scholarly journals Cardiovascular Toxicity of Carfilzomib: The Real-World Evidence Based on the Adverse Event Reporting System Database of the FDA, the United States

2021 ◽  
Vol 8 ◽  
Author(s):  
Yinghong Zhai ◽  
Xiaofei Ye ◽  
Fangyuan Hu ◽  
Jinfang Xu ◽  
Xiaojing Guo ◽  
...  
Keyword(s):  
Cardiac Failure ◽  
Real World ◽  
Cardiovascular Events ◽  
Adverse Event Reporting System ◽  
Torsade De Pointes ◽  
Onset Time ◽  
The United States ◽  
Cardiovascular Complications ◽  
Adverse Event Reporting ◽  
Real World Evidence

Background: Carfilzomib, an effective proteasome inhibitor agent for the therapy of relapsed and refractory multiple myeloma, has been related to a significant number of cardiovascular events. However, patterns of cardiovascular complications associated with this agent remain poorly characterized in real-world settings.Objective: To gain further insight into the frequency, spectrum, clinical features, timing, and outcomes of carfilzomib-related cardiovascular toxicities.Methods: This disproportionality (case/non-case) study was conducted leveraging records from FAERS database from 2014 to 2019. Cardiovascular events were defined and broadly categorized eight entities using narrow version of the Standardized MedDRA Queries (SMQs). Reporting odds ratios (ROR) and information component (IC) were calculated to measure disproportionality. Additionally, statistical shrinkage was applied to reduce false-positive signals.Results: The final number of records involved was 28,479,963, with 3,370 records submitted for carfilzomib related cardiovascular events. Significant disproportionality association between carfilzomib administration and cardiovascular events was captured (IC025/ROR025 = 0.85/1.95) when exploring in the entire database. Upon further analysis, all eight broad categories of cardiovascular toxicities were disproportionately associated with carfilzomib with varying frequencies, time-to-onset, and severities. Cardiomyopathy-related complications (N = 1,301, 38.61%), embolic and thrombotic events (N = 821, 24.36%), and cardiac failure (N = 765, 22.70%) largely comprised the reported problems. Notably, the strongest signal was detected for cardiac failure (IC025/ROR025 = 1.33/2.59), followed by pulmonary hypertension (IC025/ROR025 = 1.19/2.34). Median onset time of cardiovascular events was 41days (Q1-Q3: 9-114 days), with the shortest median time being 16 days (Q1–Q3: 4–85 days) for ischemic heart disease, with the longest time being 68 days (Q1–Q3: 21–139 days) for embolic and thrombotic events. Torsade de pointes/QT prolongation was identified as a new complication (IC025/ROR025 = 0.33/1.29) and was particularly noteworthy for highest death proportion (44.11%).Conclusions: Treatment with carfilzomib can lead to severe and versatile cardiovascular events. Early and intensive monitoring is important, particularly in the first 3 months after carfilzomib initiation. Maximizing the benefit while reducing potential cardiovascular harms of carfilzomib should become a priority.

RS-ADR: A Reference Standard for Adverse Drug Reaction Signal Assessment by Integrating Real-World Evidence and Controlled Vocabularies (Preprint)

2021 ◽  
Author(s):  
Suehyun Lee ◽  
Jeong Hoon Lee ◽  
Grace Juyun Kim ◽  
Jong-Yeup Kim ◽  
Hyunah Shin ◽  
...  
Keyword(s):  
Adverse Drug Reaction ◽  
Drug Reaction ◽  
Real World ◽  
Adverse Event Reporting System ◽  
Hepatic Function ◽  
Adverse Event Reporting ◽  
Reference Standard ◽  
Real World Data ◽  
Controlled Vocabularies ◽  
Real World Evidence

