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Real-world experience of carfilzomib-associated cardiovascular adverse events: SEER-Medicare data set analysis.

ABSTRACT: Carfilzomib was approved for the treatment of multiple myeloma in 2012 and since then there have been concerns for cardiovascular toxicity from its use. With this study, we aim to further study the hazards and underlying risk factors for cardiovascular adverse events associated with carfilzomib. This study was conducted using Surveillance, Epidemiology, and End Results (SEER)-Medicare data set of multiple myeloma from 2001 to 2015. Data were analyzed for hazards ratio of cardiovascular adverse events between carfilzomib users and nonusers. We identified 7330 patients with multiple myeloma of whom 815 were carfilzomib users. Carfilzomib users had a statistically significant hazard ratio of 1.41 with p < 0.0001 for all cardiovascular adverse events as compared to nonusers. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Carfilzomib users were at higher risk of new-onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers. Age above 75 years, preexisting cardiovascular disease, obesity, and twice a week carfilzomib schedule were significant risk factors associated with cardiovascular adverse events in carfilzomib users. The median time of the onset for all cardiovascular adverse events was 3.1 months. This study has identified a significantly higher likelihood of cardiovascular adverse events in elderly Medicare patients receiving carfilzomib.

SUBMITTER: Bishnoi R

PROVIDER: S-EPMC7826471 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Real-world experience of carfilzomib-associated cardiovascular adverse events: SEER-Medicare data set analysis.

Bishnoi Rohit R Xie Zhigang Z Shah Chintan C Bian Jiang J Murthy Hemant S HS Wingard John R JR Farhadfar Nosha N

Cancer medicine 20201110 1

Carfilzomib was approved for the treatment of multiple myeloma in 2012 and since then there have been concerns for cardiovascular toxicity from its use. With this study, we aim to further study the hazards and underlying risk factors for cardiovascular adverse events associated with carfilzomib. This study was conducted using Surveillance, Epidemiology, and End Results (SEER)-Medicare data set of multiple myeloma from 2001 to 2015. Data were analyzed for hazards ratio of cardiovascular adverse e ...[more]

PMID: 33169938

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Project description:ImportanceCardiovascular adverse events (CVAE) with carfilzomib in patients with multiple myeloma can be potentially life-threatening and remain incompletely characterized. We performed the first systematic review and meta-analysis of carfilzomib-associated CVAE.ObjectiveTo determine the incidence of carfilzomib-associated CVAE and to compare the rates of carfilzomib CVAE among different doses and companion therapies.Data sourcesPubMed, EMBASE, Web of Science, and clinicaltrials.gov were queried for the keywords "carfilzomib," "Kyprolis," and "PX-171" through January 1, 2017.Study selectionPhase 1 to 3 prospective clinical trials of carfilzomib in patients with multiple myeloma with evaluable toxic effects data were eligible for meta-analysis.Data extraction and synthesisData were independently extracted by 2 reviewers following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Pooled incidence rates and relative risks (for randomized trials) and 95% confidence intervals were calculated using a random effects model. Subgroup analyses were performed to assess study-level characteristics associated with CVAE.Main outcomes and measuresCardiovascular adverse events were defined as heart failure, hypertension, ischemia, and arrhythmia. All-grade and grades 3 or higher AEs and study characteristics were recorded.ResultsA total of 514 studies were assessed for eligibility. Of those, 24 studies were eligible, including a total of 2594 patients with multiple myeloma. All-grade and grades 3 and higher CVAE were seen in 617 (18.1%) and 274 (8.2%), respectively. Phase 2 or 3 studies and carfilzomib doses of 45 mg/m2 or higher were associated with high-grade CVAE. Median age older than 65 years, prior myeloma therapies, and concurrent myeloma therapies were not associated with CVAE. For the 3 randomized clinical trials, the summary relative risk of all-grade and grade 3 or higher CVAE for patients receiving carfilzomib compared with noncarfilzomib-receiving control patients were 1.8 and 2.2, respectively.Conclusions and relevanceCarfilzomib was associated with a significant incidence of CVAE, with higher rates seen with higher doses of carfilzomib. Phase 1 studies may be underdetecting CVAE. Future studies are needed to identify patients at high risk for CVAE, develop optimal monitoring strategies, and explore strategies to mitigate these risks.

Project description: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.

Project description:BackgroundCarfilzomib improves survival in patients with recurrent myeloma. Given the strict eligibility criteria in clinical trials, the actual frequency of cardiac adverse events (CAEs) and pulmonary adverse events (PAEs) and the risk factors associated with these AEs in the general population need to be established.MethodsThe authors extracted myeloma cases in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database from 2000 through 2013 and corresponding claims through 2014. They then identified patients who received carfilzomib during their disease course. Subsequently, the International Classification of Diseases, Ninth Revision (ICD-9) was used to identify all the codes for CAEs, PAEs, and respiratory infections associated with carfilzomib use. Preexisting diagnoses corresponding to the CAEs and PAEs of interest were excluded to distinguish toxicity from comorbidity. Multivariate Cox regression was performed to determine those variables independently associated with the development of CAEs and PAEs.ResultsOf the 635 patients analyzed, the median age was 72 years (range, 36-94 years); 55% of the patients were male and 79% were white. The median duration of carfilzomib treatment was 58 days (range, 1-716 days). Overall, approximately 66% of the patients had codes for either CAEs or PAEs. In terms of CAEs, approximately 22% of patients developed hypertension, 15% developed peripheral edema, and 14% experienced heart failure. With regard to PAEs, approximately 28% of patients developed dyspnea, 15% developed cough, and 15% developed pneumonia. Only chronic obstructive pulmonary disease (COPD) was found to be independently associated with the development of CAEs. Patients with preexisting COPD were found to have a 40% increase in their hazard of developing CAEs (adjusted hazard ratio, 1.40; 95% CI, 1.03-1.90).ConclusionsIn older adults with myeloma who are undergoing treatment with carfilzomib, new cardiac and pulmonary diagnoses were common. Patients with preexisting COPD were found to be at an increased risk of developing CAEs.

Dataset Information

Real-world experience of carfilzomib-associated cardiovascular adverse events: SEER-Medicare data set analysis.

Publications

Real-world experience of carfilzomib-associated cardiovascular adverse events: SEER-Medicare data set analysis.

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