Safety Reports Research Articles

COVID-19 pandemic period - adverse drug reactions reporting, observing, assessing and analysis at tertiary care teaching hospital, IMS-BHU Varanasi – 3-years observational study

Background: Effects of drugs that are undesirable and beyond their therapeutic effect are labeled as adverse drug reactions (ADRs). These often lead to increase hospital stay, repeated hospitalization, adversely affecting the quality of life, and perhaps, one of the causes of mortality making it a chief challenge in modern health-care system. This observational study analyzed and summarized details linked to ADRs identification, reporting, severity, treatment, and preventive measures for health professionals. Aims and Objectives: The objectives of the study are to assess and evaluate demographic profile, drug prescribed with its dosage, clinical findings, seriousness, outcome, causality, and organ system affected by concerned ADRs. Materials and Methods: An observational prospective study analyzing submitted ADRs mentioned in individual case safety reports (ICSR), mentioning demographics profile, suspected drug, involved bodily organ system, causality and reaction severity in different age groups of indoor and outdoor patients reported from 2020 January to 2022 December at ADR monitoring center, Department of Pharmacology, IMS-BHU. Performa used for ADRs reporting is ICSR, which later on transferred to the Indian database (VigiFlow) for data collection and analysis. Results: Total 1096 ADRs were identified and reported in 36-month duration, with male (629/1096) to female (466/1096) ratio of 1.35:1. On age group analysis, 74.8% (820/1096) adults (18–59 years) followed by 23.4% (256/1096) elderly (>59 years) and only 1.8% (20/1096) children and adolescents (<17 years) cases were found. Endocrine system was the most common organ system affected with 27.9% case (306/1096), succeeded by 25.4% (278/1096). ADRs were linked to the gastrointestinal system and 15.69% (172/1096) cases were related to dermatological problems. Antimicrobial drugs were most involved group, which on further analyzing and classifying revealed majority of ADRs were related to antiviral drugs, followed by antibiotics with 27.2% (298/1096) and 23.4% (257/1096) cases, respectively. Antiallergic and antifungal drug groups were found be least involved with only 1.6% (17/1096) cases each. On assessment of causality, majority of ADRs were possible in 60.40% (662/1096) cases and probable in 39.14% (429/1096) cases. Conclusion: Occurrence of ADRs is very common and perhaps a serious concern regarding well-being and safety of public as may lead to non-serious to serious health problems. This observational study identified the need of increased awareness of ADR monitoring, reporting and benefits, to fulfill the space created by under-reporting, especially in geriatrics and pediatric age group patients. A detail evaluation and removal of the barriers so that all the patients may easily approach for spontaneous reporting of side effects after start usage of any medicinal product, if any. In addition, surveillance studies emphasizing on reporting are essential for early recognition, detection, and avoidance of ADRs leading to appropriate with safe usage of drugs.

Assessment of antitubercular treatment induced adverse drug reactions data at a tertiary care hospital

Background: Standard anti-tuberculosis (TB) treatment is highly effective, but managing adverse drug responses is a major challenge that can negatively affect treatment compliance and outcomes of an anti-tubercular treatment (ATT) regimen. Hence, monitoring of these adverse drug reactions (ADRs) is very essential wherein the drug-causing ADR can be detected and an appropriate therapeutic regimen can be given to the patient. Aims and Objectives: To assess the ATT-induced ADRs in Individual Case Safety Reports (ICSRs), to find the incidence and prevalence of ADRs due to ATT, and to analyze the causality assessment of the ADRs due to ATT. Materials and Methods: A retrospective observational study was carried out using spontaneous ICSRs data from the ADR monitoring centre at Madras Medical College, Chennai. A suspected adverse drug reaction reporting form (sADR reporting form) provided by the Pharmacovigilance Programme of India was used to collect the data of an ICSR. Results: A total of 93 ICSRs were assessed during the study period. The majority of the ADRs occurred in males (n = 55), and the maximum number of ADRs were found in the age group of 18–44 years (n = 46). The majority of the ICSRs were categorized as “serious” (n = 60), of which the maximum number of ADRs belonged to the “hospitalization/prolonged hospital stay” category (n = 45). Most of the suspected ATT drugs involved in implicating ADRs were found to be fixed-dose combination pills of Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol (n = 71). Most of the ADRs were “skin and subcutaneous disorders” (n = 51) of the system organ class. The outcome of the ADRs was assessed and found that the majority of them were in the “recovering” (n = 54) category, and the majority of the ICSRs were found to be “probable” (n = 67). Conclusion: An effective implementation of a Pharmacovigilance system with early detection and management of ADRs is needed to overcome the nonadherence to TB therapy.

