Abstract
Purpose:
While anti-vascular endothelial growth factor (anti-VEGF) agents are effective treatments for diabetic macular edema (DME), long-term use may be associated with an increased risk of arterial thromboembolic events (ATEs). Ranibizumab (RBZ) is a humanized Fab fragment with no Fc-portion developed specifically for intraocular use. It shows limited systemic exposure relative to other anti-VEGF agents, with a well-established safety profile in DME in clinical trials. Long-term ATE incidence in studies of intravitreal RBZ treatment for DME for up to 36 months is evaluated here.
Methods:
A retrospective pooled analysis of ATEs from five controlled studies, RESOLVE, RESTORE, REVEAL, RESTORE-core+extension and RETAIN studies was performed. Patients received RBZ 0.5 mg in all studies (patients from RESOLVE who received 0.3mg, 0.6 mg and 1.0 mg doses were also included). Myocardial infarctions and non-myocardial ATEs (including but not limited to cerebrovascular accidents and transient ischemic attacks) were captured across trials. Analyses were conducted on a 12-month pooled sham- or laser- controlled dataset from RESOLVE, RESTORE and REVEAL (pro-re-nata; PRN); a 24-month dataset from RESTORE-core+extension and RETAIN (PRN and treat-and-extend); and a 36-month dataset from RESTORE-core+extension (PRN).
Results:
Within the 12-month dataset, ATE rates were similar for RBZ (10; 2.9%) and control (11; 3.8%) arms. Six RBZ patients (n=350) had myocardial and six had non-myocardial ATEs (1.7% each), while seven (2.4%) and five (1.7%) control patients (n=287) had myocardial and non-myocardial ATEs, respectively. Relative risk (RBZ/control) for any ATE was 0.75, and was 0.98 for non-myocardial ATE. Over 24-months’ RBZ treatment (N=327), four patients (1.2%) had myocardial and 18 (5.5%) had non-myocardial ATEs. The ATE rates/year were 3.2% (total), 0.6% (myocardial) and 2.8% (non-myocardial). In the 36-month dataset (N=83), four (4.8%) patients had ATEs, all non-myocardial, with an ATE rate/year of 1.6%. A cardiovascular and cerebrovascular risk factor analysis is ongoing.
Conclusions:
ATE rates were similar between RBZ and control arms from the pooled studies, and annualized ATE rates were consistent over time. These data suggest that intravitreal injections of RBZ 0.5 mg in DME patients are not associated with an increased risk of ATEs.