Absence of Bilateral Vision Loss From Amiodarone: A Randomized Trial
Background: Amiodarone's role as a cause of toxic optic neuropathy is based on case reports. Annual frequency estimates of 0.36% to 2.0%, which have been made without reference to the dose or duration of treatment, are 12 to 200 times higher than those for idiopathic nonarteritic anterior ischemic neuropathy. The object of this study was to determine the incidence, dose, and time until onset of bilateral vision loss from amiodarone as a secondary end point in an investigation of amiodarone's role in preventing sudden death.
Methods: Randomized subjects received body weight-determined doses of closed-label amiodarone (n = 837) or placebo (n = 832) in a prospective double-masked manner. Closed-label amiodarone subjects were followed, unless death occurred, for a minimum of 27 months. Median follow-up in survivors was 45.5 months. The end point was removal from the study because of bilateral vision loss.
Results: No subject was removed from the study because of bilateral vision loss. Subjects receiving continuous amiodarone for 4 to >60 months at daily doses of >2.0 mg/kg (n = 696), >3.0 mg/kg (n = 559), or >4.0 mg/kg (n = 219) had maximum possible (95% confidence) annual incidences of bilateral toxic vision loss of 0.23%, 0.29%, or 0.74%, respectively. The maximum possible annual incidence rate of bilateral vision loss from amiodarone in all 837 subjects (median age 60 years) receiving a mean daily dose of 3.7 mg/kg (300 mg) was 0.13%.
Conclusions: At the doses commonly used clinically, bilateral vision loss from amiodarone toxic optic neuropathy occurs infrequently, if at all.
An argument for the existence of amiodarone toxic optic neuropathy (ON) is its higher frequency in those taking the drug than can be attributed to idiopathic nonarteritic anterior ischemic optic neuropathy (NAION). However, frequency estimates of both conditions have been based solely on retrospective analyses. Idiopathic NAION annual estimates range from 0.01% to 0.03% (a 10-year incidence of 0.3%). Annual incidence estimates of amiodarone toxic ON have been 12 to 200 times higher, that is, 0.36% (a 5-year incidence of 1.79%), approximately 2% (unstated time interval), and 2%. These estimates have not been correlated with either the dose or the duration of treatment. Even if correct, these higher incidences of amiodarone-associated ON could be the result of an increased prevalence in cardiac patients of idiopathic NAION risk factors, such as diabetes and hypertension, rather than drug toxicity.
Obstacles to performing a prospective, double-masked, randomized, placebo-controlled study of the incidence of amiodarone toxic ON include the ethical dilemma of enrolling a matched placebo control group, the large number of subjects required, the unmasking effect of amiodarone corneal deposits, and the lack of drug company interest.
With regard to study size, an initial enrollment of 668 subjects would be needed to determine with 95% confidence that amiodarone toxic ON occurred, assuming a 1.5% annual incidence, a 42-month study, an annual death rate of 8%, and a 0.03% annual incidence of idiopathic NAION. The second obstacle is the unmasking effect caused by amiodarone corneal deposits present in >97% of patients receiving 200 to 300 mg amiodarone daily and 99% of patients receiving 200 to 1200 mg amiodarone 5 days per week. Techniques that may reveal corneal deposits such as slit lamp, funduscopic, and retinoscopic examinations would have to be excluded. However, the largest obstacle may be drug company disinterest in funding such a study. After a $22.8-million judgment against Wyeth-Ayerst Pharmaceuticals (Philadelphia, PA) in 1997, labeling was changed to emphasize the possible occurrence of amiodarone-associated ON. This shifted a pharmaceutical product liability issue to a physician malpractice problem.
The present study was part of a long-term placebo-controlled trial designed to compare amiodarone and defibrillators in the prevention of sudden death. Described is the failure of amiodarone toxic ON to manifest itself as bilateral vision loss in 837 subjects followed at 3-month intervals for a median duration of 45.5 months and, unless death occurred, a minimum duration of 27 months.
