Myocarditis following the use of different immune checkpoint inhibitor regimens: A real-world analysis of post-marketing surveillance data.

Although myocarditis has been reported in patients treated with immune checkpoint inhibitors (ICIs), there are few real-world studies to compare the occurrences and characteristics of myocarditis after different ICI regimens. Disproportionality analysis and Bayesian analysis were utilized for data mining of the suspected adverse events of myocarditis after ICIs use based on the Food and Drug Administration's Adverse Event Reporting System (FAERS) from January 2004 to June 2018. The times to onset and fatality rates of myocarditis following different ICI regimens were also compared. A total of 315 reports of myocarditis adverse events were identified with ICIs. Among 6 ICI monotherapies, avelumab had the highest association with myocarditis based on the highest reporting odds ratio (ROR = 42.65, 95% two-sided CI = 15.86-114.72), proportional reporting ratio (PRR = 42.61, χ2 = 159.63) and empirical Bayes geometric mean (EBGM = 41.87, 95% one-sided CI = 15.57). The combination therapies of ipilimumab plus pembrolizumab or nivolumab had higher RORs, PRRs and EBGMs than did pembrolizumab or nivolumab monotherapy. Myocarditis associated with the ipilimumab plus nivolumab treatment appeared to have earlier onset (16.5 [IQR 14-29.75] days vs 32 [IQR 16-77] days, p<0.01) and higher fatality rate (65.75% vs 50.40%, p<0.05) than that associated with nivolumab monotherapy. Analysis of FAERS data provides more precise profile on the occurrences and characteristics of myocarditis after different ICI regimens. The findings support continued surveillance, risk factor identification, and comparative studies.

Fan Q ，Hu Y ，Yang C ，Zhao B ... -  《-》

Renal adverse effects following the use of different immune checkpoint inhibitor regimens: A real-world pharmacoepidemiology study of post-marketing surveillance data.

Although kidney impairments have been reported following immune checkpoint inhibitors (ICIs) in clinical studies, there are few pharmacoepidemiology studies to compare the occurrences, clinical features, and prognosis of renal adverse effects. Disproportionality and Bayesian analysis were used in data mining to screen the suspected renal adverse effects after the administration of different ICIs, based on FDA's Adverse Event Reporting System (FAERS) from January 2004 to September 2019. The time to onset, fatality and hospitalization rates of renal adverse effects were also investigated. We identified 1444 reports of renal adverse effects. Affected patients tended to be older than 65 years (52.7%). Renal effects were most commonly reported in nivolumab monotherapy (33.24%). Atezolizumab appeared the strongest association among six ICI monotherapies, based on the highest reporting odds ratio (ROR = 144.38, two-sided 95% CI = 123.08 -169.37), proportional reporting ratio (PRR = 139.13, χ2  = 21 425.38), and empirical Bayes geometric mean (EBGM = 131.75, one-sided 95% CI = 115.28). The combination treatments showed higher RORs, PRRs, and EBGMs, compared with either nivolumab or pembrolizumab monotherapy. The median onset time of renal adverse effects was 48 (interquartile range [IQR] 18.75-121.25) days after the monotherapies of ICI regimens. Patients treated with the combination of nivolumab plus ipilimumab were younger than receivers in nivolumab monotherapy (63.81 ± 12.03 vs 66.39 ± 11.53, P = .004); The fatality rate of renal adverse effects appeared lower in the combination group, compared to nivolumab monotherapy (18.53% vs 27.50%, P = .004). The top hospitalization rates due to renal effects occurred in patients with combination therapies. Based on the FAERS database, we profiled renal adverse effects after various ICIs with real-world data in occurrences, clinical characteristics, and prognosis. Renal effects should be tightly monitored, especially within the first several months after ICIs administration. Particular concern should be paid for patients with a tendency for kidney impairments, such as old age.

Chen G ，Qin Y ，Fan QQ ，Zhao B ，Mei D ，Li XM ... -  《Cancer Medicine》

Colitis following the use of immune checkpoint inhibitors: A real-world analysis of spontaneous reports submitted to the FDA adverse event reporting system.

