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Vascular Safety of Ranibizumab in Patients With Diabetic Macular Edema: A Pooled Analysis of Patient-Level Data From
Marco A Zarbin1, Cornelia Dunger-Baldauf2, Zdenka Haskova3
1Institute of Ophthalmology and Visual Science, New Jersey Medical School, Rutgers University, Newark.
Importance:
Patients with diabetic macular edema (DME) are at high risk of vascular complications, including stroke and myocardial infarction (MI). Concerns have been raised that intravitreal dosing of vascular endothelial growth factor inhibitors in DME could be associated with an increase in cardiovascular and cerebrovascular adverse events.
Objective:
To evaluate the cardiovascular and cerebrovascular safety of ranibizumab, 0.5 mg and 0.3 mg, compared with sham with and without laser in DME.
Data Sources:
Patient-level data from 6 randomized, double-masked, sham- and laser-controlled clinical trials.
Study Selection:
Company-sponsored (Genentech or Novartis) studies in DME completed as of December 31, 2013.
Data Extraction And Synthesis:
Pairwise comparisons (ranibizumab, 0.5 mg, vs sham and laser; ranibizumab, 0.3 mg, vs sham) were performed using Cox proportional hazard regression (hazard ratios, 95% CIs) and rates per 100 person-years. Data analysis was conducted from June 1 to July 15, 2015.
Main Outcomes And Measures:
Standardized Medical Dictionary for Regulatory Activities queries and extended searches were prospectively defined to identify relevant safety end points, including arterial thromboembolic events, MI, stroke or transient ischemic attack, vascular deaths, and major vascular events as defined by the Antiplatelet Trialists' Collaboration (APTC).
Results:
Overall, 936 patients were treated with ranibizumab, 0.5 mg; 250 patients with ranibizumab, 0.3 mg; and 581 patients with sham/laser. The hazard ratios associated with all pairwise comparisons included 1 for all key cardiovascular and cerebrovascular safety end points. For ranibizumab, 0.5 mg, vs sham/laser and ranibizumab, 0.3 mg, vs sham, the hazard ratios were, respectively, arterial thromboembolic events, 1.05 (95% CI, 0.66-1.68) and 0.78 (95% CI, 0.43-1.40); MI, 0.84 (95% CI, 0.41-1.72) and 0.94 (95% CI, 0.43-2.06); stroke or transient ischemic attack, 0.94 (95% CI, 0.44-1.99) and 0.53 (95% CI, 0.19-1.42); stroke (excluding transient ischemic attack), 1.63 (95% CI, 0.65-4.07) and 0.59 (95% CI, 0.14-2.46); vascular death, 2.17 (95% CI, 0.57-8.29) and 2.51 (95% CI, 0.49-12.94); and APTC-defined events, 1.09 (95% CI, 0.63-1.88) and 1.00 (95% CI, 0.51-1.96).
Conclusions And Relevance:
This pooled analysis includes 1 of the largest patient-level data sets on treatment of DME with ranibizumab. Although still underpowered to detect small differences for infrequent events, such as stroke, the findings suggest that intravitreous ranibizumab does not increase the risk of systemic vascular events. However, uncertainty remains for patients with DME who are at high risk for vascular disease and were not included in these trials.
Insights
Intravitreal ranibizumab injections for diabetic macular edema (DME) show no increased risk of major vascular events like stroke or heart attack. This analysis of pooled clinical trial data supports its cardiovascular safety in DME patients.
Area of Science:
- Ophthalmology and Cardiovascular Safety
- Pharmacological Interventions for Retinal Diseases
Background:
- Diabetic macular edema (DME) patients face elevated risks for vascular complications, including stroke and myocardial infarction (MI).
- Concerns exist regarding potential cardiovascular and cerebrovascular adverse events associated with intravitreal vascular endothelial growth factor (VEGF) inhibitors used in DME treatment.
Purpose of the Study:
- To assess the cardiovascular and cerebrovascular safety profile of ranibizumab (0.5 mg and 0.3 mg) in patients with DME.
- To compare the safety outcomes of ranibizumab treatment against sham injections with and without laser therapy.
Main Methods:
- Pooled patient-level data from six randomized, double-masked, sham- and laser-controlled clinical trials involving DME patients.
- Analysis included pairwise comparisons of ranibizumab (0.5 mg and 0.3 mg) versus sham/laser using Cox proportional hazard regression.
- Safety endpoints prospectively identified using standardized queries, including arterial thromboembolic events, MI, stroke, vascular deaths, and Antiplatelet Trialists' Collaboration (APTC) defined events.
Main Results:
- A total of 936 patients received ranibizumab 0.5 mg, 250 received ranibizumab 0.3 mg, and 581 received sham/laser.
- Hazard ratios for all key cardiovascular and cerebrovascular safety endpoints were consistently below or included 1 across all pairwise comparisons.
- Specific hazard ratios for ranibizumab 0.5 mg vs. sham/laser and 0.3 mg vs. sham showed no significant increase in risks for arterial thromboembolic events, MI, stroke, or vascular death.
Conclusions:
- This large pooled analysis suggests that intravitreous ranibizumab treatment for DME does not elevate the risk of systemic vascular events.
- While the study is powered to detect significant differences, findings indicate a favorable safety profile regarding cardiovascular and cerebrovascular events.
- Further investigation may be needed for high-risk DME patients not included in these trials.
