Real-World Data Analysis of Vascular and Lymphatic Adverse Events Associated with Anti-Tumor Angiogenesis Drugs: A WHO-VigiAccess Study

Real-World Data Analysis of Vascular and Lymphatic Adverse Events Associated with Anti-Tumor Angiogenesis Drugs: A WHO-VigiAccess Study | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 11 February 2025 V1 Latest version Share on Real-World Data Analysis of Vascular and Lymphatic Adverse Events Associated with Anti-Tumor Angiogenesis Drugs: A WHO-VigiAccess Study Authors : Yue Zu 0009-0003-2511-7424 , Lingling Dai [email protected] , and Peng Meng Authors Info & Affiliations https://doi.org/10.22541/au.173927007.70765969/v1 274 views 125 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Pro-angiogenic factors play a crucial role in the treatment of malignant tumors, particularly in anti-angiogenic therapies. This study evaluated vascular and lymphatic adverse events (AEs) associated with four anti-tumor angiogenesis drugs in the WHO-VigiAccess database. It also compared the adverse drug reaction (ADR) profiles of these drugs to support personalized treatment decisions and optimize therapeutic benefits and safety. Real-World Data Analysis of Vascular and Lymphatic Adverse Events Associated with Anti-Tumor Angiogenesis Drugs: A WHO-VigiAccess Study Yue Zu 1 , Lingling Dai 2 , Peng Meng 2 Shandong University of Traditional Chinese Medicine Yantai Hospital of Traditional Chinese Medicine Corresponding author: Lingling Dai, [email protected] Fund program: Science and Technology Project, Department of Science and Technology, National Administration of Traditional Chinese Medicine (GDY-KJS-SD-2023-017); Chinese Medicine Science and Technology Project of Shandong Province (2020M132);2024 Binzhou Medical College ”Traditional Chinese Medicine discipline Integration Technology Plan” special project(2024ZYYKJ07) Abstract: Pro-angiogenic factors play a crucial role in the treatment of malignant tumors, particularly in anti-angiogenic therapies. This study evaluated vascular and lymphatic adverse events (AEs) associated with four anti-tumor angiogenesis drugs in the WHO-VigiAccess database. It also compared the adverse drug reaction (ADR) profiles of these drugs to support personalized treatment decisions and optimize therapeutic benefits and safety. Methods: This study was designed as a descriptive retrospective analysis. Adverse reactions of four commonly used drugs for the clinical treatment of malignant tumors were reviewed using reports from the WHO-VigiAccess database. Data collected included demographic characteristics (age group, gender, and region), annual AE reports, and system organ class (SOC) data and symptoms associated with the reported adverse events. The overall characteristics of the ADR reports were examined, and the distribution of the 27 SOC categories was analyzed. The most common vascular and lymphatic AEs associated with these drugs were subsequently compared. Finally, similarities and differences in vascular and lymphatic AEs among the drugs were assessed. Results: A total of 130,801 adverse events (AEs) associated with four anti-VEGF drugs were identified. The analysis revealed that 42.91% of the AEs occurred in females, 36.14% in males, and 20.96% in cases where the gender was unspecified. The age group of 45–64 years had the highest reporting frequency. Nearly half of the AE reports originated from the Americas (49.43%). The ten most common types of AEs were: general disorders and administration site conditions (41.10%), gastrointestinal disorders (30.04%), eye disorders (23.02%), injuries, poisoning, and procedural complications (17.31%), investigations (16.80%), nervous system disorders (16.04%), infections and infestations (12.83%), blood and lymphatic system disorders (12.32%), respiratory, thoracic, and mediastinal disorders (11.85%), and vascular and lymphatic disorders (10.60%). Compared to the other three inhibitors, bevacizumab had a significantly higher reporting rate for vascular and lymphatic disorders. The most common vascular and lymphatic AEs associated with these four anti-VEGF drugs were hypertension, hemorrhage, hypotension, and deep vein thrombosis. However, differences in AE profiles were observed among the drugs. Conclusion: The occurrence of vascular and lymphatic adverse events associated with the clinical use of anti-angiogenic drugs for the treatment of malignant tumors warrants significant clinical attention. Clinicians should carefully evaluate the specific manifestations of these adverse events to optimize the rational use of these costly medications and develop personalized treatment plans tailored to individual patient needs. Keywords: vascular endothelial growth factor, VEGF inhibitors, vascular and lymphatic disorders, adverse drug reactions, pharmacovigilance, spontaneous reporting, VigiAccess Introduction During embryonic development, mesodermal cells form the vascular system at early stages to facilitate gas exchange, nutrient delivery, and waste metabolism. This process involves two critical stages: vasculogenesis and angiogenesis (Naito, Iba, & Takakura, 2020). In normal adult physiology, angiogenesis is typically active only during processes such as wound healing, the menstrual cycle, and tissue repair. However, during the growth of malignant tumors, new blood vessels are formed around the tumor to supply oxygen and nutrients while removing metabolic waste (Jain, 2005). As early as 1971, the research team led by Judah Folkman at the U.S. National Academy of Sciences identified angiogenesis as a critical and rate-limiting factor for the growth and development of solid tumors larger than 1–2 mm³ (Folkman, 1971). Tumor progression is closely associated with the initiation of tumor angiogenesis. In the tumor microenvironment, pro-angiogenic factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and placental growth factor (PIGF) are primarily produced and secreted by tumor and stromal cells. Extensive vascularization contributes to tumor recurrence, progression, invasion, and metastasis. Among these factors, the signaling pathways mediated by VEGF, PDGF, and FGF, as well as their interactions, are the primary mechanisms regulating tumor angiogenesis (Apte, Chen, & Ferrara, 2019). With the conceptual shift towards targeting tumor vasculature to inhibit cancer cells, traditional tumor-centric therapies have evolved into strategies focusing on anti-tumor angiogenesis. Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis, acting on vascular endothelial cells. It performs multiple functions, including promoting endothelial cell proliferation and differentiation, inducing angiogenesis, and increasing microvascular permeability (Ferrara, Gerber, & LeCouter, 2003). Platelet-derived growth factor (PDGF), a pro-angiogenic factor originally isolated from platelets, plays a vital role in angiogenesis and cellular mitosis (Demoulin & Essaghir, 2014). Fibroblast growth factor (FGF), a member of the receptor tyrosine kinase superfamily, regulates cell proliferation, differentiation, and survival, contributing to physiological processes such as embryonic development, tissue repair, and metabolic regulation (Maddaluno, Urwyler, & Werner, 2017). Placental growth factor (PIGF) regulates angiogenesis during embryonic development and under pathological conditions, such as tumor growth and inflammation, by enhancing endothelial cell proliferation and migration (Albonici, Giganti, Modesti, Manzari, & Bei, 2019). Although pro-angiogenic factors induce vascular formation, their overexpression can lead to abnormal vascular proliferation in malignant tumors. This disrupts the vascular barrier function in diseased tissues, facilitating tumor cell growth, extravasation, and widespread metastasis (Weis & Cheresh, 2005). Anti-angiogenic drugs are primarily classified into three categories: monoclonal antibodies with a single target, small-molecule inhibitors with multiple targets, and broad-spectrum recombinant human endostatin. Currently, globally approved monoclonal antibody drugs for malignant tumor treatment include aflibercept, bevacizumab, olaratumab, and ramucirumab. Aflibercept was approved by the FDA in 2012 for the treatment of advanced colorectal cancer. It is a fusion protein that tightly binds to VEGF-A, VEGF-B, and PIGF, inhibiting their interaction and activation of endogenous receptors, thereby reducing neovascularization and vascular permeability. In addition to its indication for advanced colorectal cancer, aflibercept is also used for wet age-related macular degeneration, macular edema secondary to retinal vein occlusion, and diabetic macular edema. Bevacizumab was the first anti-tumor angiogenesis targeted therapy approved worldwide. It received FDA approval in 2004 for the treatment of metastatic colorectal cancer. Bevacizumab specifically binds to VEGF-A, preventing the activation of VEGFR-1 and VEGFR-2, thereby inhibiting cell proliferation and neovascularization. It is now widely used as a first-line therapy for various malignancies. Olaratumab received accelerated FDA approval in 2016 for the treatment of soft tissue sarcoma (STS) in adult patients. Olaratumab binds with high affinity to human PDGFR-α, blocking its interaction with the PDGF ligand and preventing excessive activation of the receptor and downstream signaling pathways, thus inhibiting tumor angiogenesis. Ramucirumab was approved by the FDA in 2014 for the treatment of advanced gastric or gastroesophageal junction adenocarcinoma, metastatic non-small cell lung cancer, hepatocellular carcinoma, and colorectal cancer. Ramucirumab is a fully human IgG1 monoclonal antibody targeting VEGFR-2. It inhibits ligand-stimulated VEGFR-2 activation, thereby blocking endothelial cell proliferation and migration. The primary components of monoclonal antibody drugs used in malignant tumor treatment are proteins, which are inherently unstable and require cold chain storage and intravenous infusion. Despite rigorous clinical trials conducted prior to market approval, the real-world safety of these drugs may not be fully identified due to variations in environmental and clinical conditions. Therefore, evaluating drug safety using large real-world datasets remains a critical area of research. Currently, collecting drug safety data through spontaneous reporting systems (SRS) is considered an authoritative and reliable method. The Uppsala Monitoring Centre (UMC), representing the World Health Organization (WHO), oversees the global Pharmacovigilance Program (PIDM) and collects adverse drug reaction (ADR) data worldwide. As of 2018, the UMC’s VigiBase system contained over 20 million ADR reports from more than 170 countries. Additionally, VigiAccess is a publicly accessible web application that allows users to query global ADR data in VigiBase. This study retrieved data on four anti-VEGF drugs approved by the U.S. Food and Drug Administration (FDA) for malignant tumor treatment: aflibercept, bevacizumab, olaratumab, and ramucirumab. To compare differences in vascular and lymphatic adverse events associated with these drugs, we conducted a descriptive analysis of spontaneously reported ADRs in VigiAccess and compared the reporting rates of vascular and lymphatic adverse events between the drugs. Notably, real-world studies on the ADRs of these anti-VEGF drugs are limited, particularly regarding the differences in vascular and lymphatic adverse events among the four drugs. The findings of this study aim to provide clinicians with a theoretical basis for comparing these drugs and tailoring personalized treatment plans for patients. Materials and Methods Structurally, aflibercept is a humanized fusion protein, while bevacizumab, olaratumab, and ramucirumab are monoclonal antibodies. Table 1 provides the basic information for these four anti-VEGF drugs. The mechanisms of action of these drugs also differ. Aflibercept simultaneously blocks VEGF-A, VEGF-B, and PIGF. Bevacizumab primarily binds to VEGF-A. Olaratumab inhibits PDGFR-α, while ramucirumab primarily targets VEGFR-2. Regarding therapeutic indications in malignant tumor treatment, aflibercept is primarily used for metastatic colorectal cancer (mCRC). Bevacizumab is indicated for mCRC, non-small cell lung cancer (NSCLC), glioblastoma (GBM), metastatic renal cell carcinoma (mRCC), and cervical cancer (CCA). Olaratumab is primarily used for the treatment of soft tissue sarcoma (STS). Ramucirumab is approved for gastric cancer (GC), NSCLC, mCRC, and hepatocellular carcinoma (HCC). Drug name and trade name Drug target Tumor main treatment indication Time of first sale Aflibercept-Zaltrap® VEGF-A,VEGF-B,PlGF mCRC 2011 Bevacizumab-Avastin® VEGF-A mCRC,NSCLC,GBM,mRCC,CCA 2004 Olaratumab-Lartruvo® PDGFR-α STS 2016 Ramucirumab-Cyramza® VEGFR-2 GC,NSCLC,mCRC,HCC 2014 Data Source All data were obtained from the WHO-VigiAccess website (https://www.vigiaccess.org). Adverse events (AEs) associated with each drug from 2000 to 2023 were retrieved using both generic and brand names. The WHO information system includes data on age groups, gender, reporting year, and major continents worldwide. Descriptive statistical analyses were performed using Excel 2021. WHO-VigiAccess is a free portal providing access to the PIDM database, allowing users to retrieve drug safety reports submitted to the UMC. The definitions of the reports are based on the Medical Dictionary for Regulatory Activities (MedDRA) System Organ Classes (SOC) and Preferred Terms (PTs). Accordingly, we retrieved records related to each anti-VEGF drug and classified individual adverse events using MedDRA’s SOC and PT standards to assess their toxicity profiles. MedDRA terminology is derived from multiple dictionaries, including the WHO Adverse Reaction Terminology (WHO-ART). In MedDRA, there are a total of 27 SOCs, and we analyzed those directly related to disease symptoms. Our analysis focused on PTs, with data sourced from aggregated reports available in the VigiBase database through WHO-VigiAccess. Disproportionality Analysis Based on disproportionality analysis, we employed two disproportionality reporting methods: the Reporting Odds Ratio (ROR) (Rothman, Lanes, & Sacks, 2004) and the Proportional Reporting Ratio (PRR) (Evans, Waller, & Davis, 2001). The principles for calculating ROR and PRR are based on measures of odds imbalance, a widely used method for signal detection in adverse event (AE) reporting (van Puijenbroek, Diemont, & van Grootheest, 2003). The ROR was calculated to measure the odds imbalance of reporting a specific AE for a given drug compared to other drugs. The ROR is given by the following formula: \begin{equation} \text{ROR}=\frac{a\times d}{b\times c}\nonumber \\ \end{equation} Where:a represents the number of reports for the specific drug and specific AE,b represents the number of reports for the specific drug and other AEs,𝑐 represents the number of reports for other drugs and the specific AE,𝑑 represents the number of reports for other drugs and other AEs. A minimum of five cases(a≥5)，for the specific drug-AE combination is required to ensure statistical robustness in ROR calculations. The PRR is another measure used to quantify the disproportionality in AE reporting and is calculated as follows: \begin{equation} \text{PRR}=\frac{a/(c+d)}{c/(a+b)}\nonumber \\ \end{equation} Similar to ROR, the PRR calculation requires at least five cases (a≥5) for the specific drug-AE combination to be considered valid. A signal is deemed disproportional and potentially indicative of a safety issue if the ROR value exceeds 2 (ROR>2)and the lower limit of the 95% confidence interval (CI) for the ROR is greater than 1 (95%CI>1). These criteria ensure that the observed disproportionality is not due to random variability. In our analysis, the application of ROR and PRR allowed us to systematically assess the disproportionality of ocular disease reports associated with anti-VEGF drugs. The results of this analysis contribute to strengthening pharmacovigilance efforts in drug safety monitoring. Statistical Analysis This study utilized a retrospective quantitative research design to evaluate the characteristics of adverse reaction (AR) victims associated with four specific drugs. A comprehensive descriptive analysis was conducted in Excel, where the adverse reaction reporting rate for each drug was calculated by dividing the total number of adverse reactions by the total number of adverse reaction reports. The most common adverse reactions for each drug were defined as the top 20 symptoms ranked by reporting rate. Additionally, the incidence rates of adverse reactions for each drug were computed and compared through an integrated analysis. Descriptive variables were presented as frequencies and percentages. Overall Characteristics of Adverse Reaction Reports for Four Anti-VEGF Drugs The earliest adverse reaction reports in the WHO-VigiAccess database for aflibercept, bevacizumab, olaratumab, and ramucirumab were recorded in 2008, 2000, 2010, and 2010, respectively. As of 2023, the WHO received a total of 130,801 adverse event (AE) reports for these drugs: 30,331 for aflibercept, 90,665 for bevacizumab, 571 for olaratumab, and 9,234 for ramucirumab. As shown in Table 2, of the 314,891 reports associated with the four anti-VEGF drugs, excluding 27,410 cases with unknown gender, females accounted for a higher number of adverse reactions (56,126 cases, 54.29%) than males (47,265 cases, 45.71%), with a female-to-male ratio of 1:1.19. Among reports with known age, the 45–64 age group exhibited the highest incidence of adverse reactions. Nearly half of the AE reports originated from the Americas (49.43%), followed by Europe (27.38%). Table 2 also lists the reporting years for each drug. Prior to 2010, the majority of AE reports were related to bevacizumab. In the past decade, adverse reactions for aflibercept and bevacizumab peaked in 2018 and 2017, respectively. As a relatively newer drug, olaratumab showed a notable increase in AE reports after 2016, with 2018 marking the year with the highest reports. For ramucirumab, AE reports surged significantly after 2015, reaching a peak in 2018. Before 2018, the rising incidence of AEs paralleled the widespread clinical application of these four drugs. In recent years, advancements in the study of adverse drug reactions (ADRs) have led to improved awareness and measures for drug safety in both