BACKGROUND Pharmacovigilance using real-world data (RWD), such as multicenter electronic health records (EHRs), yields massively parallel adverse drug reaction (ADR) signals. However, proper validation of computationally detected ADR signals is not possible due to the lack of a reference standard for positive and negative associations. OBJECTIVE To develop a reference standard for ADR (RS-ADR) to streamline the systematic detection, assessment, and understanding of almost all drug-ADR associations suggested by RWD analyses. METHODS We integrated well-known reference sets for drug-ADR pairs, including Side Effect Resource (SIDER), Observational Medical Outcomes Partnership, and EU-ADR. We created a pharmacovigilance dictionary using controlled vocabularies and systematically annotated EHR data. Drug-ADR associations computed from MetaLAB and MetaNurse analyses of multicenter EHRs and extracted from the FDA Adverse Event Reporting System (FAERS) were integrated as ‘empirically determined’ positive and negative reference sets by means of cross-validation between institutions. RESULTS The RS-ADR consisted of 1,344 drugs, 4,485 ADRs, and 6,027,840 drug-ADR pairs with positive and negative consensus votes as pharmacovigilance reference sets. After curation of the initial version of RS-ADR, novel ADR signals such as ‘famotidine’-‘hepatic function abnormal’ were detected and reasonably validated by RS-ADR. While the validation of the entire reference standard is challenging, especially with this initial version, the reference standard will improve as more RWD participate in the consensus voting with advanced pharmacovigilance dictionaries and analytic algorithms. One can check if a drug-ADR pair has been reported by our web-based search interface for RS-ADRs available at https://bioemr2.snubi.org:19108/. CONCLUSIONS RS-ADRs enriched with the pharmacovigilance dictionary, ADR knowledge, and real-world evidence from EHRs may streamline the systematic detection, evaluation, and causality assessment of computationally detected ADR signals.

scholarly journals Age and Gender Disparities in Adverse Events Following COVID-19 Vaccination: Real-World Evidence Based on Big Data for Risk Management

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiaomo Xiong ◽  
Jing Yuan ◽  
Minghui Li ◽  
Bin Jiang ◽  
Z. Kevin Lu
Keyword(s):  
Adverse Events ◽  
Real World ◽  
Adverse Event Reporting System ◽  
Adverse Event Reporting ◽  
Gender Disparities ◽  
Permanent Disability ◽  
Younger Adults ◽  
Age And Gender ◽  
Real World Evidence ◽  
And Gender

Background: Two coronavirus disease 2019 (COVID-19) vaccines have received emergency use authorizations in the U.S. However, the safety of these vaccines in the real-world remains unknown.Methods: We reviewed adverse events (AEs) following COVID-19 vaccination among adults in the Vaccine Adverse Event Reporting System (VAERS) from December 14, 2020, through January 22, 2021. We compared the top 10 AEs, serious AEs, along with office and emergency room (ER) visits by age (18–64 years, ≥65 years) and gender (female, male).Results: There were age and gender disparities among adults with AEs following COVID-19 vaccination. Compared to younger adults aged between 18 and 64 years, older adults were more likely to report serious AEs, death, permanent disability, and hospitalization. Males were more likely to report serious AEs, death, and hospitalization compared to females.Conclusions: COVID-19 vaccines are generally safe but possible age and gender disparities in reported AEs may exist.

scholarly journals Cardiovascular Safety Profile of Romosozumab: A Pharmacovigilance Analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS)

2021 ◽  
Vol 10 (8) ◽  
pp. 1660
Author(s):  
Annika Vestergaard Kvist ◽  
Junaid Faruque ◽  
Enriqueta Vallejo-Yagüe ◽  
Stefan Weiler ◽  
Elizabeth M. Winter ◽  
...  
Keyword(s):  
Adverse Event ◽  
Drug Administration ◽  
Cardiovascular Events ◽  
Reporting System ◽  
Food And Drug Administration ◽  
Adverse Event Reporting System ◽  
Adverse Event Reporting ◽  
Cardiovascular Safety ◽  
Event Reporting ◽  
The Us