Comparison of injective related reactions following ofatumumab and ocrelizumab in patients with multiple sclerosis: data from the European spontaneous reporting system.

In 2021 ofatumumab, a recombinant human anti-CD20 monoclonal antibody (mAb) already authorized for the treatment of chronic lymphocytic leukemia, received the marketing approval for the treatment of relapsing forms of multiple sclerosis (MS). Differently from ocrelizumab, that is administered intravenously, ofatumumab if the first anti-CD20 mAb to be administered subcutaneously without a premedication. In this study we aimed to describe and compare the main characteristics of Individual Case Safety Reports (ICSRs) describing the occurrence of Injective Related Reactions (IRRs) following the treatment with ocrelizumab and ofatumumab reported in the Eudravigilance (EV) database during years 2021-2023. A total of 860 ICSRs with either ofatumumab and ocrelizumab as suspected drug were retrieved from Eudravigilance, of which 51% associated with ofatumumab and 49% with ocrelizumab. The majority of patients who experienced IRRs following ocrelizumab belonged to the age group of 18-64 years (73%), while the age-group was mostly not specified (55%) in ICSRs reporting ofatumumab as suspected. The distribution of gender was almost similar in the two groups, with the majority of ICSRs related to female patients. "Pyrexia" was the Preferred Term (PT) most reported for ofatumumab, while "Infusion related reaction" were more frequently reported with ocrelizumab. Premedication drugs were reported in 148 ICSRs. Out of 89 ICSRs for which the Time to Event (TTE) was calculated, 74 reported IRRs that occurred the same day of the drug administration. Based on the results of this study, although a risk of ofatumumab-induced IRRs cannot be excluded, it should be considered as manageable considering that the drug seems to be mostly associated with the occurrence of fever. Thus, it is important to continue to closely monitor the use of these in clinical practice to improve the knowledge on their long-term safety.

Harmonization of individual case safety reports transmission requirements among PAHO reference authorities: a review of their current regulation.

To perform optimal monitoring of the safety profile in the postmarketing phase, Marketing Authorization Holders and National Regulatory Authorities (NRAs) must evaluate the adverse drug reactions (ADRs) that occurred and characterize their nature, frequency, and severity. Management is possible through Individual Case Safety Reports (ICSRs), which are the reports of organized and processed data. Globally, the International Council for Harmonisation (ICH) E2B guideline suggests harmonized activities for the ICSR electronic content and transmission. In America, the Pan American Health Organization (PAHO) is the agency responsible to implement cooperation among its members, which are recognized as National Regulatory Authorities of Reference (NRARs) such as Argentina, Brazil, Canada, Chile, Colombia, Cuba, Mexico, and the United States. PAHO published the 'Good Pharmacovigilance Practices for the Americas' suggesting improvement and harmonization in the region. After reviewing the regulatory framework, it is assumed that all NRARs have a regulated ICSR transmission system (i.e. a systematic vigilance system for collecting, analyzing, and disseminating information from ADRs). However, significant differences exist, such as the requirement for social media vigilance, expedited and non-expedited ICSRs, coding, severity, and transmission. The volume of ICSRs has significantly increased, due to using electronic standards managed by the NRAs, which facilitates early identification of new ADRs, allowing the implementation of novel minimization activities, contributing to the continuous assessment of the benefit-risk balance of medicines. Nevertheless, there is still area for improvement, especially in Latin America.

LERCause: Deep learning approaches for causal sentence identification from nuclear safety reports.