academic and clinical settings. For instance, clinicians’ ability to recognize ADRs early has improved significantly, and individualized treatment regimens and dosage adjustments have become more precise. Concurrently, measures such as identifying drug incompatibilities, enhancing pharmacovigilance systems, and educating patients have effectively reduced the occurrence of ADRs. As a result, the incidence of AEs associated with these four drugs has shown a downward trend, indicating positive progress in the safety management of these drugs in clinical practice. However, ongoing vigilance is required to monitor emerging drugs and the safety of diverse patient populations to further mitigate the risks of adverse reactions. Aflibercept Bevacizumab Olaratumab Ramucirumab Number of ADR reports 30331 90665 571 9234 Female 8339(27.49%) 44732(49.34%) 244(42.73%) 2811(30.44%) Male 8078(26.63%) 33065(36.47%) 242(42.38%) 5880(63.68%) Gender ambiguity 13914(45.87%) 12868(14.19%) 85(14.89%) 543(5.88%) < 18 years old 26(0.09%) 770(0.85%) 8(1.40%) 6(0.06%) 18-44 years old 423(1.39%) 5667(6.25%) 57(9.98%) 510(5.52%) 45-64 years old 3376(11.13%) 26734(29.49%) 146(25.57%) 2700(29.24%) 65-74 years old 3621(11.94%) 17295(19.08%) 84(14.71%) 2165(23.45%) > 75 years old 5573(18.37%) 8507(9.38%) 35(6.13%) 940(10.18%) Age unknown 17312(57.08%) 31692(34.96%) 241(42.21%) 2193(23.75%) Africa 1174(3.87%) 778(0.86%) 0(0.00%) 72(0.78%) America 17354(57.22%) 45633(50.33%) 330(57.79%) 1338(14.49%) Asia 2537(8.36%) 16878(18.62%) 76(13.31%) 5713(61.87%) Europe 7194(23.72%) 26353(29.07%) 165(28.90%) 2103(22.77%) Oceania 2072(6.83%) 1023(1.13%) 0(0.00%) 8(0.09%) Before 2010 48(0.16%) 10129(11.17%) 1(0.18%) 8(0.09%) 2011 23(0.08%) 3064(3.38%) 3(0.53%) 11(0.12%) 2012 72(0.24%) 3753(4.14%) 1(0.18%) 31(0.34%) 2013 414(1.36%) 7360(8.12%) 0(0.00%) 25(0.27%) 2014 1492(4.92%) 6643(7.33%) 0(0.00%) 15(0.16%) 2015 1710(5.64%) 5839(6.44%) 0(0.00%) 390(4.22%) 2016 2160(7.12%) 5384(5.94%) 10(1.75%) 567(6.14%) 2017 2820(9.30%) 8635(9.52%) 109(19.09%) 978(10.59%) 2018 5787(19.08%) 7984(8.81%) 230(40.28%) 1490(16.14%) 2019 5231(17.25%) 5740(6.33%) 127(22.24%) 1358(14.71%) 2020 2373(7.82%) 3979(4.39%) 35(6.13%) 834(9.03%) 2021 3121(10.29%) 5491(6.06%) 40(7.01%) 1290(13.97%) 2022 1717(5.66%) 4669(5.15%) 7(1.23%) 657(7.12%) 2023 1506(4.97%) 6939(7.65%) 5(0.88%) 742(8.04%) soc distribution of four anti-VEGF drugs Table 3 presents the reporting rates of 27 System Organ Classes (SOCs) for four anti-angiogenesis drugs. Due to their longer duration of use, aflibercept and bevacizumab exhibit significantly higher incidence rates across various systems and organs compared to the other two newer anti-VEGF drugs.The ten most common types of adverse reactions were:General disorders and administration site reactions (53,753 cases, 17.07%),Gastrointestinal disorders (39,297 cases, 12.48%),Eye disorders (30,116 cases, 9.56%),Injury, poisoning, and procedural complications (22,638 cases, 7.19%),Investigations (21,971 cases, 6.98%),Nervous system disorders (20,977 cases, 6.66%),Infections and infestations (16,782 cases, 5.33%),Blood and lymphatic system disorders (16,119 cases, 5.12%),Respiratory, thoracic, and mediastinal disorders (15,505 cases, 4.92%),Vascular and lymphatic disorders (13,859 cases, 4.40%). Aflibercept showed a significantly higher number of adverse reactions related to eye disorders, while bevacizumab had more reports concerning vascular and lymphatic disorders. Olaratumab was associated with a higher frequency of reports related to injury, poisoning, and procedural complications, as well as blood and lymphatic system disorders. Ramucirumab demonstrated a higher incidence of gastrointestinal disorders and also reported a notable number of cases involving blood and lymphatic system disorders. Systematic organ classification Aflibercept（N=30331） Bevacizumab (N=90665) Olaratumab (N=571) Ramucirumab (N=9234) Systemic disease and various reactions at the administration site 20.25% 12137 16.48% 38964 0.00% 0 15.38% 2652 Gastrointestinal diseases 4.71% 2822 14.02% 33145 13.94% 185 18.24% 3145 Ocular organ disease 33.81% 20262 4.08% 9650 9.87% 131 0.42% 73 Various injuries, poisonings and operational complications 9.95% 5961 6.76% 15982 14.54% 193 2.91% 502 Various inspection 3.16% 1896 7.64% 18067 7.01% 93 11.10% 1915 All kinds of neurological diseases 4.97% 2976 7.10% 16785 4.67% 62 6.69% 1154 Infections and infectious diseases 6.19% 3711 5.16% 12206 1.88% 25 4.87% 840 Diseases of blood and lymphatic system 1.13% 675 5.56% 13144 12.43% 165 12.38% 2135 Respiratory, chest and mediastinal diseases 1.98% 1187 5.98% 14130 6.86% 91 0.56% 97 Vascular and lymphatic diseases 1.94% 1160 5.08% 12017 3.24% 43 3.71% 639 Diseases of the skin and subcutaneous tissue 1.26% 753 3.52% 8310 4.97% 66 4.74% 818 Benign, malignant and of unknown nature(including sacs and polyps) 0.75% 451 3.16% 7463 4.30% 57 5.35% 923 Metabolic and nutritional diseases 0.86% 516 3.13% 7393 1.81% 24 3.89% 671 Various musculoskeletal and connective tissue diseases 1.18% 707 2.98% 7040 2.03% 27 2.44% 421 Kidney and urinary diseases 1.10% 662 2.64% 6231 0.90% 12 2.57% 444 Heart organ disease 1.70% 1020 2.20% 5196 4.52% 60 1.37% 237 Psychosis 1.11% 668 1.36% 3223 0.98% 13 0.91% 157 Diseases of hepatobiliary system 0.22% 129 1.06% 2495 0.53% 7 1.06% 183 Various surgical and medical procedures 1.94% 1164 0.37% 874 0.08% 1 0.08% 14 Diseases of immune system 0.37% 223 0.48% 1144 4.14% 55 0.63% 109 Reproductive system and breast diseases 0.10% 58 0.36% 858 0.15% 2 0.19% 33 Ear and labyrinthine diseases 0.44% 266 0.22% 517 0.23% 3 0.17% 30 Product problem 0.39% 236 0.21% 505 0.00% 0 0.03% 6 Endocrine system diseases 0.04% 22 0.21% 502 0.75% 10 0.12% 20 Social environment 0.37% 221 0.12% 286 0.00% 0 0.09% 15 Various congenital familial hereditary diseases 0.04% 25 0.09% 208 0.15% 2 0.07% 12 Pregnancy, puerperal and perinatal conditions 0.03% 19 0.02% 57 0.00% 0 0.00% 0 Incongruity analysis based on vascular and lymphatic diseases By observing and comparing the SOC distribution of 4 antiangiogenic drugs, it was found that vascular and lymphatic diseases were common