Anti-VEGF Treatment Reduces Mortality Risk in Older Adults with nAMD

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Long-term anti-VEGF treatment for nAMD was linked to a reduction in mortality risk, with a slight increase in CVD risk, across 16-years of follow-up in Denmark.

A new nationwide study revealed a decreased risk of all-cause mortality and a modest increased risk of cardiovascular disease (CVD) among patients with neovascular age-related macular degeneration (nAMD) treated with vascular endothelial growth factor (VEGF) inhibitors.1

Across 16 years of follow-up data, these findings from the register-based cohort study in Denmark provided support for the safety of VEGF inhibitor therapy for mortality and CVD risk among patients with nAMD aged 65 years or older.

“Our findings provide strong evidence for the high safety profile of intravitreal VEGF inhibitors in patients with nAMD, which has not been previously confirmed in a large-scale nationwide population-based study,” wrote the investigative team led by Benjamin Sommer Thinggaard, MD, department of clinical research, University of Southern Denmark.

VEGF inhibitors have transformed the therapeutic landscape for nAMD and other retinal disorders, with strong efficacy as a first-line therapy since approvals in the early 2000s.2 However, the impact of systemic VEGF suppression on adverse events remains in doubt, making it crucial to consider its potential risk-benefit profile.

In this analysis, Thinggaard and colleagues investigated whether treatment with anti-VEGF agents was associated with an increased mortality risk or composite CVD in nAMD.1 The team also explored the impact of treatment doses and time-dependent relationship on the identified association. The analysis used data from the Danish National Patient Registry, with the study population residing in Denmark between January 2007 and December 2022.

Within the registry, investigators identified 37,733 individuals with nAMD and 1,897,073 individuals without nAMD aged ≥65 years. Of the study population, 63.7% were women and had an average age of 66.9 years. The average duration of follow-up was 4.8 years in the analysis of all-cause mortality and 4.5 years of CVD risk for patients with nAMD.

Upon analysis, the fully adjusted model revealed those exposed to VEGF inhibitors exhibited a reduced risk of all-cause mortality than individuals without nAMD (hazard ratio [HR], 0.79; 95% CI, 0.78 - 0.81) and an increased risk of composite CVD (HR, 1.04; 95% CI, 1.01 - 1.07). After stratification by age group and sex, investigators identified a significant decrease in all-cause mortality.

After excluding participants in both cohorts due to incident CVD before study entry, investigators observed an increased composite CVD risk in people with nAMD (HR, 1.04; 95% CI, 1.01 - 1.07). The team found no association between anti-VEGF treatment exposure and CVD in any age group, except men and women aged 65 to 70 years in the fully adjusted model.

A secondary analysis centered around only patients with nAMD and restricted the time counting as exposure to a VEGF inhibitor from the day of treatment to 60 days after the injection. In this analysis, investigators observed a low HR for all-cause mortality (HR, 0.26; 95% CI, 0.25 - 0.27) and composite CVD (HR, 0.82; 95% CI, 0.78 - 0.86).

When patients with nAMD were categorized based on number of doses, the HR for all-cause mortality was lower among those receiving >20 injections (HR, 0.89; 95% CI, 0.84 - 0.94), >40 injections (HR, 0.84; 95% CI, 0.78 - 0.91), and >70 injections (HR, 0.78; 95% CI, 0.67 - 0.91). However, there were no statistically significant association with composite CVD risk in any category.

As the decreased risk of all-cause mortality had not been reported in prior literature, Thinggaard and colleagues noted they do not anticipate the medication to have a protective effect on mortality or CVD development. Noting the outcome’s implausibility, they hypothesized the potential presence of confounding by indication, despite adjusting for comorbidities.

“This speculation arises from the possibility that patients selected for VEGF inhibitor treatment may exhibit lower frailty and less severe comorbidities, factors that may not be adequately captured in registry-based data,” investigators wrote.


  1. Thinggaard BS, Frederiksen K, Subhi Y, et al. VEGF Inhibition Associates With Decreased Risk of Mortality in Patients With Neovascular Age-related Macular Degeneration. Ophthalmol Sci. 2023;4(3):100446. Published 2023 Dec 7. doi:10.1016/j.xops.2023.100446
  2. Finger RP, Daien V, Eldem BM, et al. Anti-vascular endothelial growth factor in neovascular age-related macular degeneration - a systematic review of the impact of anti-VEGF on patient outcomes and healthcare systems. BMC Ophthalmol. 2020;20(1):294. Published 2020 Jul 17. doi:10.1186/s12886-020-01554-2