Background: Cardiovascular safety concerns for major cardiovascular events (MACE) were raised during the clinical trials of romosozumab. We aimed to evaluate the cardiovascular safety profile of romosozumab in a large pharmacovigilance database. Methods: All cases reported between January 2019 and December 2020 where romosozumab was reported were extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS). The outcome of interest was MACE (myocardial infarction (MI), stroke, or cardiovascular death). A disproportionality analysis was conducted by estimating the reporting odds ratios (RORs) and 95% confidence intervals. Disproportionality analyses were stratified by sex and reporting region (US, Japan, other). Results: Of the 1995 eligible cases with romosozumab, the majority (N = 1188; 59.5%) originated from Japan. Overall, 206 suspected MACE reports were identified, of which the majority (n = 164; 13.8%) were from Japan, and 41 (5.2%) were from the United States (US). Among Japanese reports, patients were older and more frequently male than reports from the US. Similarly, cases with a reported MACE were older and had higher reports of cardioprotective drugs than those without cardiovascular events. Elevated reports for MACE (ROR 4.07, 95% CI: 2.39–6.93) was identified overall, which was primarily driven by the significant disproportionality measures in the Japanese reports. Conclusions: The current pharmacovigilance study identified a potential signal for elevated MACE, particularly in Japan. The results support the current safety warnings from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to avoid use in high-risk patients.

Estimating costs of adverse events (AEs) and healthcare resource use (HRU) in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) receiving tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel): A summary of real-world evidence.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19551-e19551
Author(s):  
Hongbo Yang ◽  
Cynthia Zhengyun Qi ◽  
Anand Dalal ◽  
Vamsi Bollu ◽  
Jie Zhang ◽  
...  
Keyword(s):  
Real World ◽  
B Cell Lymphoma ◽  
The United States ◽  
Median Number ◽  
Cost Burden ◽  
Real World Evidence ◽  
Car T ◽  
Grade 3 ◽  
Cost Implications ◽  
The Cost

e19551 Background: The AE rates and HRU reported in multiple real-world evidence (RWE) studies of chimeric antigen receptor T-cell (CAR-T) therapies tisa-cel and axi-cel in r/r DLBCL have differed from those in their clinical trials. However, the cost implications from these findings are not well understood in existing literature. This study summarizes information from these RWE studies of tisa-cel and axi-cel and quantifies the associated costs. Methods: A literature review was conducted to identify RWE studies reporting AE rates and HRU of tisa-cel and axi-cel in the United States (US). AE rates and HRU were summarized and the associated costs were estimated using a micro-costing approach. Costs of AE management included hospitalization and pharmacy costs, such as intensive care unit (ICU) stays, inpatient admissions, and medications for the treatment of cytokine release syndrome (CRS) and neurotoxicity events (NE). HRU costs included hospitalization, ICU stays, and outpatient visit costs. Unit costs were from public health databases that are representative of US healthcare system and from literature. Costs were inflated to 2020 US dollars. A range was reported to present evidence if inputs are available from multiple studies. Results were summarized for tisa-cel and axi-cel separately. Results: Four publications were identified: Jaglowski 2019, Pasquini 2019, Riedell 2019, and Jacobson 2020. Across studies, grade 3+ CRS and NE occurred in 1%-4% and 0%-5% of tisa-cel-treated patients and 7%-16% and 20%-35% of axi-cel-treated patients, respectively. Tocilizumab usage was reported in 14%-20% of tisa-cel- and 62%-71% of axi-cel-treated patients. CAR-T infusion was inpatient for 36% of tisa-cel- and 92%-100% of axi-cel-treated patients. The median hospitalization days was 2 for tisa-cel and 15-16 for axi-cel. ICU transfer was observed for 7% and 28%-38% of tisa-cel- and axi-cel-treated patients, respectively, with median stays of 4 and 5 days, respectively. The median number of outpatient visits within 28 days after infusion was 6 for tisa-cel and 4 for axi-cel. The total estimated costs for managing AEs per patient were $843-$1,962 for tisa-cel and $5,979-$10,878 for axi-cel. The total estimated HRU costs per patient were $3,321 for tisa-cel and $32,394-33,166 for axi-cel. Conclusions: RWE studies suggest that patients with r/r DLBCL receiving tisa-cel had numerically lower AE rates, HRU, and cost burden than those receiving axi-cel in the US. The additional cost burden for axi-cel was primarily driven by the incremental ICU and hospitalization care due to a higher proportion of inpatient infusion among patients receiving axi-cel. Further research is warranted to compare the costs associated with the two CAR-Ts in r/r DLBCL.

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