adverse reactions. To further compare these four drugs, we performed a disproportionation analysis based on vascular and lymphatic diseases. We use the methods of ROR and PRR. Table 4 shows that, through disproportionation analysis, we found that the ROR values of the four drugs were: Arbocept :0.37(0.36-0.40); Bevacizumab 2.26 (2.15-2.38); Olamumab: 0.73 (0.54-0.99); Ramumab :0.78(0.72-0.84). The PRR values of the four drugs were :0.39 (0.37-0.41); Bevacizumab :2.20 (2.09-2.30); Olamumab: 0.74 (0.55-0.99); Ramumab :0.79(0.73-0.85). The results showed that bevacizumab appears to be more likely to cause vascular and lymphatic diseases than other antiangiogenic agents. ROR (95% CI) PRR (95% CI) Aflibercept 0.37（0.36-0.40） 0.39（0.37-0.41） Bevacizumab 2.26（2.15-2.38） 2.20（2.09-2.30） Olaratumab 0.73（0.54-0.99） 0.74（0.55-0.99） Ramucirumab 0.78(0.72-0.84) 0.79(0.73-0.85) The most common vascular and lymphatic adverse reactions of the four anti-VEGF drugs Table 5 lists the most common vascular and lymphatic adverse reactions associated with the four drugs, expressed as Preferred Terms (PTs) within the System Organ Class (SOC). For aflibercept, common vascular and lymphatic adverse reactions included hypertension (1.94%), hemorrhage (0.20%), hypotension (0.18%), deep vein thrombosis (0.17%), and thrombosis (0.17%). For bevacizumab, the most frequently reported vascular and lymphatic adverse reactions were hypertension (5.60%), deep vein thrombosis (1.28%), hemorrhage (0.78%), hypotension (0.74%), and thrombosis (0.68%). For olaratumab, common vascular and lymphatic adverse reactions included hypotension (2.62%), flushing (1.93%), circulatory collapse (0.53%), hot flush (0.53%), and deep vein thrombosis (0.35%). For ramucirumab, the common vascular and lymphatic adverse reactions were hypertension (3.34%), hemorrhage (0.56%), hypotension (0.52%), deep vein thrombosis (0.38%), and flushing (0.23%). Compared to the other three inhibitors, bevacizumab showed a significantly higher incidence of vascular and lymphatic adverse reactions. Among the most common vascular and lymphatic adverse reactions reported for these four anti-angiogenesis drugs, the majority were related to hypertension. However, notable differences were observed: the incidence of hypotension and flushing was higher with olaratumab, while deep vein thrombosis and hemorrhage were more frequently reported with bevacizumab than with other drugs. Aflibercept (N=30331) Bevacizumab (N=90665) Olaratumab （N=571） Ramucirumab (N=9234) ADR Report rate (%) ADR Report rate (%) ADR Report rate (%) ADR Report rate (%) hypertension 1.94 587 Hypertension 5.6 5079 Hypotension 2.63 15 Hypertension 3.34 308 hemorrhage 0.2 61 Deep vein thrombosis 1.28 1164 Flushing 1.93 11 Hemorrhage 0.56 52 hypotension 0.18 54 Hemorrhage 0.78 705 Cyclic collapse 0.53 3 Hypotension 0.52 48 Deep vein thrombosis 0.17 52 Hypotension 0.74 675 Hot flash 0.53 3 Deep vein thrombosis 0.38 35 Thrombosis 0.17 52 Thrombosis 0.68 616 Deep vein thrombosis 0.35 2 Flushing 0.23 21 Hypertensive crisis 0.16 48 Embolism 0.47 426 Hemorrhage 0.35 2 Thrombosis 0.17 16 Embolism 0.06 19 Hypertensive crisis 0.27 241 Hypertension 0.35 2 Embolism 0.15 14 Cyclic collapse 0.05 15 Venous thrombosis 0.24 221 Arteriosclerosis 0.18 1 Hot flash 0.1 9 Arterial occlusive disease 0.04 13 Flushing 0.23 205 Cyanosis 0.18 1 Hemorrhagic shock 0.09 8 Flushing 0.04 12 Venous embolism 0.16 142 Hypovolemic shock 0.18 1 Venous embolism 0.08 7 Blood pressure fluctuation 0.03 9 Hot flash 0.13 115 Peripheral embolism 0.18 1 Hypertensive crisis 0.06 6 infarct 0.03 8 Venous thrombosis of the extremities 0.12 112 Shock 0.18 1 Thrombosis of the jugular vein 0.06 6 Angiopathy 0.02 7 Hematoma 0.11 101 - - - Pale 0.06 6 Poor blood pressure control 0.02 7 Arterial thrombosis 0.09 81 - - - Shock 0.06 6 Orthostatic hypotension 0.02 7 Thrombosis of the jugular vein 0.08 77 - - - Venous thrombosis 0.06 6 Giant cell arteritis 0.02 6 Aortic dissection 0.08 73 - - - Internal hemorrhage 0.05 5 Hematoma 0.02 6 lymphedema 0.08 73 - - - Aortic dissection 0.04 4 Hot flash 0.02 6 Vena cava thrombosis 0.07 66 - - - Cyclic collapse 0.04 4 Ischemia 0.02 6 Pale 0.07 65 - - - Orthostatic hypotension 0.04 4 Thrombophlebitis 0.02 6 Shock 0.07 63 - - - Venous thrombosis of the extremities 0.04 4 Common and different vascular and lymphatic side effects of four anti-VEGF drugs Table 6 shows a comparison of the top 20 vascular and lymphatic adverse reactions reported for each anti-angiogenesis drug within the SOC. Among the Preferred Terms (PTs), seven common adverse reactions were identified across all four drugs: hypertension, hemorrhage, hypotension, deep vein thrombosis, embolism, flushing, and hot flush. However, distinct PTs of adverse reactions were also identified for each drug (Table 6). For example:Aflibercept was associated with infarction, giant cell arteritis, and thrombophlebitis.Bevacizumab was linked to lymphedema.Olaratumab was associated with arteriosclerosis, cyanosis, and hypovolemic shock.Ramucirumab was linked to hemorrhagic shock. These findings highlight both shared and unique adverse reaction profiles among the four anti-angiogenesis drugs, emphasizing the importance of individualized monitoring and management in clinical applications. Aflibercept Bevacizumab Olaratumab Ramucirumab The same adverse events Hypertension, Bleeding, Hypotension, Deep vein thrombosis, Embolism, Flushing,Hot flashes Distinct adverse events Infarction, Giant cell Arteritis, Thrombophlebitis Lymphedema Arteriosclerosis, Cyanosis, Hypovolemic Shock Hemorrhagic shock Discussion Currently, the monitoring and acquisition of adverse event (AE) information primarily rely on spontaneous reporting systems (SRS). SRS is a system where healthcare professionals or patients voluntarily submit AE information to an adverse drug reaction (ADR) database. Although clinical drug trials adhere to strict protocols, the data from SRS databases better reflect the safety profiles of specific drugs in real-world settings compared to clinical trial data. SRS data typically include information on demographics, drug usage, AE descriptions, primary