 430 healthy subjects (44). Aspirin is not beneficial for primary prevention in healthy individuals except possibly in women above the age of 65 (45). These data were most significant for women above 65 over a 10-year period. However, with the addition of any cardiovascular risk factor that would affect a patient's life, aspirin reduces ischemic stroke risk and is recommended in the primary prevention of ischemic stroke (46). The risk of major hemorrhage does increase with aspirin usage even at low dose, but this is primarily related to gastrointestinal hemorrhage and not intracerebral hemorrhage and is dose related (47). Therefore, aspirin usage even at 81 mg a day should not be indiscriminate, but tailored to those patients with at least one vascular risk factor (48). Because many patients with AION suffer from at least one vascular risk factor, it makes perfect sense to prescribe Egan et al: J Neuro-Ophthalmol 2020; 40: 428-433 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point low-dose aspirin for them even if the data of prevention of second eye involvement is weak but provocative. I would also propose an idea for a future double-blind, interventional, clinical study for the usage of dual antiplatelet therapy, which carries an increased risk of intracerebral hemorrhage if used long-term, vs aspirin and/or placebo for a 6-12 month period to see whether the rate of second eye involvement in AION can be reduced. The feasibility of performing this type of study would have to also be examined. Rebuttal: Anthony C. Arnold, MD It is reasonable to consider, as Dr. Egan does, that because ASA has proven effectiveness for the secondary prevention of cardiovascular events, including stroke, it may show a similar benefit for NAION in preventing second eye involvement. However, most strokes are thromboembolic events related to large vessel disease; as I indicated previously, the evidence that thrombosis plays a role in NAION is very weak: the available data suggest that this is a small vessel disease more likely related to hypoperfusion and a compartment syndrome than to thrombus. Although I have disagreed with Dr. Hayreh on several points regarding pathogenesis of NAION, I do agree with him on this point, described in his 2010 editorial (43) in NeuroOphthalmology: "Pathogenetically, NA-AION and cerebral stroke are not similar." The use of ASA for prevention in NAION does not share the same rationale as for stroke. I would also like to place into perspective Dr. Egan's citation of the Beck study of 1997 (11). Although his quotation of the 2 year cumulative probability of fellow eye NAION involvement at 7% in ASA vs 15% in non-ASA subjects is accurate, the study actually concluded that although the short-term data suggested a benefit, the long-term (5 year) data of 17% vs 20% did not. Moreover, when Salomon and associates, in their paper supporting ASA use for prevention (12), quoted this study as "advocating administration of aspirin for prevention of a second event of nonarteritic anterior ischemic optic neuropathy (NAION)," Dr. Beck responded in print (41) that "This is a miscitation. On the contrary, we did not conclude, based on our data, that aspirin was beneficial." In addition, as I previously noted, both the Salomon and the Kupersmith studies he cites as demonstrating effectiveness (10,12) showed very high non-ASA second eye involvement rates near 50%, unlike other studies of the natural history, making the non-ASA vs ASA comparison difficult to evaluate. In summary, although we tell our patients that NAION is "like a stroke of the optic nerve," the analogy does not apply for pathogenesis or for prevention. The evidence does not support ASA use either for primary prevention of CNS or cardiac events or for prevention of second eye involvement. Conclusions: Andrew G. Lee, MD, and Gregory P. van Stavern, MD The efficacy of daily aspirin to prevent second eye involvement in NAION remains unproven. As noted by the authors, obtaining high quality evidence proving benefit (or lack thereof) is challenging given the rarity of the disease, the relatively low risk of second eye involvement and the need for long-term follow-up. 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