Cardiovascular and Cerebrovascular Adverse Events Associated with Intravitreal Anti-VEGF Monoclonal Antibodies

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 (IC₀₂₅) 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 (IC₀₂₅ 0.75; ROR: 1.78 [95% CI, 1.70–1.86]), angina pectoris (IC₀₂₅ 0.53; ROR: 1.61 [95% CI, 1.47–1.77]), arrhythmias including atrial fibrillation, atrial flutter, ventricular fibrillation, supraventricular tachycardia (all IC₀₂₅ > 0, ROR>1), hypertension (IC₀₂₅ 2.22; ROR: 4.91 [95% CI, 4.82–5.01]), and hypertensive crisis (IC₀₂₅ 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 (IC₀₂₅ 4.34; ROR: 23.19 [95% CI, 22.10–24.34]), carotid artery stenosis (IC₀₂₅ 1.85; ROR: 5.24 [95% CI, 3.98–6.89]), cerebral hemorrhage (IC₀₂₅ 2.29; ROR: 5.38 [95% CI, 5.03–5.76]), and subarachnoid hemorrhage (IC₀₂₅ 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.