BackgroundThe profiles of cardiovascular toxicity associated with angiogenesis inhibitors, including intravenous monoclonal antibodies (mAbs) and oral tyrosine kinase inhibitors (TKIs), targeting vascular endothelial growth factor (VEGF) remain poorly elucidated in real-world settings. This pharmacovigilance analysis aimed to comprehensively investigate the frequency, spectrum, timing, and outcomes of cardiovascular toxicities associated with angiogenesis inhibitors and to explore the differences in such patterns between mAbs and TKIs.MethodsDisproportionality analysis was performed by leveraging reports from the FDA Adverse Event Reporting System (FAERS) database from 2014 to 2021. Cardiovascular adverse events (AEs) were grouped into nine narrow categories using the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs). Reporting odds ratio (ROR) and information components (ICs) were calculated with statistical shrinkage transformation formulas and a lower limit of 95% confidence interval (CI) for ROR (ROR025) > 1 or IC (IC025) > 0, with at least three reports being considered statistically significant.ResultsA total of 757,577 reports of angiogenesis inhibitors and 70,668 (9.3%) reports of cardiovascular AEs were extracted. Significant disproportionality was detected in angiogenesis inhibitors for cardiovascular AEs (IC025/ROR025 = 0.35/1.27). Bevacizumab (31.8%), a mAb, presented the largest number of reports, followed by sunitinib (12.4%), a TKI. Hypertension (SMQ) was detected with the strongest signal value (IC025/ROR025 = 1.73/3.33), followed by embolic and thrombotic events (SMQ) (IC025/ROR025 = 0.32/1.26). Hypertension showed the shortest time to onset with a median (interquartile range) value of 23 (8, 69) days, while embolic and thrombotic events had the longest value of 51 (16, 153) days. Notably, hypertension presented the lowest proportions of death and life-threatening events (10.9%), whereas embolic and thrombotic events posed the highest (29.3%). Furthermore, both mAbs (IC025/ROR025 = 0.47/1.39) and TKIs (IC025/ROR025 = 0.30/1.23) showed increased cardiovascular AEs. Hypertension was detected in both agents (IC025/ROR025 = 1.53/2.90 for mAbs and IC025/ROR025 = 1.83/3.56 for TKIs) with a shorter time to onset of 17 (6, 48) days for TKIs than mAbs of 42 (14, 131) days. By contrast, embolic and thrombotic events were detected for mAbs (IC025/ROR025 = 0.90/1.87) without TKI (IC025/ROR025 = −0.08/0.95).ConclusionAngiogenesis inhibitors were associated with increased cardiovascular toxicity with a discrepancy between intravenous mAbs and oral TKIs, deserving distinct monitoring and appropriate management.
Objective The haematopoietic cytopenia (HC) of the cyclin-dependent kinase (CDK)4/6 inhibitors was evaluated using the Food and Drug Administration Adverse Event Reporting System (FAERS). Method Data from 1 January 2015 to 31 December 2021 has been retrieved from the FAERS database. Disproportionality analysis and Bayesian analysis were utilized in the data mining. The reporting odds ratio (ROR) with 95% confidence interval (CI) for HC was calculated for each CDK 4/6 inhibitor agent. Clinical features of the patients were collected and compared between death outcome and non-death outcome groups. Time to onset (TTO), proportion of deaths, life-threatening and hospitalizations of CDK 4/6 inhibitors-associated HC were also studied. Results A total of 17,235 cases of HC associated with CDK 4/6 inhibitors were identified with a median age of 65 years (interquartile range [IQR] 57–73). Palbociclib appeared the strongest signal, with the highest (ROR 9.64, 95% CI 9.46–9.83), followed by ribociclib (ROR 6.38, 95% CI 6.04–6.73) and then abemaciclib (ROR 2.72, 95% CI 2.49–2.97). Patients aged 18–64 had a higher proportion of deaths than those aged 65–84 (12.21% vs. 9.91%, p = 0.001). In Africa and Asia, the proportions of deaths were higher (31.65% and 26.13%, respectively). The median TTO was 26 days (IQR 14–65) for abemaciclib, 33 days (IQR 15–134) for palbociclib and 23 days (IQR 14–69) for ribociclib, respectively. The highest proportion of deaths, life-threatening and hospitalizations all occurred in abemaciclib (13.00%, 5.42% and 44.04%, respectively). Conclusions Greater proportions of deaths occurred in Africa and Asia. HC may occur early in any CDK 4/6 inhibitor regimen. Abemaciclib had the highest proportion of deaths, life-threatening and hospitalizations. Health care workers should be more concerned about CDK 4/6 inhibitors. The higher proportions of serious events, including deaths, from Africa and Asia, as well as for abemaciclib, deserve further investigations through additional pharmacoepidemiological approaches.