Although colitis has been reported in patients treated with immune checkpoint inhibitors (ICIs), associations between colitis and ICIs had not been thoroughly assessed in real-world studies. Here, we identified and characterized significant colitis-associated with ICIs. Based on the Food and Drug Administration Adverse Event Reporting System (FAERS) from January 2004 to December 2019, the disproportionality analysis and Bayesian analysis, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN) and the multi-item gamma Poisson shrinker (MGPS) algorithms were adopted to data mining of the suspected adverse events of colitis after ICIs administrating. Clinical characteristics of patients with ICIs-associated colitis and the time to onset of colitis following different ICI regimens were collected. A total of 3786 reports of colitis adverse events were identified with ICIs. Seven ICI monotherapies were associated with the reporting of colitis. Statistically significant ROR, PRR, information component (IC), and empirical Bayesian geometric mean (EBGM) emerged for all ICI monotherapies and combination therapies. ICIs-associated colitis affected mostly male (53.51%), with a wide mean age range (60.65 to 72 years). Colitis adverse events were commonly reported in patients with melanoma and lung cancer. Adverse outcomes of colitis concerning ICI were mainly outcomes of hospitalization-initiated or prolonged and other serious. Among colitis cases, 17.43% cases of colitis concerning ICI lead to death. The adverse event ofcolitis occurred earliest in ipilimumab monotherapy with a median time to onset of 64.21 days (IQR: 27-69 days) among all monotherapies. ICI may lead to severe and disabling ICIs-associated colitis during therapy. Analysis of FAERS data identified signals for adverse events of colitis with ICI regimens. Practitioners should consider the factors that may increase the likelihood of colitis. The findings support a continued surveillance and risk factor identification studies.

Hu Y ，Gong J ，Zhang L ，Li X ，Li X ，Zhao B ，Hai X ... -  《-》

Hemorrhage Risk Profiles among Different Antithrombotic Regimens: Evidence from a Real-World Analysis of Postmarketing Surveillance Data.

Although the use of direct oral anticoagulants (DOACs) has been reported in patients with atrial fibrillation (AF), there is currently no consensus on the occurrence or characteristics of the hemorrhage risk in different antithrombotic regimens. Disproportionality and Bayesian analyses were performed in mining data of suspected hemorrhagic events after antithrombotic drug use from the FDA Adverse Event Reporting System (FAERS) from January 2004 to September 2019. The time to onset and fatality rate of hemorrhage following different antithrombotic regimens were also compared. A total of 84,998 reports of hemorrhage-related adverse events with the use of antithrombotic drugs were identified. The patients included were mostly from the Americas (80.87%) and Europe (13.22%), with most data submitted by nonhealthcare professionals. Among the seven antithrombotic drug monotherapies, betrixaban had the highest association with hemorrhage based on the highest reporting odds ratio (ROR, 829.95; 95% CI = 113.61-6063.15), proportional reporting ratio (PRR, 24.68, χ2 = 804.24), and multi-item gamma Poisson shrinker (MGPS, 24.68, 95% one-sided CI = 4.67). The combination therapies of clopidogrel plus new oral anticoagulants had higher RORs, PRRs, and empirical Bayesian geometric means (EBGMs) than the antithrombotic drug monotherapies. Hemorrhage associated with rivaroxaban plus clopidogrel appeared to have an earlier onset (171 days vs 219 days, 95% two-sided CI =68.68-27.34, p < 0.0001) and a lower fatality rate (15.30% vs 17.74%, p<0.05) than that associated with rivaroxaban monotherapy. This study provides a relevant overview of the hemorrhagic complications/fatalities associated with different antithrombotic regimens in their real-world use. Among the combination therapies, clopidogrel plus DOACs were found to have stronger associations with hemorrhage than traditional dual antithrombotic therapies. Rivaroxaban showed a stronger association with hemorrhage than other antithrombotic drug monotherapies, and apixaban monotherapy appeared to have weaker associations with hemorrhage than others.

Sun X ，Ze B ，Zhang LJ ，BaiMa YZ ，Zuo W ，Zhao B ，GeSang LB ... -  《-》

Immune checkpoint inhibitors-related myocarditis in patients with cancer: an analysis of international spontaneous reporting systems.

Ma R ，Wang Q ，Meng D ，Li K ，Zhang Y ... -  《-》