Serious Adverse Events of Oral and Topical Carbonic Anhydrase Inhibitors

Abstract

Importance: Some ophthalmologists may be reluctant to prescribe oral carbonic anhydrase inhibitors, given the potential for life-threatening systemic adverse reactions.

Objective: To conduct a population-based analysis of the safety of oral or topical carbonic anhydrase inhibitors in clinical care.

Design, setting, and participants: This matched longitudinal cohort study took place in Ontario, Canada. Consecutive patients older than 65 years who were prescribed an oral or topical carbonic anhydrase inhibitor in Ontario, Canada, between January 1, 1995, and January 1, 2020, were identified. Patients were matched 1-to-1 based on age, sex, and diabetes status. Time zero was defined as the date of the first identified prescription for the medication, and the primary analysis focused on the first 120 days of follow-up.

Main outcomes and measures: The primary end point was a severe complicated adverse event of either Stevens-Johnson syndrome, toxic epidermal necrolysis, or aplastic anemia.

Results: Overall, 128 942 matched patients initiated an oral or topical carbonic anhydrase inhibitor during the 25-year study period. The mean (SD) age was 75 (6.6) years, 71 958 (55.8%) were women, and 25 058 (19.4%) had a diagnosis of diabetes. The oral and topical carbonic anhydrase inhibitor groups had similar baseline demographics. Patients prescribed an oral carbonic anhydrase inhibitor had an absolute risk of a severe complicated adverse event of 2.90 per 1000 patients, whereas patients prescribed a topical carbonic anhydrase inhibitor had an absolute risk of 2.08 per 1000 patients. This difference was equivalent to a risk ratio of 1.40, with a number needed to harm of 1 in 1220 patients (95% CI, 1.12-1.74; P = .003). This generally low risk was replicated in multivariable regression controlling for confounding factors. Additional risk factors for a severe complicated adverse event included patients with more comorbidities and those with more frequent clinic contacts.

Conclusions and relevance: The risk of a serious adverse reaction following prescription of an oral or topical carbonic anhydrase inhibitor was low and similar between agents. Given the low risk of severe adverse reactions, this population-level analysis supports reconsidering the reluctance toward prescribing an oral carbonic anhydrase inhibitor.

Figure 1.. Risk of Severe Complicated Adverse Reaction

Cumulative incidence plot of absolute risk of a severe complicated adverse event. The x-axis shows time following start of medication spanning 4 months (120 days), and the y-axis shows cumulative incidence of events per 1000 patients. Those treated with an oral carbonic anhydrase inhibitor (CAI) are indicated in blue and those treated with a topical CAI are indicated in orange. Numerical counts show proportion of patients free of events at corresponding time. P values and hazard ratios are based on Fine and Gray model. Results show modest incidence of a severe complicated adverse event that is marginally increased with oral compared with topical treatment.

Figure 2.. Consistency of Risk in Subgroups

Forest plot of relative risk of a severe complicated adverse event following carbonic anhydrase inhibitor treatment in different subgroups. Circles denote estimate and horizontal lines denote 95% CIs. Null association shown as a relative risk of 1.00. Sample size in each subgroup shown as total patients along with absolute risk for each subgroup (events per 1000 patients). Relative risk calculated by comparing oral group with topical group. Summary analysis for total cohort shown at the bottom. Findings show low absolute risk, modest relative increase with oral treatment, and all subgroups overlapping the primary analysis, indicating that differences between subgroups may be attributable to chance alone. CCI indicates Charlson Comorbidity Index; SES, socioeconomic status.