Session Title: FP-15 Vascular Diseases and Diabetic Retinopathy V
Session Date/Time: Sunday 14/09/2014 | 08:00-10:00
Paper Time: 08:08
Venue: Boulevard D
First Author: : C.Bailey UK
Co Author(s): : V. Bezlyak A. Cole C. Thorburn P. Margaron R. Hashmonay P. Watson
Anti-VEGF use has increased in the treatment of diabetic macular edema (DME). Systemic anti-VEGF use in cancer patients is associated with an increased cardiovascular and cerebrovascular event risk. A theoretical increased risk of these events with intravitreal anti-VEGF use has not been substantiated in clinical studies involving ranibizumab, a Fab fragment with no Fc portion resulting in a very low systemic exposure. Although ranibizumab has a well-characterized safety profile in DME, cumulative, long-term, clinical-trial safety data are not well described. This is a review of arterial thromboembolic events (ATEs) from DME studies with up to 36 months’ ranibizumab exposure.
This is a retrospective, pooled safety analysis of ATEs from five long-term DME studies: RESOLVE, RESTORE, REVEAL, RESTORE-core+extension and RETAIN in which patients with visual impairment due to DME received intraocular ranibizumab.
The pooled ranibizumab safety data were analyzed for both ‘myocardial ATEs’ and ‘non-myocardial ATEs’. A broad search approach was used to capture all possible ATEs including but not limited to myocardial infarction (MI), CVAs and transient ischemic attack (TIA). The pooled data set included the 12-month controlled data from the RESOLVE, RESTORE and REVEAL (pro-re-nata [PRN] regimen) studies. In addition, the ATE search separately analyzed the 24-month periods for the RESTORE-core+extension and RETAIN (PRN and treat and extend [TE]) studies. The RESTORE 36-month core + extension study (PRN) was also separately analyzed using the same ATE search criteria. In these studies, patients were dosed with 0.5 mg ranibizumab, except in RESOLVE, which included 0.3 mg, 0.5 mg, 0.6 mg and 1.0 mg treatments.
For the pooled 12-month, controlled data set (RESOLVE, RESTORE and REVEAL, N=637), total ATEs (myocardial and non-myocardial) were similar for patients in the ranibizumab (n=350) and control (n=287) treatment arms. Six patients (1.7%) with myocardial ATEs and six patients with non-myocardial ATEs (1.7%) were reported from 350 ranibizumab recipients. For the sham/laser control arms, seven (2.4%) patients with myocardial ATEs and five (1.7%) patients with non-myocardial ATEs were reported from 287 control patients. The relative risks (ranibizumab/control) for all ATEs, myocardial and non-myocardial ATEs were 0.75, 0.70 and 0.98, respectively. For the 24-month RESTORE-core+extension and RETAIN PRN and TE populations, a total of 21 (6.4%) of 327 patients treated with ranibizumab 0.5 mg experienced an ATE, with four (1.2%) patients experiencing a myocardial ATE and 18 (5.5%) patients reporting non-myocardial ATEs. The percentage of patients with these events per year was 3.2% for all ATEs, 0.6% for myocardial ATE and 2.8% for non-myocardial ATEs, including stroke and TIA. For the 36-month RESTORE-core+extension (n=83), 4 (4.8%), 0 (0.0%), and 4 (4.8%) of patients were reported with all ATEs, myocardial ATEs and non-myocardial ATEs, respectively
Ranibizumab safety has been evaluated in multiple, well-designed, controlled clinical studies. These studies were designed with efficacy parameters as primary endpoints and were not powered to support formal, quantitative comparison between treatment arms for safety events that may be seen in an elderly, diabetic patient population. The number of patients with safety events of interest (myocardial and non-myocardial ATEs) is low across the treatment arms of the ranibizumab studies analyzed here, even in this high-risk patient population. Of the numerical differences in events noted above, no clear pattern suggestive of a causal relationship with ranibizumab was evident for cardiovascular or cerebrovascular events, such that these safety observations were similar for the different treatment groups. These results are numerically similar to the recently reported RIDE and RISE DME clinical studies. These observations provide further support that the limited suppression of systemic VEGF levels by ranibizumab, as a result of its minimal systemic exposure, is consistent with its favorable safety with respect to these events. This analysis suggests that the cumulative, long-term safety findings in patients with DME who are receiving ranibizumab appear consistent with the known positive benefit-risk profile of the drug, and currently does not suggest a systemic safety concern.