The REporting of A Disproportionality Analysis for DrUg Safety Signal Detection Using Individual Case Safety Reports in PharmacoVigilance (READUS-PV): Explanation and Elaboration.

In pharmacovigilance, disproportionality analyses based on individual case safety reports are widely used to detect safety signals. Unfortunately, publishing disproportionality analyses lacks specific guidelines, often leading to incomplete and ambiguous reporting, and carries the risk of incorrect conclusions when data are not placed in the correct context. The REporting of A Disproportionality analysis for drUg Safety signal detection using individual case safety reports in PharmacoVigilance (READUS-PV) statement was developed to address this issue by promoting transparent and comprehensive reporting of disproportionality studies. While the statement paper explains in greater detail the procedure followed to develop these guidelines, with this explanation paper we present the 14 items retained for READUS-PV guidelines, together with an in-depth explanation of their rationale and bullet points to illustrate their practical implementation. Our primary objective is to foster the adoption of the READUS-PV guidelines among authors, editors, peer reviewers, and readers of disproportionality analyses. Enhancing transparency, completeness, and accuracy of reporting, as well as proper interpretation of their results, READUS-PV guidelines will ultimately facilitate evidence-based decision making in pharmacovigilance.

The Reporting of a Disproportionality Analysis for Drug Safety Signal Detection Using Individual Case Safety Reports in PharmacoVigilance (READUS-PV): Development and Statement.

BACKGROUND AND AIM: Disproportionality analyses using reports of suspected adverse drug reactions are the most commonly used quantitative methods for detecting safety signals in pharmacovigilance. However, their methods and results are generally poorly reported in published articles and existing guidelines do not capture the specific features of disproportionality analyses. We here describe the development of a guideline (REporting of A Disproportionality analysis for drUg Safety signal detection using individual case safety reports in PharmacoVigilance [READUS-PV]) for reporting the results of disproportionality analyses in articles and abstracts. METHODS: We established a group of 34 international experts from universities, the pharmaceutical industry, and regulatory agencies, with expertise in pharmacovigilance, disproportionality analyses, and assessment of safety signals. We followed a three-step process to develop the checklist: (1) an open-text survey to generate a first list of items; (2) an online Delphi method to select and rephrase the most important items; (3) a final online consensus meeting. RESULTS: Among the panel members, 33 experts responded to round 1 and 30 to round 2 of the Delphi and 25 participated to the consensus meeting. Overall, 60 recommendations for the main body of the manuscript and 13 recommendations for the abstracts were retained by participants after the Delphi method. After merging of some items together and the online consensus meeting, the READUS-PV guidelines comprise a checklist of 32 recommendations, in 14 items, for the reporting of disproportionality analyses in the main body text and four items, comprising 12 recommendations, for abstracts. CONCLUSIONS: The READUS-PV guidelines will support authors, editors, peer-reviewers, and users of disproportionality analyses using individual case safety report databases. Adopting these guidelines will lead to more transparent, comprehensive, and accurate reporting and interpretation of disproportionality analyses, facilitating the integration with other sources of evidence.

T-Cell Malignant Neoplasms After Chimeric Antigen Receptor T-Cell Therapy.

This cohort study assesses the increase in second primary malignant neoplasms and T-cell malignant neoplasm cases associated with chimeric antigen receptor­T cells.

The Perfect Circle Technique Shows Poor Inter-rater Reliability in Measuring Anterior Glenoid Bone Loss on Magnetic Resonance Imaging.

