Acute Nonarteritic Anterior Ischemic Optic Neuropathy and Exposure to Phosphodiesterase Type 5 Inhibitors

Abstract

Introduction Nonarteritic anterior ischemic optic neuropathy (NAION), a rare visual disorder, has been reported in men using phosphodiesterase type 5 inhibitors (PDE5i) for erectile dysfunction. Aim We examined whether intermittent use of PDE5i is associated with acute NAION onset within approximately five half-lives following drug ingestion. Methods One hundred two ophthalmology centers in the United States and Europe identified potential cases of NAION. An expert adjudication committee conducted a blind review of the records of those with recent PDE5i use to classify cases as Definite, Possible, or not NAION. Subjects provided information on PDEi use via telephone interview. Each NAION case’s PDE5i exposure immediately prior to onset was compared against his recent patterns of use in an observational case–crossover design. A sample size of 40 cases with intermittent PDE5i exposure in the 30 days prior to NAION onset was needed to detect an odds ratio (OR) of 3.0 with 80% power. Main Outcome Measures The daily relative risk for acute NAION on days within five half-lives of PDE5i use vs. other days was estimated via an OR obtained from conditional logistic regression. Results Among 43 Definite NAION cases with PDE5i exposure in the prior 30 days, the OR was 2.15 (95% confidence interval [CI]: 1.06, 4.34). When 21 Possible NAION cases were included (n = 64), the OR was 2.36 (95% CI: 1.33, 4.19). Conclusions We found an approximately twofold increased risk of acute NAION within five half-lives of PDE5i use compared with use in a more prior time period. Bias from inaccurate recall of exposure was unlikely to have substantially affected the results. Based on our results, we estimate that weekly use of PDE5i adds three NAION cases per 100,000 men 50 years and older annually.

Ischemic Optic Neuropathies

“…18 Several medications have been implicated in the occurrence of nonarteritic anterior ION, including amiodarone, 19 vasopressor agents, vasoconstricting drugs (e.g., nasal decongestants), 20 and phosphodiesterase type 5 inhibitors used for erectile dysfunction. 21 However, establishing a direct relationship between the use of a specific medication and the development of nonarteritic anterior ION is difficult, because most patients have concurrent vascular risk factors and an underlying disc at risk.…”

Risk of sudden sensorineural hearing loss in adults using phosphodiesterase type 5 inhibitors: Population‐based cohort study

“…We made assumptions about frequency of PDE5 inhibitor use based on results from recent surveys, which suggested that about 40 to 50% of the men interviewed took the medication once or twice per week, and about 75% use it once or twice per month . Duration of exposure was calculated accordingly as the number of prescribed tablets multiplied by 7 days.…”

Sample size estimation for case‐crossover studies

“…The accuracy of formula (5) for correlated paired matched studies inspired us to derive another sample size formula for case-crossover studies, which accounts for correlation and multiple matches. As noted in the previous section, sample size formula (5) is valid for pair-matched studies or studies where each subject has only one control and one hazard period.…”

“…Exposure in the hazard period is compared to exposure in the control periods to estimate the odds ratio of experiencing the event immediately after exposure compared to anytime during the control periods. For example, in a recent postmarket safety study, the occurrence of nonarteritic anterior ischemic optic neuropathy (NAION) in men using phosphodiesterase type 5 inhibitors (PDE5i) for erectile dysfunction was examined using a case‐crossover design . In their study, the authors designated the observation period to be 30 days prior to acute NAION onset, with the case window defined as the day prior to acute NAION onset and control windows defined as 29 1‐day periods prior to the case window.…”

“…For example, in a recent postmarket safety study, the occurrence of nonarteritic anterior ischemic optic neuropathy (NAION) in men using phosphodiesterase type 5 inhibitors (PDE5i) for erectile dysfunction was examined using a case-crossover design. 5 In their study, the authors designated the observation period to be 30 days prior to acute NAION onset, with the case window defined as the day prior to acute NAION onset and control windows defined as 29 1-day periods prior to the case window. Subjects were considered exposed in a window if they used a PDE5i on the day of or a day prior to the one-day period.…”