diseases, and report sources (Lindquist, Stahl, Bate, Edwards, & Meyboom, 2000). VigiBase, the global database for individual case safety reports (ICSRs) maintained by the World Health Organization (WHO), contains ICSRs submitted by medical centers worldwide since 1968 (Tantikul et al., 2008). VigiAccess, a user-friendly web application launched by WHO, allows public access to VigiBase to provide global drug safety information (Yamoah et al., 2022). This study aimed to evaluate the AEs associated with four commonly used anti-angiogenic drugs for the treatment of malignant tumors using the VigiAccess database. Results showed that the age group with the highest incidence of AEs related to these drugs was 45–64 years, followed by 65–74 years. The 45–64 age group corresponds to the peak incidence of several solid tumors, such as lung cancer, colorectal cancer, and breast cancer (Bray et al., 2018). Additionally, this age group represents a transitional phase of aging, during which cardiovascular, renal, and immune functions may decline. Such changes may increase susceptibility to AEs induced by anti-angiogenic drugs, including hypertension, bleeding, and proteinuria. Moreover, patients in this age group often exhibit higher treatment tolerance and may receive higher doses of anti-angiogenic drugs or combination chemotherapy, which elevates the risk of AEs. From an economic perspective, individuals aged 45–64 are typically economically active or approaching retirement, demonstrating higher engagement in treatment and potentially reporting AEs more actively, thereby increasing the representation of this age group in the dataset. Nearly half of the AE reports originated from the Americas (49.43%), followed by Europe (27.38%), primarily due to the concentration of clinical research and drug approvals in these regions, the better-developed drug monitoring systems, the widespread use of oncology treatments, and the complexity of patient conditions. Furthermore, cultural and legal factors can influence the recognition and reporting of AEs in different regions. The number of females experiencing AEs was higher than that of males. The higher incidence of AEs related to anti-angiogenic drugs in female patients can be attributed to multiple factors, including physiological and biological differences, cancer type distribution, sensitivity to side effects, and sociocultural factors. Although both males and females may experience side effects from anti-angiogenic drugs, these factors contribute to a relatively higher incidence and reporting rate of AEs in female patients. The primary indications for the four drugs include ophthalmologic and oncology-related conditions. Analysis of the distribution across 27 System Organ Classes (SOCs) revealed that vascular and lymphatic disorders are common adverse events (AEs), accounting for 12.32%. This is primarily due to the mechanism of action of these anti-angiogenic agents, which reduce blood flow and nutrient supply by inhibiting angiogenesis. These effects can lead to vascular wall fragility, increased vascular permeability, impaired lymphatic drainage, and ischemia, triggering various vascular and lymphatic disorders. Among SOCs reporting an adverse drug reaction (ADR) incidence greater than 10%, there were 2 cases associated with aflibercept, 2 with bevacizumab, 3 with olaratumab, and 4 with ramucirumab. Comparative analysis of these drugs showed that aflibercept had a higher incidence of ocular organ-related ADRs but a lower incidence of gastrointestinal (GI) system ADRs. Olaratumab demonstrated a higher incidence of injury, poisoning, and procedural complications compared to the other three drugs, with no reports of systemic disorders or injection-site reactions. Ramucirumab had the highest incidence of GI-related ADRs but the lowest incidence of ocular organ-related ADRs among the four drugs. The higher incidence of ocular organ-related ADRs with aflibercept compared to the other three drugs may be attributed to differences in drug targets and mechanisms of action. Aflibercept not only inhibits VEGF-A but also VEGF-B and placental growth factor (PlGF). This broad-spectrum activity could result in more significant inhibition of angiogenesis, thereby increasing the risk of intraocular inflammation and retinal tissue damage (Ma et al., 2022). The molecular design and high affinity of aflibercept may also lead to prolonged retention in retinal and choroidal layers, potentially heightening tissue responses and the likelihood of adverse events (Schnichels et al., 2013). Moreover, studies have found that aflibercept can cause intraocular inflammation and elevated intraocular pressure in some patients, potentially related to its potent effects on vascular structures. By contrast, other drugs like bevacizumab might exhibit more localized actions (Ma et al., 2022). Olaratumab was associated with a higher incidence of injury, poisoning, and procedural complications. This could be related to its targeting of platelet-derived growth factor receptor-α (PDGFR-α), affecting angiogenesis and the microenvironment of surrounding tissues. This mechanism may increase the risk of tissue injury in specific patients, such as those with fragile tumor-associated vasculature or delayed healing (Chiorean et al., 2014). Furthermore, olaratumab is often used in combination with chemotherapeutic agents like doxorubicin or other highly toxic drugs, which could exacerbate drug-related adverse effects, including hematological toxicity, tissue damage, and procedural complications (Tap et al., 2016). Ramucirumab exhibited a higher incidence of GI-related ADRs, potentially due to its inhibition of VEGFR-2, which blocks angiogenesis, particularly effective in gastrointestinal tumors. However, this mechanism might reduce GI blood flow, increasing the risk of ischemia and tissue damage, such as GI perforation or ulceration (Fuchs et al., 2014). Studies have reported that ramucirumab may delay mucosal healing in the GI tract, increasing the risk of perforation or ulcer formation. This effect is linked to impaired tissue repair caused by angiogenesis inhibition (Orimoto