Purpose: To evaluate the reliability of the perfect circle methodology for measurement of glenoid bone loss in patients with anterior glenohumeral instability. Methods: We performed a chart review of retrospectively collected patients who underwent isolated arthroscopic anterior labral repair between January 1 and June 30, 2021, using our institution's electronic medical records. The inclusion criteria included isolated anterior shoulder instability with anterior labral repair and corroborated tears on magnetic resonance imaging. A total of 9 raters, either sports or shoulder and elbow fellowship-trained orthopaedic surgeons, each evaluated the affected shoulder magnetic resonance imaging scans twice, with a minimum of 2 weeks between measurements. Measurements followed the "perfect circle" technique and included projected anterior-to-posterior glenoid diameter, amount of posterior bone loss, and percentage of posterior bone loss. Intrarater reliability and inter-rater reliability were then determined by calculating intraclass correlation coefficients (ICCs). Results: Ten consecutive patients meeting the selection criteria were chosen for inclusion in this analysis. Average estimated bone loss for the cohort was 2.45 mm, and the mean estimated glenoid diameter of the involved shoulder was 28.82 mm. The average percentage of bone loss measured 8.54%. The ICC for interobserver reliability was 0.55 for the perfect circle diameter and 0.17 for the anterior bone loss measurement (poorly to moderately reliable). The ICC for intraobserver reliability was 0.69 for the perfect circle diameter and 0.71 for anterior bone loss (moderately reliable). Conclusions: The perfect circle technique for estimating anterior glenoid bone loss on magnetic resonance imaging was found to have moderate intrarater reliability; however, reliability between observers was found to be moderate to poor. Level of Evidence: Level IV, diagnostic case series.

The Perfect-Circle Technique Demonstrates Poor Inter-Rater Reliability in Measuring Posterior Glenoid Bone Loss on Magnetic Resonance Imaging.

Purpose: To evaluate the reliability of the "perfect-circle" methodology for measurement of glenoid bone loss with magnetic resonance imaging (MRI) in patients with posterior glenohumeral instability. Methods: A prospective chart review was performed on patients who underwent isolated arthroscopic posterior labral repairs in our institution's electronic medical records between January 1, 2021, and June 30, 2021. Inclusion criteria included isolated posterior shoulder instability with posterior labral repair and corroborated tears on MRI. A total of 9 raters, either sports or shoulder and elbow fellowship-trained orthopaedic surgeons, each evaluated the affected shoulder MRI scans twice, at over 2 weeks apart. Measurements followed the "perfect-circle" technique and included projected anterior-to-posterior (AP) glenoid diameter, amount of posterior bone loss, and percentage of posterior bone loss. Results: Ten consecutive patients between the ages of 17 and 46 years with diagnosed posterior glenohumeral instability were selected. The average age was 28 ± 10 years, and 60% of patients were male. The patient's dominant arm was affected in 40%, and 50% of cases involved the right shoulder. The average glenoid diameter was 29.62 ± 3.69 mm, and the average measured bone loss was 2.8 ± 1.74 mm. The average percent posterior glenoid bone loss was 9.41 ± 5.78%. The inter-rater reliability was poor for the AP diameter and for the posterior glenoid bone loss with intraclass correlation coefficients at 0.30 (0.12-0.62) and 0.22 (0.07-0.54) respectively. The intrarater reliability was poor for AP diameter and moderate for posterior glenoid bone loss, with intraclass correlation coefficients at 0.41 (0.22-0.57) and 0.50 (0.33-0.64), respectively. Conclusions: Using the "perfect-circle" technique for evaluating posterior glenohumeral bone loss has poor-to-moderate inter- and intrarater reliability from MRI. Level of Evidence: Level IV, prospective diagnostic study.

Mild renal impairment is associated with increased cardiovascular events and all-cause mortality following cancer diagnosis.

BACKGROUND: The association between mildly decreased renal function and cardiovascular (CV) outcomes in cancer patients remains unestablished. AIMS: We sought to explore this association in asymptomatic self-referred healthy adults. METHOD: We followed 25, 274 adults, aged 40-79 years, who were screened in preventive healthcare settings. Participants were free of CV disease or cancer at baseline. The estimated glomerular filtration rate (eGFR) was calculated according to the CKD Epidemiology Collaboration equation and categorized into groups [≤59, 60-69, 70-79, 80-89, 90-99, ≥100 (ml/min/1.73 m²)]. The outcome included a composite of death, acute coronary syndrome, or stroke, examined using a Cox model with cancer as a time-dependent variable. RESULTS: Mean age at baseline was 50 ±â€…8 years and 7973 (32%) were women. During a median follow-up of 6 years (interquartile range: 3-11), 1879 (7.4%) participants were diagnosed with cancer, of them 504 (27%) develop the composite outcome and 82 (4%) presented with CV events. Multivariable time-dependent analysis showed an increased risk of 1.6, 1.4, and 1.8 for the composite outcome among individuals with eGFR of 90-99 [95% confidence interval (CI): 1.2-2.1 P = 0.01], 80-89 (95% CI: 1.1-1.9, P = 0.01) and 70-79 (95% CI: 1.4-2.3, P < 0.001), respectively. The association between eGFR and the composite outcome was modified by cancer with 2.7-2.9 greater risk among cancer patients with eGFR of 90-99 and 80-89 but not among individuals free from cancer ( Pinteraction < 0.001). CONCLUSION: Patients with mild renal impairment are at high risk for CV events and all-cause mortality following cancer diagnosis. eGFR evaluation should be considered in the CV risk assessment of cancer patients.

