Cardiovascular and Cerebrovascular Adverse Events Associated with Intravitreal Anti-VEGF Monoclonal Antibodies: A World Health Organization Pharmacovigilance Study.

Purpose: To analyze cardiovascular and cerebrovascular adverse drug reactions (ADRs) after intravitreal anti-VEGF (aflibercept, bevacizumab, brolucizumab, and ranibizumab) treatment.

Participants: VigiBase, a World Health Organization (WHO) global safety report database.

Design: Pharmacovigilance study.

Methods: The individual case safety reports (ICSRs) of cardiovascular and cerebrovascular ADRs after intravitreal anti-VEGF treatment were compared with those reported in the full database. From 2004 to 2023, there were 23 129 ADRs after intravitreal anti-VEGF therapy and 25 015 132 ADRs associated with any drug (full database).

Main Outcome Measures: The reporting odds ratio (ROR) and information components (ICs) were calculated, and the 95% lower credibility interval end point of the information component (IC) was used for disproportionate Bayesian reporting. Inter-drug comparisons were performed using the ratio of odds ratio (rOR).

Results: Compared with the full database, anti-VEGFs were associated with an increased reporting of myocardial infarction (IC 0.75; ROR: 1.78 [95% CI, 1.70-1.86]), angina pectoris (IC 0.53; ROR: 1.61 [95% CI, 1.47-1.77]), arrhythmias including atrial fibrillation, atrial flutter, ventricular fibrillation, supraventricular tachycardia (all IC > 0, ROR>1), hypertension (IC 2.22; ROR: 4.91 [95% CI, 4.82-5.01]), and hypertensive crisis (IC 1.97; ROR: 4.49 [95% CI, 4.07-4.97]). Moreover, anti-VEGFs were associated with a higher reporting of cerebrovascular ADRs such as cerebral infarction (IC 4.34; ROR: 23.19 [95% CI, 22.10-24.34]), carotid artery stenosis (IC 1.85; ROR: 5.24 [95% CI, 3.98-6.89]), cerebral hemorrhage (IC 2.29; ROR: 5.38 [95% CI, 5.03-5.76]), and subarachnoid hemorrhage (IC 1.98; ROR: 4.81 [95% CI, 4.14-5.6]). Inter-drug comparison indicated that compared with ranibizumab, patients receiving aflibercept showed overall under-reporting of cardiovascular and cerebrovascular ADRs such as myocardial infarction (rOR 0.55 [95% CI, 0.49-0.52]), atrial fibrillation (rOR 0.28 [95% CI, 0.23-0.35]), cerebrovascular accident (rOR, 0.15 [95% CI, 0.14-0.17]), and cerebral hemorrhage (rOR, 0.51 [95% CI, 0.40-0.65]).

Conclusions: In this pharmacovigilance case-noncase study, there was significantly increased reporting of cardiovascular and cerebrovascular ADRs after intravitreal anti-VEGF treatment. Although ranibizumab may exhibit superior systemic safety regarding its biological characteristics, it is crucial not to overlook the occurrence of cardiovascular and cerebrovascular ADRs considering its higher reporting rate than bevacizumab or aflibercept.

Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.