et al., 2020). Additionally, ramucirumab has been associated with an increased risk of GI bleeding during treatment. While the incidence of severe bleeding remains low, it may exert additional pressure on fragile tumor-associated vasculature or ulcerated regions (Arnold et al., 2017). Through an analysis of data from the VigiAccess database, we identified common vascular and lymphatic adverse reactions (AEs) associated with aflibercept, including hypertension, hemorrhage, hypotension, deep vein thrombosis (DVT), and thrombosis. Bevacizumab was associated with similar AEs, including hypertension, DVT, hemorrhage, hypotension, and thrombosis. For olaratumab, the vascular and lymphatic AEs included hypotension, flushing, circulatory collapse, hot flashes, and DVT. Ramucirumab was associated with hypertension, hemorrhage, hypotension, DVT, and flushing. Our analysis revealed that the common vascular and lymphatic AEs across these four anti-angiogenic drugs typically involved hypertension, hemorrhage, hypotension, DVT, embolism, flushing, and hot flashes. Notably, aflibercept had additional AE reports of infarction, giant cell arteritis, and thrombotic phlebitis compared to the other three drugs. Bevacizumab was uniquely associated with reports of lymphedema. Olaratumab was linked to reports of arteriosclerosis, cyanosis, and hypovolemic shock. Ramucirumab, on the other hand, had AE reports of hemorrhagic shock. Aflibercept, bevacizumab, and ramucirumab are classified as anti-VEGF agents. The mechanism by which anti-VEGF drugs induce hypertension is related to vascular constriction and vascular wall thickening, which increase peripheral vascular resistance, ultimately leading to hypertension (Yin & Zhao, 2022). Given that most anti-angiogenic therapy regimens include drug-free intervals, rebound hypotension may occur during these periods (de Jesus-Gonzalez, Robinson, Moslehi, & Humphreys, 2012). Anti-VEGF therapy can cause endothelial cell damage, increasing vascular fragility and the risk of hemorrhage. By inhibiting VEGF and reducing neovascular formation, these drugs may lead to vascular rupture and bleeding (Kamba & McDonald, 2007). Anti-VEGF agents may also increase the risk of deep vein thrombosis (DVT) and embolism by impairing angiogenesis and coagulation-inhibitory pathways, such as the tissue factor pathway inhibitor. The molecular mechanisms of thrombosis include platelet aggregation and activation of tissue factor (Sugimoto et al., 2019). VEGF inhibitors affect vascular relaxation, alter endothelial cell function, and cause autonomic dysfunction. They may also trigger inflammatory responses, increasing endothelial permeability, which can lead to symptoms such as flushing and hot flashes (Cooney et al., 2006; Crowley et al., 2024). Olaratumab, a PDGFR-α inhibitor, has a higher incidence of hypotension-related adverse events compared to the other three drugs. The antitumor activity of olaratumab is mediated by inhibiting the PDGFR-α signaling pathway, which also plays a critical role in vascular homeostasis. PDGFR-α blockade may result in dysfunction of vascular smooth muscle cells, causing vasodilation and blood pressure reduction (Van Tine et al., 2019). During olaratumab therapy, changes in vascular tone regulation can lead to symptoms such as orthostatic hypotension or autonomic dysfunction (Wagner et al., 2017). Clinical trials have reported that olaratumab can induce severe hypotension, particularly during or shortly after infusion. This hypotensive effect is likely related to the direct impact of the drug on PDGFR-α signaling, resulting in decreased vascular tone and abnormal blood flow distribution (Penniman, Parmar, & Patel, 2018). The adverse reaction of infarction associated with aflibercept may be related to its mechanism of action. Aflibercept blocks angiogenesis by inhibiting VEGF-A, VEGF-B, and PlGF; however, this potent anti-angiogenic effect may negatively impact endothelial function, increasing the risk of thrombosis and vascular occlusion. Studies have suggested that this mechanism may be linked to an elevated risk of infarction (Trichonas & Kaiser, 2013). Aflibercept treatment has been significantly associated with a risk of hypertension, which is thought to result from impaired endothelium-dependent relaxation and reduced nitric oxide (NO) production. These changes may further contribute to increased risks of vascular sclerosis and thrombosis, potentially leading to infarction events (Dong et al., 2021). Inhibition of VEGF reduces NO production, which, in addition to increasing the likelihood of thrombotic and infarction events, impairs endothelial function and upregulates pro-inflammatory factor expression. This pro-inflammatory environment may elevate the risk of giant cell arteritis and thrombotic phlebitis associated with aflibercept use. The occurrence of thrombotic phlebitis following aflibercept administration may be related to the inhibition of VEGF-A and VEGF-B, which reduces angiogenesis and affects endothelial cell function. VEGF inhibition may lead to endothelial damage and dysfunction, increasing platelet aggregation and the risk of thrombosis, which is considered a key mechanism in the development of thrombotic phlebitis (Jin et al., 2010). Bevacizumab-induced lymphedema is associated with its VEGF inhibition mechanism. VEGF not only plays a critical role in promoting angiogenesis but also significantly affects lymphatic vessel growth and function. By inhibiting VEGF, bevacizumab may impair lymphatic vessel function, leading to lymphedema. In some patients, bevacizumab has been shown to significantly reduce interstitial fluid pressure in the affected limbs. This change in fluid pressure could indirectly impact lymphatic function and fluid accumulation, further contributing to lymphedema (Miller et al., 2009). Additionally, bevacizumab promotes the normalization of tumor vasculature, reducing vascular permeability and lymphatic obstruction in tumor regions. While this effect improves tumor treatment, it may negatively impact lymphatic fluid flow, potentially resulting in lymphedema (Arjaans et al., 2013). Research