Identifying causal sentences from nuclear incident reports is essential for advancing nuclear safety research and applications. Nonetheless, accurately locating and labeling causal sentences in text data is challenging, and might benefit from the usage of automated techniques. In this paper, we introduce LERCause, a labeled dataset combined with labeling methods meant to serve as a foundation for the classification of causal sentences in the domain of nuclear safety. We used three BERT models (BERT, BioBERT, and SciBERT) to 10,608 annotated sentences from the Licensee Event Report (LER) corpus for predicting sentence labels (Causal vs. non-Causal). We also used a keyword-based heuristic strategy, three standard machine learning methods (Logistic Regression, Gradient Boosting, and Support Vector Machine), and a deep learning approach (Convolutional Neural Network; CNN) for comparison. We found that the BERT-centric models outperformed all other tested models in terms of all evaluation metrics (accuracy, precision, recall, and F1 score). BioBERT resulted in the highest overall F1 score of 94.49% from the ten-fold cross-validation. Our dataset and coding framework can provide a robust baseline for assessing and comparing new causal sentences extraction techniques. As far as we know, our research breaks new ground by leveraging BERT-centric models for causal sentence classification in the nuclear safety domain and by openly distributing labeled data and code to enable reproducibility in subsequent research.

Development, assessment and educational impact of a blended e-learning training program on pharmacovigilance implemented in four African countries.

Efforts to improve medication access in low-and middle-income countries, particularly in Sub-Saharan Africa, have made progress, especially in the fight against infectious diseases such as tuberculosis. However, challenges exist in establishing effective pharmacovigilance systems. The PhArmacoVIgilance Africa (PAVIA) project was committed to enhancing pharmacovigilance in Tanzania, Eswatini, Nigeria, and Ethiopia, with an emphasis on anti-tuberculosis drugs, utilizing various methods, including training. This study evaluates the PAVIA training program's effectiveness and its adaptation during the COVID-19 pandemic. A blended e-learning program, incorporating two courses and a platform for educational materials, was developed. This program, designed to train healthcare professionals in pharmacovigilance, was incorporated into a Training of Trainers model. To evaluate the program effectiveness, we used multiple measures such as assessing knowledge gain through pre-and post-test scores, assessing learners' satisfaction and attitudes via questionnaires, and analyzing Individual Case Safety Reports (ICSRs) in VigiBase to determine the impact on spontaneous reporting systems in the PAVIA countries. 121 learners enrolled in the pilot trainings, including 36 from Tanzania, 34 from Eswatini, 25 from Nigeria, and 26 from Ethiopia. Notably, post-test scores were significantly higher than pre-test scores in all four countries. Following the pilot trainings, multiple step-down training sessions were held in Tanzania, Eswatini, and Nigeria, with a total of 827 learners registering and 421 successfully completing the program. Learners' scores on the post-tests were significantly higher than on the pre-tests for both courses in all three countries. Learners' feedback on the training was overwhelmingly positive. Additionally, a qualitative analysis of ICSRs revealed a substantial increase in reports after the training in Tanzania, Eswatini, and Nigeria. An innovative e-learning program trained healthcare professionals in pharmacovigilance and anti-tuberculosis drug safety over 3 years in four PAVIA countries. The program effectively improved participants' knowledge, received positive feedback, and likely had an impact on reporting rates in Tanzania, Eswatini, and Nigeria, although a direct causal link could not be definitively established due to data limitations and other factors, such as the heightened reporting rates associated with COVID-19 vaccines, that could have contributed to the notable increase in ICSRs.

Lumbar CSF fluid drainage in patients with severe acute spinal cord injury. Preliminary safety report of a randomized clinical prospective study. (Preliminary data)

Lumbar CSF fluid drainage in patients with severe acute spinal cord injury. Preliminary safety report of a randomized clinical prospective study. (Preliminary data)

Semantic Encoding Algorithm for Classification and Retrieval of Aviation Safety Reports

Semantic Encoding Algorithm for Classification and Retrieval of Aviation Safety Reports

Lumbar CSF fluid drainage in patients with severe acute spinal cord injury. Preliminary safety report of a randomized clinical prospective study. (Preliminary data)

Lumbar CSF fluid drainage in patients with severe acute spinal cord injury. Preliminary safety report of a randomized clinical prospective study. (Preliminary data)

Resumption of Intravenous Anti-Cancer Therapy in Breast Cancer: A Real-World Experience During the SARS-CoV-2 Pandemic.