BackgroundImmune checkpoint inhibitors (ICIs) combined with angiogenesis inhibitors (AGIs) have become increasingly available for multiple types of cancers, although the cardiovascular safety profiles of this combination therapy in real-world settings have not been elucidated to date. Therefore, we aimed to comprehensively investigate the cardiovascular toxicity profiles of ICIs combined with AGIs in comparison with ICIs alone.MethodsThe Food and Drug Administration Adverse Event Reporting System (FAERS) database from the 1st quarter of 2014 to the 1st quarter of 2022 was retrospectively queried to extract reports of cardiovascular adverse events (AEs) associated with ICIs alone, AGIs alone and combination therapy. To perform disproportionality analysis, the reporting odds ratios (RORs) and information components (ICs) were calculated with statistical shrinkage transformation formulas and a lower limit of the 95% confidence interval (CI) for ROR (ROR025) > 1 or IC (IC025) > 0 with at least 3 reports was considered statistically significant.ResultsA total of 18 854 cardiovascular AE cases/26 059 reports for ICIs alone, 47 168 cases/67 595 reports for AGIs alone, and 3 978 cases/5 263 reports for combination therapy were extracted. Compared to the entire database of patients without AGIs or ICIs, cardiovascular AEs were overreported in patients with combination therapy (IC025/ROR025 = 0.559/1.478), showing stronger signal strength than those taking ICIs alone (IC025/ROR025 = 0.118/1.086) or AGIs alone (IC025/ROR025 = 0.323/1.252). Importantly, compared with ICIs alone, combination therapy showed a decrease in signal strength for noninfectious myocarditis/pericarditis (IC025/ROR025 = 1.142/2.216 vs. IC025/ROR025 = 0.673/1.614), while an increase in signal value for embolic and thrombotic events (IC025/ROR025 = 0.147/1.111 vs. IC025/ROR025 = 0.591/1.519). For outcomes of cardiovascular AEs, the frequency of death and life-threatening AEs was lower for combination therapy than ICIs alone in noninfectious myocarditis/pericarditis (37.7% vs. 49.2%) as well as in embolic and thrombotic events (29.9% vs. 39.6%). Analysis among indications of cancer showed similar findings.ConclusionOverall, ICIs combined with AGIs showed a greater risk of cardiovascular AEs than ICIs alone, mainly due to an increase in embolic and thrombotic events while a decrease in noninfectious myocarditis/pericarditis. In addition, compared with ICIs alone, combination therapy presented a lower frequency of death and life-threatening in noninfectious myocarditis/pericarditis and embolic and thrombotic events.
BackgroundImmune checkpoint inhibitors (ICIs), the treatment of multiple cancer types, can be associated with respiratory system adverse events (AEs). The aim of this study is to quantify the association of respiratory system AEs and ICIs and to characterize the profiles of ICI-related respiratory system complications from Food and Drug Administration Adverse Event Reporting System (FAERS) data.MethodsThe disproportionality of respiratory system AE-related ICIs based on FAERS data from January 2014 to September 2021 was analyzed using the reporting odds ratio (ROR) and information component (IC) as measures of potential risk increase.ResultsA total of 38,415,849 records were involved; among these, 36,923 records related to respiratory system AEs after ICI treatment were identified. In the first 3 months, the cumulative proportion of respiratory system AEs was 75.40%. Men had a slightly higher reporting frequency than that of women (ROR = 1.74, 95% CI: 1.70–1.78). Death cases had a slightly higher reporting frequency in ICI-associated respiratory system AEs than that of other drug-associated respiratory system AEs (ROR = 1.40, 95% CI: 1.38–1.41). Anti-programmed cell death 1 (PD-1) drugs and anti-programmed cell death ligand 1 (PD-L1) drugs were significantly associated with respiratory system toxicities. However, anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) drugs did not demonstrate an association with respiratory system toxicities. Interstitial lung disease and pneumonitis were found to be significantly associated with all eight types of ICIs. In addition, 7 in 10 class-specific respiratory system AEs (lower respiratory tract disorders, pleural disorders, pulmonary vascular disorders, respiratory disorders not elsewhere classified (NEC), respiratory tract infections, respiratory tract neoplasms, and thoracic disorders) were associated with ICIs. The signal values of IC025 were from 0.08 to 2.66.ConclusionsOverall, this study showed a high reporting frequency of respiratory system toxicities caused by ICIs. Early recognition and management of ICI-related respiratory system AEs are of vital importance in practice. Maximizing the benefit while reducing potential respiratory system toxicities of ICIs should become a priority.
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