The real-world safety of sacubitril / valsartan among older adults (≥75): A pharmacovigilance study from the FDA data.

BACKGROUND: Heart failure is a major cause of morbidity and mortality among older adults. Sacubitril-Valsartan (Sac/Val) has been shown to improve patients' outcomes; however, its safety profile among older adults has not been adequately examined. We therefore aimed to examine its safety profile among this population. METHODS: We conducted a retrospective pharmacovigilance study utilizing the FDA's database of safety reports (FAERS). We employed disproportionality analysis comparing Sac/Val to angiotensin receptor blockers (ARBs). We aim to evaluate the reporting of pre-defined adverse events associated with Sac/Val (hypotension, acute kidney injury (AKI), hyperkalemia and angioedema) in two age groups: adults (< 75 years) and older adults (≥ 75). For each subgroup, we calculated reporting odds ratio (ROR) and compared them by calculating P for interaction. RESULTS: The FAERS database encompassed 18,432 unique reports of Sac/Val. Of them, 12,630 (68.5%) subjects were adults (< 75 years), and 5802 (31.5%) were older adults (≥ 75 years), with a median age (IQR) of 68 (59-77). When compared to ARBs, Sac/Val was associated with higher reporting of hypotension, lower reporting of acute kidney injury (AKI) and hyperkalemia, and similar reporting of angioedema. Notably, we did not observe a significant interaction between the age subgroups and the risk estimates (AKI: Pinteraction = 0.72, hyperkalemia: Pinteraction = 0.94, hypotension: Pinteraction = 0.31, and angioedema: Pinteraction = 0.61). CONCLUSIONS: In this postmarking study, none of the prespecified adverse events was reported more frequently in older adults. These findings provide reassurance for safety use of Sac/Val in older adults.

Risk Factors for Glenoid Bone Loss in the Setting of Posterior Glenohumeral Instability.

Background: Posterior instability has been reported to account for up to 24% of cases of shoulder instability in certain active populations. However, there is a paucity of data available regarding the risk factors associated with posterior glenoid bone loss. Purpose: To characterize the epidemiology of, and risk factors associated with, glenoid bone loss within a cohort of patients who underwent primary arthroscopic shoulder stabilization for isolated posterior-type glenohumeral instability. Study Design: Cross-sectional study; Level of evidence, 3. Methods: This was a retrospective analysis of patients who underwent primary arthroscopic shoulder stabilization for posterior-type instability between January 2011 and December 2019. Preoperative magnetic resonance arthrograms were used to calculate posterior glenoid bone loss using a perfect circle technique. Patient characteristics and revision rates were obtained. Bone loss (both in millimeters and as a percentage) was compared between patients based on sex, age, arm dominance, sports participation, time to surgery, glenoid version, history of trauma, and number of anchors used for labral repair. Results: Included were 112 patients with a mean age of 28.66 ± 10.07 years; 91 patients (81.25%) were found to have measurable bone loss. The mean bone loss was 2.46 ± 1.68 mm (8.98% ± 6.12%). Significantly greater bone loss was found in athletes versus nonathletes (10.09% ± 6.86 vs 7.44% ± 4.56; P = .0232), female versus male patients (11.17% ± 6.53 vs 8.17% ± 5.80; P = .0212), and patients dominant arm involvement versus nondominant arm involvement (10.26% ± 5.63 vs 7.07% ± 6.38; P = .0064). Multivariate regression analysis identified dominant arm involvement as an independent risk factor for bone loss (P = .0033), and dominant arm involvement (P = .0024) and athlete status (P = .0133) as risk factors for bone loss >13.5%. At the conclusion of the study period, 7 patients had experienced recurrent instability (6.25%). Conclusion: The findings of this study are in alignment with existing data suggesting that posterior glenoid bone loss is highly prevalent in patients undergoing primary arthroscopic stabilization for posterior-type shoulder instability. Our results suggest that patients with dominant arm involvement are at risk for greater posterior glenoid bone loss. Athlete status and dominant arm involvement were identified as independent risk factors for bone loss >13.5%.