The coronavirus disease-2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has delayed medical consultations, especially for patients receiving intravenous anti-cancer therapy. We aim to investigate alterations in immune function among breast cancer patients who experience delayed intravenous therapy due to SARS-CoV-2 infection. We performed an observational investigation of breast cancer patients in Nanjing Drum Tower Hospital from December 27, 2022, to January 20, 2023. Patients who recovered from SARS-CoV-2 infection were eligible for enrollment. Peripheral blood samples were taken prior to the restart of intravenous anti-cancer therapy to examine hematologic parameters. A total of 131 patients were included in the final analysis. Cough (74.0%), fever (62.6%), and expectoration (46.6%) were identified as the most presenting symptoms of SARS-CoV-2 infection in breast cancer. The average nucleic acid conversion time and delayed treatment time was 13.4 days and 13.9 days, respectively. The patients >60 years old experienced prolonged nucleic acid conversion time (P = 0.017) and delayed treatment time (P = 0.028) compared to those <= 60 years old. Dysregulated lymphocyte subsets and cytokines were found post-SARS-CoV-2 infection. Treatment-related adverse events of grade 3 or 4 occurred in 7.6% after resuming intravenous anti-cancer therapy. Our findings reveal that the SARS-CoV-2 infection led to imbalanced immune responses and postponed intravenous anti-cancer therapy in breast cancer. The safety report encourages timely resumption of intravenous anti-cancer therapy after adequately weighing the risks and benefits.

Monitoring of adverse drug reactions during seasonal malaria chemoprevention campaigns in children aged 3–59 months in Burkina Faso

Seasonal malaria chemoprevention (SMC) by mass administration of sulfadoxine pyrimethamine + amodiaquine (SPAQ) reduces the burden of malaria in children aged 3-59 months. The occurrence of adverse drug reaction (ADR) may affect the success of this intervention. There are few studies of SMC adverse event surveillance in sub-Saharan Africa, particularly in Burkina Faso, a highly endemic country. Our main objective was to characterize the ADRs reported during SMC campaigns in Burkina Faso. Secondly, we evaluated the performance of the pharmacovigilance integrated into the SMC program in order to support safe administration of SMC. This was a retrospective descriptive study of SMC individual case safety reports recorded in VigiBase® in Burkina Faso from 2014 to 2021. We used the P-method for the analysis of preventable serious adverse drug reactions and WHO criteria for assessing the performance of pharmacovigilance integrated into the SMC program. A total of 1,105 SMC individual case safety reports were registered in VigiBase® for 23,311,453 doses of SPAQ given between 2014 and 2021. No pharmacovigilance signal was detected. The number of serious cases was 101, of which 23 (22.8%) were preventable. In 38.1% of children, the occurrence of ADRs led to discontinuation of SMC treatment. Vomiting was the most frequently reported adverse drug reaction (48.0%). The proportion of children whose treatment was discontinued due to vomiting was 42.7%, while the proportion of treatment discontinuation for other ADRs was 32.8% (p = 0.01). The SMC program contributed at 46.2% to the national pharmacovigilance database. The reporting rate was 0.03 per 1,000 exposed children in 2021. The median completeness score of the ICSRs was 0.7 (IQR: 0.5-0.7), and the median time to register the ICSRs in VigiBase® was 204 (IQR: 143-333) days. Post-drug administration vomiting may interfere with the purpose of SMC. Measures to manage this adverse drug reaction should be taken to improve the success of the SMC program. Based on the information on reporting time and reporting rate, spontaneous reporting should be supported by active surveillance, including cohort event monitoring, in Burkina Faso.

Characteristics and patient impact of boarding in the pediatric emergency department, 2018–2022

ObjectivesBoarding admitted patients in the emergency department is an important cause of throughput delays and safety risks in adults, though has been less studied in children. We assessed changes in boarding in a pediatric ED (PED) from 2018 to 2022 and modeled associations between boarding and select quality metrics. MethodsWe performed a retrospective analysis of PED patients admitted to non-psychiatric services, broken into four periods: pre-COVID-19 (Period I, 01/2018–02/2020), early pandemic (II, 03/2020–06/2021), COVID-19 variants (III, 07/2021–06/2022), and non-COVID respiratory viruses (IV, 07/2022–12/2022). Patients were classified as critical (intensive care units (ICU)) or acute care (non-ICU inpatient services) based on their initial bed request. We compared median boarding times with Kruskal-Wallis tests. We assessed the relationship between boarding time and hospital length-of-stay (LOS) through hazard regression models, and the association between boarding time and PED return visit, readmission, and patient safety events through adjusted logistic regressions. ResultsMedian PED boarding time significantly increased from Period I (acute: 2.4 h; critical: 3.0 h) to Period II (acute: 3.0 h, critical: 4.0 h) to Period III (acute: 4.4 h, critical: 6.6 h) to Period IV (acute: 6.2 h; critical: 9.5 h). On survival analysis, as boarding time increased, hospital LOS increased for acute admissions and decreased for critical admissions. Increased acute care boarding time was associated with higher odds of a filed safety report. ConclusionsSince July 2021, PED boarding time increased for admitted children across acute and critical admissions. The relationship between acute care boarding and longer hospital LOS suggests a resource-inefficient, self-perpetuating cycle that demands multi-disciplinary solutions.

