Assessment of long-term safety of pro-angiogenic growth approaches in cardiovascular disease: A systematic review

Background Pro-angiogenic growth factor approaches are in development for atherosclerotic cardiovascular disease, e.g. angina pectoris and peripheral artery disease, but there has not been a recent review of assessment of potential long-term theoretical risks of inducing angiogenesis, such as malignancy and retinal neovascularization. We systematically evaluated whether such approaches may confer long-term safety risks compared with placebo and age-matched population benchmarks. Methods We searched PubMed and Embase (1990-2025) for clinical studies of pro-angiogenic approaches (e.g., vascular endothelial growth factor [VEGF], fibroblast growth factor [FGF], hepatocyte growth factor [HGF]) in adults with coronary or peripheral artery disease reporting at least 2 years of follow-up. Eligible studies predefined safety outcomes (malignancy, retinal events, renal dysfunction, all-cause mortality) and included either a placebo arm or age-matched population reference. Study selection and data extraction followed PRISMA guidelines. Safety outcomes were summarized as incidence rates per 100 patient-years. Results Eleven clinical studies published between 2002 and 2024 were included, comprising 636 participants (n=441 pro-angiogenic therapy, n=195 placebo) with follow-up ranging from 2.0 to 12.0 years. Interventions targeted VEGF-A isoforms, VEGF-D, FGF, or HGF in patients with angina (7 studies) or peripheral artery disease (5 studies), all using local intravascular or intramyocardial administration. Mean malignancy incidence was similar for pro-angiogenic therapy and placebo (0.84 vs 0.72 per 100 patient-years) and was below the age-matched population rate (1.0 per 100 patient-years). Retinal events were rare, with incidences of 0.12 and 0.00 per 100 patient-years in treated and placebo groups, respectively, compared with 0.97 in the general population. Long-term renal dysfunction and all-cause mortality were comparable between treatment and placebo groups. Conclusion In patients with cardiovascular disease, locally administered pro-angiogenic growth factor approaches did not show excess long-term risk of malignancy, retinal complications, renal dysfunction, or all-cause mortality compared with placebo or general population benchmarks. Although limited by the small number and size of available studies, these data suggest a reassuring long-term safety profile of pro-angiogenic strategies in atherosclerotic cardiovascular disease.v1