Aspirin Should Not Be Recommended to Prevent Second Eye Involvement in Patients With Nonarteritic Anterior Ischemic Optic Neuropathy

The discussion of the use of aspirin in patients with nonarteritic anterior ischemic optic neuropathy (NAION )includes 2 major aspects: 1) reduction of risk of subsequent cardiovascular events and 2) reduction of risk of fellow eye NAION events.

Point Counter-Point Section Editors: Andrew G. Lee, MD Gregory P. Van Stavern, MD Aspirin Should Not Be Recommended to Prevent Second Eye Involvement in Patients With Nonarteritic Anterior Ischemic Optic Neuropathy Anthony C. Arnold, MD The discussion of the use of aspirin in patients with nonarteritic anterior ischemic optic neuropathy (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 Aspirin Use to Reduce Risk of Cardiovascular Events Aspirin (ASA) may have a two-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 (1); it also has been shown to reduce the levels of proinflammatory cytokines and c-reactive protein (2). 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 preexisting cardiovascular disease (secondary prevention) (1,3). For primary prevention (so-called "healthy" patients, without previous cardiovascular events, not eliminating patients with so-called "vasculopathic risk factors" such as diabetes, hypertension, hyperlipidemia, or smoking), the Physicians' Health Study (4) concluded that low-dose ASA therapy reduced the risk of MI in healthy men $50 years. Subsequent studies and meta-analyses (5) 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 (6-8) 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 Nonarteritic Anterior Ischemic Optic Neuropathy NAION is often associated with vasculopathic risk factors, including hypertension, diabetes, hyperlipidemia, and obstructive sleep apnea, which might be expected to result in a higher risk of cardiovascular events in this patient group. The data, however, are mixed. Although Guyer et al (9), Sawle et al (10), and Hayreh et al (11) reported increased occurrence of MI or stroke, other large series by Ellenberger et al (12), Boghen et al (13), and Repka et al (14) did not. Studies assessing for carotid stenosis in patients with NAION (15,16) have not revealed an association. Recent articles from Asia remain mixed. Lee et al (17) reported an increased risk of ischemic stroke after NAION, while Park et al (18) did not. At 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 (11) 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. Department of Ophthalmology, Stein Eye Institute, University of California Los Angeles, Los Angeles, California. The authors report no conflicts of interest. Address correspondence to Anthony C. Arnold, MD, UCLA Stein Eye Institute, 100 Stein Plaza Room 2-154, Los Angeles, CA 90095; E-mail: [e-mail] Arnold: J Neuro-Ophthalmol 2020; 40: 271-273 271 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point Basis for Aspirin Use to Reduce Risk of Nonarteritic Anterior Ischemic Optic Neuropathy If we assume that there is a component of thrombosis in the pathogenesis of NAION, then antiplatelet therapy might 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 (19,20), but only one systematic study has been performed. Salomon et al (21) examined the association of prothrombotic risk factors and NAION, finding none. A later study by the same group (22) 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. Hyperhomocystinemia has also been proposed as a risk factor for NAION, particularly in younger patients. 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 (23), Pianka et al (24), Weger et al (25), and Glueck et al (26) suggested an association, but Biousse et al (27) and Salomon et al, in a much larger controlled study (21), did not. Moreover, the treatment of hyperhomocystinemia, 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 hyperhomocystinemia. Risk of Fellow Eye Involvement in Nonarteritic Anterior Ischemic Optic Neuropathy 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% (12,14), 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% (28). The subsequent follow-up data from the Ischemic Optic Neuropathy Decompression Trial (IONDT) suggested a similar 5-year fellow eye involvement rate of 15% (29). Evidence That Aspirin Reduces Fellow Eye Involvement in Nonarteritic Anterior Ischemic Optic Neuropathy 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 (29), 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 (30) 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/d 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 (31) 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 (32) 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 meta-analyses have concluded that the evidence for ASA as an agent to reduce fellow eye involvement after NAION is either "weak" (33) or nonsupportive (34). Summary The use of ASA in patients with NAION, to reduce either the risk of subsequent cardiovascular events or the develop272 ment of fellow eye NAION, is not supported by the evidence. Although ASA has been shown to be effective for Arnold: J Neuro-Ophthalmol 2020; 40: 271-273 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point secondary prevention of cardiovascular events, the evidence for benefit in primary prevention (in the population of NAION patients with no previous 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. REFERENCES 1. Patrono C, Coller B, Fitzgerald GA, Hirsh J, Roth G. Plateletactive drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. 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