No Increased Risk of Cataract in Immune Thrombocytopenia Adult Patients Treated with Eltrombopag. a French Nationwide Nested Case-Control Study

Background: In preclinical studies, eltrombopag has been associated to an increased incidence of cataract in mice and rats. No increased risk has been observed in randomized controlled trials in immune thrombocytopenia (ITP) patients. During the eltrombopag extension study EXTEND, 28/302 patients developed or worsened cataract, i.e. 9.3% of the patients over a median duration of exposure of 2.4 years. Of note, 79% of these 28 patients had at least another risk factor of cataract. Real-life studies assessing the risk of cataract in ITP adult patients exposed to eltrombopag are lacking.

Aim: To assess the risk of cataract with eltrombopag in a nationwide cohort of primary ITP adults.

Methods: The population was the cohort of all incident primary ITP adult patients (≥18 years) in France from June 2010 (date of eltrombopag marketing in France) to June 2017. This cohort was identified within the national health insurance database using a validated algorithm combining drug exposures and international classification of diseases, version 10 (ICD-10) diagnosis codes (FAITH cohort; NCT03429660). A nested case-control study was conducted within the cohort. Cases were patients who had a surgery for cataract after ITP onset, identified using appropriate codes. Up to five controls for each case were matched on age and sex. Index date was the date of cataract surgery for cases, and the date of cataract surgery of the corresponding case for controls. Two analyses were conducted: one considering the exposure to eltrombopag as ever vs. never exposed; another considering the cumulative exposure to eltrombopag, categorized by never exposed, a 1-365 Defined Daily Dose (DDD) exposure, and a ≥365 DDD exposure. Covariables were the presence of diabetes mellitus, cumulative exposure to corticosteroids considered in prednisone equivalence dosage (by quartiles), and the presence of ophthalmological risk factors of cataract (including previous ophthalmological surgery, glaucoma and other anterior chamber risk factors). Conditional logistic regression models were used to compute adjusted odds ratios (aOR) and their 95% confidence intervals (CI).

Results: The cohort included 8,502 incident primary ITP adults. During the follow-up (31,590 patient-years in total; mean follow-up: 44.4 months), 1,097 patients were exposed to eltrombopag, including 310 with a cumulative exposure ≥365 DDDs. Overall, 573 patients had a surgery of cataract; incidence: 1.90/100 person-years (95% CI: 1.75-2.06). Fifty-seven cases occurred in patients ever exposed to eltrombopag; incidence: 1.50/100 person-years (95%CI: 1.15-1.94) in this subgroup. The nested case-control study included the 573 cases and 2699 controls. Median age was 75 years and 50% were women; the median duration of disease was 24.8 months in cases and 24.2 months in controls; 57 (9.9%) cases and 314 (11.6%) controls were exposed to eltrombopag before the index date; 14 (2.4%) and 68 (2.5%) patients had cumulative exposure to eltrombopag ≥365 DDDs, respectively. Cases were more frequently exposed to corticosteroids (83.4% vs. 75.7%), with a higher cumulative exposure to corticosteroids (median: 2800 vs. 2188 mg prednisone equivalent). Diabetes mellitus was present in 25.7% of cases vs. 25.1% of controls while ophthalmological risk factors were present in 5.4% and 2.8%, respectively. In the ever/never exposed analysis, the aOR for eltrombopag was 0.79 (95% CI: 0.58-1.07). In the cumulative exposure analysis, the aOR was 0.76 (95% CI: 0.54-1.08) in the 1-365 DDD group as compared with the never exposed group, and 0.88 (95% CI: 0.49-1.59) in the ≥365 DDD group as compared with the never exposed group.

Conclusions: This nationwide pharmacoepidemiological study did not identify an increased risk of cataract in primary ITP adult patients exposed to eltrombopag.