Baseline renal function and the risk of cancer among apparently healthy middle-aged adults.

BACKGROUND: The association between mildly impaired renal function with all-site and site-specific cancer risk is not established. We aim to explore this association among apparently healthy adults. METHODS: We followed 25,073 men and women, aged 40-79 years, free of cancer or cardiovascular disease at baseline who were screened annually in preventive healthcare settings. The estimated glomerular filtration rate (eGFR) was calculated using the CKD Epidemiology Collaboration equation (CKD-EPI) and classified into four mutually exclusive groups: <60, 60-74, 75-89, ≥90 (mL/min/1.73 m²). The primary outcome was all-site cancer while the secondary outcome was site-specific cancer. Cancer data was available from a national registry. RESULTS: Mean age at baseline was 50 ± 8 years and 7973 (32 %) were women. During a median follow-up of 9 years (IQR 3-16) and 256,279 person years, 2045 (8.2 %) participants were diagnosed with cancer. Multivariable Cox model showed a 1.2 (95 %CI: 1.0-1.4 p = 0.05), 1.2 (95 %CI: 1.0-1.4 p = 0.02), and 1.4 (95 %CI: 1.1-1.7 p = 0.003) higher risk for cancer with eGFR of 75-89, 60-74, and < 60, respectively. Site-specific analysis demonstrated a 1.8 (95 %CI: 1.2-2.6 p = 0.004), 1.7 (95 %CI: 1.2-2.6 p = 0.004) and 2.2 (95 %CI: 1.3-3.6 p = 0.002) increased risk for prostate cancer with eGFR of 75-89, 60-74, and < 60, respectively. eGFR< 60 was associated with a 2.0 (95 %CI: 1.1-3.7 p = 0.03) and 3.7 (95 %CI: 1.1-13.1 p = 0.04) greater risk for melanoma and gynecological caner respectively. CONCLUSIONS: CKD stage 2 and worse is independently associated with higher risk for cancer incidence, primarily prostate cancer. Early intervention and screening are warranted among these individuals in order to reduce cancer burden.

Adolescent Hypertension Is Associated With Stroke in Young Adulthood: A Nationwide Cohort of 1.9 Million Adolescents.

BACKGROUND: Adult hypertension is a well-established risk factor for stroke in young adults (aged <55 years), and the effects are even more deleterious than at an older age. However, data are limited regarding the association between adolescent hypertension and the risk of stroke in young adulthood. METHODS: A nationwide, retrospective cohort study of adolescents (aged 16-19 years) who were medically evaluated before compulsory military service in Israel during 1985 to 2013. For each candidate for service, hypertension was designated after constructed screening, and the diagnosis was confirmed through a comprehensive workup process. The primary outcome was ischemic and hemorrhagic stroke incidence as registered at the national stroke registry. Cox proportional-hazards models were used. We conducted sensitivity analyses by excluding people with a diabetes diagnosis at adolescence or a new diabetes diagnosis during the follow-up period, analysis of adolescents with overweight, and adolescents with baseline unimpaired health status. RESULTS: The final sample included 1 900 384 adolescents (58% men; median age, 17.3 years). In total, 1474 (0.08%) incidences of stroke (1236 [84%] ischemic) were recorded, at a median age of 43 (interquartile range, 38-47) years. Of these, 18 (0.35%) occurred among the 5221 people with a history of adolescent hypertension. The latter population had a hazard ratio of 2.4 (95% CI, 1.5-3.9) for incident stroke after adjustment for body mass index and baseline sociodemographic factors. Further adjustment for diabetes status yielded a hazard ratio of 2.1 (1.3-3.5). We found similar results when the outcome was ischemic stroke with a hazard ratio of 2.0 (1.2-3.5). Sensitivity analyses for overall stroke, and ischemic stroke only, yielded consistent findings. CONCLUSIONS: Adolescent hypertension is associated with an increased risk of stroke, particularly ischemic stroke, in young adulthood.

