Comparing the Risk of Thrombotic Events in Older Persons with Hemophilia a on Emicizumab Prophylaxis to Non-Emicizumab Products: A Single Center Observational Cohort Study

Background: Emicizumab is an effective treatment for people with hemophilia A both with and without inhibitors. The risk for thrombotic events remains a concern among older patients with hemophilia A who take emicizumab. Our previous case series study described thrombotic events in older people with hemophilia A on emicizumab at a single Hemophilia Treatment Center. Real-world data comparing the risk of thrombotic events before and after emicizumab initiation in older adults or those with cardiovascular risk factors is limited.

Objective: This observational cohort study compared the risk of thrombotic events during the time that people ≥ 50 years with severe and moderately severe hemophilia A were on emicizumab prophylaxis to the time that they were not, which may have been on either factor VIII prophylaxis or episodic factor VIII replacement.

Methods: People with severe and moderately severe hemophilia A (factor VIII levels <2%), who were ≥ 50 years old as of January 1, 2017, or turned 50 years after this date, were followed through December 31, 2023. Time on emicizumab was considered a time-varying exposure measured as the date a person began emicizumab until they discontinued use, or the study period ended. Thrombotic events were defined as myocardial infarction, transient ischemic attack (TIA), cerebrovascular accident (CVA), deep venous thrombosis, or pulmonary embolism. Descriptive statistics were computed with Fischer’s exact and t-tests. Kaplan Meier Curves were used to estimate the cumulative probabilities and Cox proportional models were used to estimate unadjusted (HR) and adjusted hazard ratios (aHR)of thrombotic risk.

Results:

During the study period, 32 patients were included, and cardiovascular risk factors were common: 46.9% of the total cohort had hyperlipidemia, 68.8% had hypertension, 12.5% had diabetes and 50% currently or formerly smoked. There were 27 patients (84.4%) that contributed to both time on and time not on emicizumab, whereas 5 patients (15.6%) contributed only to time not on emicizumab. No patient contributed to time on emicizumab only. Of the 177.5 total person-years in the study, 87.8 (49.5%) person-years were spent on emicizumab. Compared to time on emicizumab vs. time not on emicizumab there were no significant differences in inhibitor history, age, BMI, hypertension, hyperlipidemia, diabetes, and smoking status. Four thrombotic events occurred during the study period, all of which were either TIA or CVA; three events occurred while patients were on emicizumab prophylaxis. These events occurred at 876, 879, and 273 days post-emicizumab initiation. The average age at time of thrombotic event while on emicizumab was 59.3 years. One thrombotic event, in a 56-year-old patient, occurred during treatment time not on emicizumab and while on factor VIII prophylaxis. Of those never initiated on emicizumab, no thrombotic events were observed. The cumulative probabilities of a thrombotic event were 0.156 while on emicizumab and 0.043 while not on emicizumab. The risk of thrombotic events was non-significantly increased (HR=2.65 [95% CI: 0.5, 15.7]) while on emicizumab compared to time not on emicizumab. After adjusting for previous factor VIII prophylaxis use (aHR=2.54, 95%CI 0.38,17.02) and age at baseline (aHR=1.95 [95% CI: 0.3, 12.9]), the difference in risk for thrombotic events was dampened and remained insignificant. After adjusting for cardiovascular risk factors including hyperlipidemia (aHR=2.97 [95% CI: 0.58, 15.08], hypertension (aHR=3.14 [95% CI: 0.6, 17.67], BMI (aHR= 5.61 [95% CI: 0.46, 67.75], smoking (aHR= 2.64 [95% CI: 0.4, 17.22], and diabetes (aHR= 2.41 [95% CI: 0.38, 15.17], the risk also remained increased, but not statistically significant.

Conclusions: Among a relatively small sample of people with severe and moderately severe hemophilia A ≥ 50 years, there was a non-significantly greater risk of thrombotic events while people were on emicizumab vs. not on emicizumab. Given the trend towards an increase in thrombotic events, despite adjustment for cardiovascular risk factors, larger-scale studies comparing real-world data of older patients on emicizumab compared to a similar cohort of patients on non-emicizumab treatment should be conducted to accurately evaluate risk and support shared-decision making.