Safety Profile of Ranibizumab for Diabetic Macular Edema

Large randomized clinical trials have shown the efficacy and safety of intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents for treating diabetic macular edema (DME), among other ophthalmologic conditions.

Among these agents, ranibizumab (Lucentis/Roche) has the most comprehensive track record. In clinical studies across ophthalmologic indications, investigators have used ranibizumab to treat more than 55,000 patients. The estimated cumulative exposure to this anti-VEGF agent is 4.3 million patient treatment-years, and ranibizumab has been injected intravitreally more than 25 million times.

However, VEGF is a key regulator of angiogenesis, vascular permeability, and inflammation, and patients treated systemically for cancer with the anti-VEGF agent bevacizumab (Avastin/Roche) were found to have an increased risk of vascular events. Although intravitreal doses of anti-VEGF agents are lower than systemic doses, anti-VEGF agents quickly move from the eye into the systemic circulation, where they may persist for as long as 1 month. Moreover, although ranibizumab was designed to reduce systemic exposure, it may still exert systemic effects.

The risk associated with these effects is of particular concern in patients with DME, who are at high risk for macrovascular complications. For example, compared with patients with diabetes who do not have DME, DME patients have twice the risk of hospital admission for stroke and 2.5 times the risk of hospital admission for MI.

Most clinical trials are not powerful enough to evaluate macrovascular events that occur at a low frequency. However, pooling safety data from several trials increases the ability to identify macrovascular events that may be treatment-related.

To gain additional insight about the safety of intravitreal ranibizumab, an international team recently analyzed pooled safety results from key clinical trials of this agent for DME. The team was led by Marco Zarbin, MD, PhD, (pictured) of the Institute of Ophthalmology and Visual Science, New Jersey Medical School, Rutgers University, Newark, NJ.

The team analysed pooled data from six randomized, double-masked, phase 2 and 3 clinical trials of ranibizumab in DME patients. To be included in the analysis, trials had to be company-sponsored and include a control arm consisting of sham intravitreal injection with or without laser therapy and at least one treatment arm with or without laser therapy in which ranibizumab, 0.3 mg or 0.5 mg, was injected intravitreally monthly or as needed. Trials had to be completed by the end of 2013. RELATION, RESOLVE, RESTORE, REVEAL, RISE, and RIDE met these selection criteria.

Individual patient-level data from 1767 patients were included in the analysis, which was done from June 1 to July 15, 2015. The analysis included data for 936 patients injected with ranibizumab, 0.5 mg, 250 injected with ranibizumab, 0.3 mg, and 581 who received sham injection.

For each dose of ranibizumab vs. sham injection, the team made pairwise comparisons by using Cox proportional hazard regression and rates per 100 person-years. Safety endpoints included arterial thromboembolic events (ATE), MI, stroke or transient ischemic attack (TIA), vascular death, and major vascular events as defined by the Antiplatelet Trialists’ Collaboration (APTC).

Analysis revealed comparably low rates of cardiovascular and cerebrovascular events in all study arms. However, vascular death was approximately 2.5 times more common in those treated with the recommended dose of ranibizumab for DME, 0.3 mg, than in those who received sham injections.

For each category of event, rates per 100 person-years of exposure for ranibizumab, 0.3 mg, vs. for sham injection were as follows:

• ATE: 4.42 vs. 5.74
• MI: 2.62 vs. 2.87
• Stroke or TIA: 1.29 vs. 2.43
• Stroke excluding TIA: 0.64 vs. 1.09
• Vascular death: 1.07 vs. 0.43
• APTC-defined events: 3.72 vs. 3.78

Hazard ratios with their 95% confidence intervals for ranibizumab, 0.3 mg, vs. sham injection were as follows:

• ATE: 0.78 (0.43—1.40)
• MI: 0.94 (0.43—2.06)
• Stroke or TIA: 0.53 (0.19—1.42)
• Stroke excluding TIA: 0.59 (0.14—2.46)
• Vascular death: 2.51 (0.49—12.94)
• APTC-defined events: 1.00 (0.51—1.96)

The team acknowledged that the data set for their analysis was underpowered to detect small differences in infrequent events such as stroke. Nevertheless, they concluded that their findings suggest that intravitreous ranibizumab does not increase the risk of systemic vascular events in DME patients. However, they added, “it is uncertain whether this conclusion applies to patients at high risk for vascular disease who were not included in these trials.”

A report on the study, “Vascular safety of ranibizumab in patients with diabetic macular edema: a pooled analysis of patient-level data from randomized clinical trials,” was published online on April 6, 2017, in JAMA Ophthalmology.