Sex specific serum uric acid levels are associated with ischemic changes on ECG and with 20-year all-cause mortality among older adults.

BACKGROUND: Uric acid is an emerging biomarker for cardiovascular morbidity and mortality, but its association with all-cause mortality and ECG findings remains unestablished, specifically among older adults. We aimed to evaluate the association between serum uric acid (SUA) with incidental findings of ECG abnormalities and with long-term all-cause mortality. METHODS: We conducted a prospective cohort study of 851 community dwelling men and women, who were examined between 1999 and 2008, and followed over 20 years until December 2019 for all-cause mortality. Subjects free of Gout or diuretics treatment at baseline were included. SUA was categorized according to sex-specific tertiles and evaluated against baseline ECG findings and all-cause mortality. RESULTS: Mean baseline age was 72±7 years and 416 (49%) were females. Ischemic changes on ECG were observed in 85 (10.0%) participants, of them 36 (13.5%) belonged to the upper SUA tertile and 49 (8.4%) to the lower ones (p = 0.02). Multivariable logistic regression showed 80% higher odds for ischemic changes on ECG among participants in the high SUA tertile (adjusted-OR = 1.8, 95%CI 1.1-2.9, p = 0.03) compared with the lower SUA two-tertiles. During a median follow-up of 14 years, 380 (44.7%) participants died. SUA ≥5.3 mg/dl for women and ≥ 6.2 mg/dl for men, was associated with a 30% greater risk for all-cause mortality in a multivariable Cox regression model (HR = 1.3, 95%CI: 1.0-1.6, p = 0.03). CONCLUSIONS: High SUA level was associated with ischemic changes on ECG and with an increased risk for all-cause mortality over 20 years of follow-up among community dwelling older adults free of Gout. Even lower sex-specific thresholds of SUA were associated with all-cause mortality than previously proposed. SUA should be considered as a biomarker for cardiovascular risk and all-cause mortality.

Polypharmacy is differentially associated with 20-year mortality among community-dwelling elderly women and men: The Israel Glucose Intolerance, Obesity and Hypertension cohort study.

BACKGROUND: Elderly individuals are characterized by multimorbidity and high medication intake, entailing risks for adverse events. We examined the overall and sex-specific association of polypharmacy (≥5 drugs concurrently) with 20-year mortality among community-dwelling older adults. METHODS: Survivors of the longitudinal Israel Study of Glucose Intolerance, Obesity, and Hypertension underwent extensive evaluation during 1999-2004, and were followed-up for all-cause mortality until 2019. Cox regression examined association of polypharmacy with all-cause mortality. RESULTS: Data included 1210 participants (mean baseline age 72.9 ± 7.4 years, 53% females), 50.7% of them died over a median follow-up of 12.8 years. Women received a higher mean number of drugs (4.3 vs 3.5; p < 0.0001), were twice more likely to take vitamins, and had higher comorbidity. Polypharmacy prevalence was 38.3%, and more frequent with age, female sex, European-American origin, sedentary lifestyle and poor self-rated health. Polypharmacy was independently associated with mortality in women only (HR=1.41, 95%CI:1.05-1.89). An interaction was found with sex (p = 0.045). CONCLUSIONS: Polypharmacy was more prevalent in older women than men and associated with increased 20-year mortality in women only. Sex-specific adaptation of guidelines for appropriate drug use among community-dwelling older adults is warranted.

The real-world safety profile of sodium-glucose co-transporter-2 inhibitors among older adults (≥ 75 years): a retrospective, pharmacovigilance study.