on arterial sclerosis induced by olaratumab is limited, but theoretical mechanisms related to its target may explain its potential effects. Abnormal expression of PDGF and its receptor, particularly PDGFR-α, is closely associated with the pathogenesis of arterial sclerosis. PDGF is a critical regulator of vascular smooth muscle cell migration and proliferation, playing a role in multiple pathological processes of arterial sclerosis (Mantur & Koper, 2008). Cyanosis, reported as an adverse event of olaratumab, may be related to underlying cardiopulmonary or hematologic comorbidities in patients. The VigiAccess database also includes a case of hypovolemic shock following olaratumab use; however, there are no existing literature reports linking olaratumab directly to hypovolemic shock. Ramucirumab has been reported to cause hemorrhagic shock. As a recombinant monoclonal antibody that inhibits VEGFR-2, increasing evidence suggests that ramucirumab is associated with an elevated risk of bleeding and gastrointestinal perforation. These risks can be severe and, in some cases, fatal (Haider, Siddiqa, Mehmood, & Adrish, 2021). Studies indicate that the incidence of gastrointestinal perforation of all grades during ramucirumab treatment is 1.5%, with a mortality rate of 29.8% (Sashegyi, Zhang, Lin, Binder, & Ferry, 2017). Such high-grade bleeding events may lead to the occurrence of hemorrhagic shock. Although the WHO-VigiAccess database provides a comprehensive repository of adverse drug reaction (ADR) data, facilitating researchers in understanding and analyzing drug-related adverse events, its limitations must not be overlooked. Researchers utilizing this database should remain cognizant of reporting biases, issues related to data quality and accuracy, and non-randomized reporting patterns to avoid drawing inaccurate or incomplete conclusions. Incorporating data from clinical trials, observational studies, and other sources alongside database analysis can offer more robust support for drug safety studies. In this study, we collected historical ADR counts and Preferred Terms (PTs), comparing the ADR reporting rates of four anti-angiogenic drugs while attempting to minimize the influence of drug market availability. However, the findings are limited to relative outcomes for these four anti-angiogenic drugs and require further clinical studies for higher-level evidence. Conclusion Anti-angiogenic biologics are a cornerstone in the treatment of cancer. Our study revealed over 130,000 ADRs reported in the WHO-VigiAccess database associated with the four anti-angiogenic drugs studied, with vascular and lymphatic disorders being among the most frequently reported ADRs. Among the four inhibitors, bevacizumab exhibited a significantly higher ADR reporting rate for vascular and lymphatic disorders. While most vascular and lymphatic ADRs were mild and self-limiting, severe ADRs such as embolism, hypertensive crises, and shock were also observed. Countries worldwide should actively pursue comprehensive safety studies for biologics, particularly high-risk drugs like anti-angiogenic agents. These efforts should involve systematic monitoring methods, such as cohort event monitoring, case-control studies, and long-term follow-up. By establishing representative surveillance systems to collect and analyze ADRs experienced by diverse patient populations in real-world settings, researchers can identify causal relationships between drugs and adverse events. This will not only enhance the understanding of the safety profiles of high-risk biologics, including anti-angiogenic and immunotherapy drugs, but also provide robust scientific evidence for regulatory decision-making, ensuring the safety of medication use. Such research outcomes can further inform clinical practice by providing precise guidance for drug use. Biologics like anti-angiogenic drugs and immunosuppressants often elicit unique ADRs distinct from those of traditional chemical drugs due to their specific mechanisms of action. Through in-depth analysis of these ADR characteristics, clinicians can better identify patients at higher risk for certain adverse events. They can then tailor treatment plans based on individual patient factors, such as comorbidities, age, and immune status. Given the high costs of many biologics and the potential for ADRs to result in additional medical expenses and treatment risks, early identification of high-risk patients and targeted interventions can optimize drug utilization, improve therapeutic outcomes, and reduce healthcare costs. In conclusion, conducting extensive and in-depth safety studies on biologics, particularly through methodologies like cohort event monitoring, can enable regulatory agencies, clinicians, and patients worldwide to better understand the ADR profiles of these drugs. By leveraging this information to develop personalized diagnostic and therapeutic strategies, we can maximize the therapeutic benefits of biologics while ensuring patient safety, thereby advancing global drug safety management. Data Availability Statement The datasets generated and analyzed during the current study are available in the WHO-VigiAccess database, with the persistent web link: https://www.vigiaccess.org Declaration of Competing Interests The authors declare that they have no competing financial or personal interests that could influence the work described in this manuscript titled “Real-World Data Analysis of Vascular and Lymphatic Adverse Events Associated with Anti-Tumor Angiogenesis Drugs: A WHO-VigiAccess Study.” The research was supported by the following funding sources:Science and Technology Project, Department of Science and Technology, National Administration of Traditional Chinese Medicine (GDY-KJS-SD-2023-017);Chinese Medicine Science and Technology Project of Shandong Province (2020M132);Binzhou Medical College ”Traditional Chinese Medicine Discipline Integration Technology Plan” Special Project (2024ZYYKJ07) These funding bodies had no role in the design, data collection, analysis, interpretation, or writing of this manuscript. 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