Abstract and Introduction
Abstract
Background: Amiodarone's role as a cause of toxic optic neuropathy is based on case reports. Annual frequency estimates of 0.36% to 2.0%, which have been made without reference to the dose or duration of treatment, are 12 to 200 times higher than those for idiopathic nonarteritic anterior ischemic neuropathy. The object of this study was to determine the incidence, dose, and time until onset of bilateral vision loss from amiodarone as a secondary end point in an investigation of amiodarone's role in preventing sudden death.
Methods: Randomized subjects received body weight-determined doses of closed-label amiodarone (n = 837) or placebo (n = 832) in a prospective double-masked manner. Closed-label amiodarone subjects were followed, unless death occurred, for a minimum of 27 months. Median follow-up in survivors was 45.5 months. The end point was removal from the study because of bilateral vision loss.
Results: No subject was removed from the study because of bilateral vision loss. Subjects receiving continuous amiodarone for 4 to >60 months at daily doses of >2.0 mg/kg (n = 696), >3.0 mg/kg (n = 559), or >4.0 mg/kg (n = 219) had maximum possible (95% confidence) annual incidences of bilateral toxic vision loss of 0.23%, 0.29%, or 0.74%, respectively. The maximum possible annual incidence rate of bilateral vision loss from amiodarone in all 837 subjects (median age 60 years) receiving a mean daily dose of 3.7 mg/kg (300 mg) was 0.13%.
Conclusions: At the doses commonly used clinically, bilateral vision loss from amiodarone toxic optic neuropathy occurs infrequently, if at all.
Introduction
An argument for the existence of amiodarone toxic optic neuropathy (ON) is its higher frequency in those taking the drug than can be attributed to idiopathic nonarteritic anterior ischemic optic neuropathy (NAION). However, frequency estimates of both conditions have been based solely on retrospective analyses. Idiopathic NAION annual estimates range from 0.01% to 0.03% (a 10-year incidence of 0.3%). Annual incidence estimates of amiodarone toxic ON have been 12 to 200 times higher, that is, 0.36% (a 5-year incidence of 1.79%), approximately 2% (unstated time interval), and 2%. These estimates have not been correlated with either the dose or the duration of treatment. Even if correct, these higher incidences of amiodarone-associated ON could be the result of an increased prevalence in cardiac patients of idiopathic NAION risk factors, such as diabetes and hypertension, rather than drug toxicity.
Obstacles to performing a prospective, double-masked, randomized, placebo-controlled study of the incidence of amiodarone toxic ON include the ethical dilemma of enrolling a matched placebo control group, the large number of subjects required, the unmasking effect of amiodarone corneal deposits, and the lack of drug company interest.
With regard to study size, an initial enrollment of 668 subjects would be needed to determine with 95% confidence that amiodarone toxic ON occurred, assuming a 1.5% annual incidence, a 42-month study, an annual death rate of 8%, and a 0.03% annual incidence of idiopathic NAION. The second obstacle is the unmasking effect caused by amiodarone corneal deposits present in >97% of patients receiving 200 to 300 mg amiodarone daily and 99% of patients receiving 200 to 1200 mg amiodarone 5 days per week. Techniques that may reveal corneal deposits such as slit lamp, funduscopic, and retinoscopic examinations would have to be excluded. However, the largest obstacle may be drug company disinterest in funding such a study. After a $22.8-million judgment against Wyeth-Ayerst Pharmaceuticals (Philadelphia, PA) in 1997, labeling was changed to emphasize the possible occurrence of amiodarone-associated ON. This shifted a pharmaceutical product liability issue to a physician malpractice problem.
The present study was part of a long-term placebo-controlled trial designed to compare amiodarone and defibrillators in the prevention of sudden death. Described is the failure of amiodarone toxic ON to manifest itself as bilateral vision loss in 837 subjects followed at 3-month intervals for a median duration of 45.5 months and, unless death occurred, a minimum duration of 27 months.
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