BACKGROUND: As indications for sodium-glucose co-transporter-2 inhibitors (SGLT2i) are expanding, a growing number of older adults have become candidates for treatment. We studied the safety profile of SGLT2i among older adults. METHODS: A retrospective, pharmacovigilance study of the FDA's global database of safety reports. To assess reporting of pre-specified adverse events following SGLT2i among adults (< 75 years) and older adults (≥ 75), we performed a disproportionality analysis using the sex-adjusted reporting odds ratio (adj.ROR). RESULTS: We identified safety reports of 129,795 patients who received non-insulin anti-diabetic drugs (NIAD), including 24,253 who were treated with SGLT2i (median age 60 [IQR: 51-68] years, 2,339 [9.6%] aged ≥ 75 years). Compared to other NIAD, SGLT2i were significantly associated with amputations (adj.ROR = 355.1 [95%CI: 258.8 - 487.3] vs adj.ROR = 250.2 [79.3 - 789.5]), Fournier gangrene (adj.ROR = 45.0 [34.5 - 58.8] vs adj.ROR = 88.0 [27.0 - 286.6]), diabetic ketoacidosis (adj.ROR = 32.3 [30.0 - 34.8] vs adj.ROR = 23.3 [19.2 - 28.3]), genitourinary infections (adj.ROR = 10.3 [9.4 - 11.2] vs adj.ROR = 8.6 [7.2 - 10.3]), nocturia (adj.ROR = 5.5 [3.7 - 8.2] vs adj.ROR = 6.7 [2.8 - 15.7]), dehydration (adj.ROR = 2.5 [2.3 - 2.8] vs adj.ROR = 2.6 [2.1 - 3.3]), and fractures (adj.ROR = 1.7 [1.4 - 2.1] vs adj.ROR = 1.5 [1.02 - 2.1]) in both adults and older adults, respectively. None of these safety signals was significantly greater in older adults (Pinteraction threshold of 0.05). Acute kidney injury was associated with SGLT2i in adults (adj.ROR = 1.97 [1.85 - 2.09]) but not in older adults (adj.ROR = 0.71 [0.59 - 0.84]). Falls, hypotension, and syncope were not associated with SGLT2i among either adults or older adults. CONCLUSION: In this global post-marketing study, none of the adverse events was reported more frequently among older adults. Our findings provide reassurance regarding SGLT2i treatment in older adults, although careful monitoring is warranted.

Ocular Adverse Events Induced by Immune Checkpoint Inhibitors: A Comprehensive Pharmacovigilance Analysis.

PURPOSE: Characterize ocular adverse events (oAEs) caused by immune checkpoint inhibitors (ICIs). METHODS: Retrospective analysis of 41,674 cancer patients in the FDA Adverse Event Reporting System (FAERS) pharmacovigilance database receiving anti-PD-1/PD-L1, anti-CTLA-4, or anti-PD-1+ anti-CTLA-4 combination. Reporting odds ratio (ROR) was used to approximate oAE rate across regimens and indications. RESULTS: The most common indications were lung cancer (27.3%) and melanoma (22.7%); 76.3% received anti-PD-1/PD-L1 monotherapy. 1,268 patients (3.0%) reported oAEs, namely vision disorders (30.8%), uveitis (15.1%), and retinal, lacrimal, and optic nerve disorders (10.7%, 9.0%, 8.4%). Melanoma showed the highest proportion of uveitis (117/9,471 cases; 1.2%). Addition of anti-CTLA-4 to anti-PD-1 increased the ROR of uveitis from 4.77 (95% CI 3.83-5.94) to 17.1 (95% CI 12.9-22.7). Among anti-PD-1/PD-L1 cases, uveitis was differentially reported in melanoma (ROR 14.7, 95% CI 10.7-20.2) compared with lung cancer (ROR 2.67, 95% CI 1.68-4.23). CONCLUSION: ICI-induced oAEs are rare, and uveitis is significantly associated with melanoma and anti-PD-1+ anti-CTLA-4 combination.

Hyperglycaemic disorders associated with PCSK9 inhibitors: a real-world, pharmacovigilance study.

