NEWS & PERSPECTIVE
Intravitreal anti-VGFR drugs not associated with increase in major adverse cardiovascular events
Diabetic retinopathy and age-related macular degeneration (AMD) are the common causes of blindness among developed countries.1,2 These ocular diseases are caused by the overproduction of vascular endothelial growth factor (VEGF) due to hypoxia in regions of the ischemic retina or hyperglycemia.1,2 While anti-VEGF treatment is one treatment option to delay vision loss and typically administered by intravitreal injection, anti-VEGF drugs may increase the risk of cardiovascular disease including heart attacks and strokes.1,2 To evaluate the risk of anti-VEGF treatment, a recently published systemic review investigated the association between anti-VEGF drugs and the risk of developing major adverse cardiovascular events (MACEs) in patients with ocular diseases.3
Anti-VEGF drugs administered by intravitreal injection can block the action of VEGF-A isoforms, inhibit VEGF-driven neovascularization and have shown efficacy in preserving visual acuity in AMD, diabetic macular edema (DME) and retinal vein occlusion (RVO).2 However, as VEGF mediates angiogenesis and promotes vascular permeability, a detectable level of anti-VEGF in systemic circulation may increase the occurrence of systemic adverse events including serious cardiovascular adverse events among patients receiving anti-VEGF agents.2,4 These systemic adverse events could be serious for patients with diabetes or elderly patients who are already at increased risk for cardiovascular adverse events.2
To address the concerns of using anti-VEGF drugs, a systemic review with meta-analysis was performed to evaluate the relationship between systemic adverse events and intravitreal anti-VEGF drugs compared with non-anti-VEGF agents in adult patients with ocular diseases.3 The review indicated MACEs and total mortality as the main outcomes, while non-ocular hemorrhage, components of MACEs, other cardiovascular outcomes, serious systemic adverse events and all systemic adverse events are considered as secondary outcomes.3
Among the 74 randomized clinical trials selected from multiple sources, 32 trials (43%) involved 14,190 patients with AMD, 24 trials (32%) included 5,424 patients with diabetic retinopathy (DME or proliferative diabetic retinopathy), 17 trials (23%) involved 3,757 patients with RVO, and 1 trial (1%) included 122 patients with myopic choroidal neovascularization.3 Based on the meta-analysis, the use of anti-VEGF drugs did not increase MACEs (OR=1.16; 95% CI: 0.85-1.58) or total mortality (OR=1.27; 95% CI: 0.82-1.96) when compared with control agents.3 Although there was an increase in the risk of death in patients with diabetic retinopathy (OR=1.80; 95% CI: 1.03-3.16; p=0.04), no increase in mortality was observed in patients with AMD or RVO.3
Nevertheless, anti-VEGF drugs was not found to be fully safe.3 Besides the increased mortality risk in patients with diabetic retinopathy as listed above, an elevated risk of non-ocular hemorrhage (OR=1.46; 95% CI: 1.01-2.10) was also associated with the use of anti-VEGF agents, mainly in patients with AMD.3 These evidences suggested a safety concern among high-risk patients and a continued surveillance for systemic adverse events related to anti-VEGF drugs was recommended by the study investigators.3
In conclusion, this meta-analysis suggested that intravitreal anti-VEGF drugs were not associated with an increase in MACEs but an increase in mortality risk among patients with diabetic retinopathy and risk of non-ocular hemorrhage among those with AMD.3 Therefore, cardiologists and ophthalmologists should be aware of these safety signals and other related systemic adverse events, especially in patients at high risk.3 Regular investigations and updates in the systemic safety of these drugs were also recommended.