AIMS: While genetic and biological studies indicated a potential association between proprotein-convertase subtilisin/kexin type 9 inhibitors (PCSK9i) and hyperglycaemia, real-world data are limited. Therefore, we sought to investigate this association using the FDA adverse event reporting system (FAERS). METHODS AND RESULTS: The FAERS database (2015-2020) was retrospectively queried to characterize reporting of hyperglycaemic adverse events (AEs) with PCSK9i. Disproportionality analyses were performed using the adjusted reporting odds ratio (adj.ROR), and the lower bound of the information component (IC) 95% credibility interval (IC025 > 0 is deemed significant). Among 7 295 624 eligible patients, 71 748 reports of evolocumab and 15 976 of alirocumab were identified. Compared to the full database, PCSK9i treatment was associated with increased reporting of hyperglycaemic AEs [n = 1841, adj.ROR = 1.14 (1.07-1.22), IC025 = 0.13]. Hyperglycaemic AEs were primarily mild hyperglycaemia [n = 1469, adj. ROR = 1.48 (1.36-1.62), IC025 = 0.51] rather than diabetes [n = 372, adj. ROR = 0.67 (0.60-0.74), IC025 = -0.90]. Among PCSK9i agents, evolocumab, but not alirocumab, was associated with hyperglycaemic AEs [n = 1587, adj. ROR = 1.24 (1.15-1.32), IC025 = 0.20; n = 254, adj. ROR = 0.73 (0.60-0.88), IC025 = -0.38, respectively]. Hyperglycaemic AEs were reported more often with PCSK9i compared to ezetimibe [adj.ROR = 1.99 (1.35-2.94)], and less often compared to statins [adj.ROR = 0.26 (0.25-0.28)]. Notably, hyperglycaemic AEs were reported more frequently by diabetic than by non-diabetic patients (P < 0.001), mostly occurred within 6 months of treatment and were reversible upon drug discontinuation. CONCLUSION: In a real-world setting, PCSK9i treatment was associated with increased reporting of mild hyperglycaemia, but not diabetes. While initial monitoring is warranted, the favourable glycaemic safety profile compared to statins supports their essential role in the management of lipid disorders.

Adverse Cardiovascular and Pulmonary Events Associated With Chimeric Antigen Receptor T-Cell Therapy.

BACKGROUND: Pivotal trials of chimeric antigen receptor T-cell (CAR-T) have identified common toxicities but may have been underpowered to detect cardiovascular and pulmonary adverse events (CPAEs). OBJECTIVES: This study sought to investigate CPAEs associated with commercial CD19-directed CAR-T therapy. METHODS: In this retrospective, pharmacovigilance study, the authors used the Food and Drug Administration adverse event reporting system to identify CPAEs associated with axicabtagene-ciloleucel and tisagenlecleucel. The authors evaluated disproportionate reporting by the reporting odds ratio (ROR) and the lower bound of the information component 95% credibility interval (IC025 >0 is deemed significant). Significant associations were further adjusted to age and sex (adj.ROR). RESULTS: The authors identified CAR-T reports of 2,657 patients, including 546 CPAEs (20.5%). CPAEs overlapped with cytokine release syndrome in 68.3% (373 of 546) of the reports. Compared with the full database, CAR-T was associated with overreporting of tachyarrhythmias (n = 74 [2.8%], adj.ROR = 2.78 [95% CI: 2.21-3.51]), cardiomyopathy (n = 69 [2.6%], adj.ROR = 3.51 [2.42-5.09]), pleural disorders (n = 46 [1.7%], adj.ROR = 3.91 [2.92-5.23]), and pericardial diseases (n = 11 [0.4%], adj.ROR = 2.26 [1.25-4.09], all IC025 >0). Venous thromboembolic events (VTEs) were associated only with axicabtagene-ciloleucel therapy (n = 28 [1.6%], adj.ROR = 1.80 [1.24-2.62], IC025 >0). Atrial fibrillation (n = 55) was the leading tachyarrhythmia, followed by ventricular arrhythmias (n = 14). Tachyarrhythmias and VTEs were reported more often following axicabtagene-ciloleucel than tisagenlecleucel in an age- and sex-adjusted model (adj.ROR = 1.82 [1.04-3.18] and adj.ROR = 2.86 [1.18-6.93], respectively). Finally, the fatality rate of CPAEs was 30.9%. CONCLUSIONS: In this largest post-marketing study to date, the authors identified an association between CAR-T and various CPAEs, including tachyarrhythmias, cardiomyopathy, pericardial and pleural disorders, and VTEs. These findings should be considered in the multidisciplinary assessment for and monitoring of CAR-T therapy recipients.