SARS-CoV-2 Vaccination and the Multi-Hit Hypothesis of Oncogenesis.

Cancer is a complex and dynamic disease. The "hallmarks of cancer" were proposed by Hanahan and Weinberg (2000) as a group of biological competencies that human cells attain as they progress from normalcy to neoplastic transformation. These competencies include self-sufficiency in proliferative signaling, insensitivity to growth-suppressive signals and immune surveillance, the ability to evade cell death, enabling replicative immortality, reprogramming energy metabolism, inducing angiogenesis, and activating tissue invasion and metastasis. Underlying these competencies are genome instability, which expedites their acquisition, and inflammation, which fosters their function(s). Additionally, cancer exhibits another dimension of complexity: a heterogeneous repertoire of infiltrating and resident host cells, secreted factors, and extracellular matrix, known as the tumor microenvironment, that through a dynamic and reciprocal relationship with cancer cells supports immortality, local invasion, and metastatic dissemination. This staggering intricacy calls for caution when advising all people with cancer (or a previous history of cancer) to receive the COVID-19 primary vaccine series plus additional booster doses. Moreover, because these patients were not included in the pivotal clinical trials, considerable uncertainty remains regarding vaccine efficacy, safety, and the risk of interactions with anticancer therapies, which could reduce the value and innocuity of either medical treatment. After reviewing the available literature, we are particularly concerned that certain COVID-19 vaccines may generate a pro-tumorigenic milieu (i.e., a specific environment that could lead to neoplastic transformation) that predisposes some (stable) oncologic patients and survivors to cancer progression, recurrence, and/or metastasis. This hypothesis is based on biological plausibility and fulfillment of the multi-hit hypothesis of oncogenesis (i.e., induction of lymphopenia and inflammation, downregulation of angiotensin-converting enzyme 2 (ACE2) expression, activation of oncogenic cascades, sequestration of tumor suppressor proteins, dysregulation of the RNA-G quadruplex-protein binding system, alterationof type I interferon responses, unsilencing of retrotransposable elements, etc.) together with growingevidence and safety reports filed to Vaccine Adverse Effects Report System (VAERS) suggesting that some cancer patients experienced disease exacerbation or recurrence following COVID-19 vaccination. In light of the aboveand because some of these concerns (i.e., alteration of oncogenic pathways, promotion of inflammatory cascades, and dysregulation of the renin-angiotensin system) also apply to cancer patients infected with SARS-CoV-2, we encourage the scientific and medical community to urgently evaluate the impact of both COVID-19 and COVID-19 vaccination on cancer biology and tumor registries, adjusting public health recommendations accordingly.

“A shot reputation:” rape in colonial Australia and why it matters today

emotion that is a learned response and its effect on society. The roots of the framing of rape and sexual assault as we see it today in Australia go back to colonial times and the narratives of sexual crime executed in racy language that were freely circulated in Australian colonial press. The reports of Mount Rennie rape case by the frequency and “cross-cultural references invoked in discussing the crime achieved a singular level of cultural production which has far wider references than legal history” (Peers 1998). They gave birth to the debate of the “real rape” vs. “simple rape” as defined by Susan Estrich (1987) and marked Australian public discourse and public attitude toward rape until the present day. Thus, in November 2015 Michaelia Cash, Minister for Employment and Minister for Women claimed “We have a national crisis when it comes to violence against women in Australia” to which testify reports of the Australian Bureau of Statistics on women’s safety, National Student Safety report, all the way to Brittany Higgins’ story and the way it was dealt with in the media and within the legal system. As long as “One in seven young Australians say rape is justified if women change their mind” according to National Community Attitudes Towards Violence Against Women Survey (NCAS) there is still a lot to be done to change the cultural narrative of “real rape” so that rape does not go underreported and unpunished as women fear shot reputation.

Surgical Resection of Neurogenic Heterotopic Ossification around Hip Joint in Stroke Patients: A Safety and Outcome Report.

Resection remains the most reliable treatment for established heterotopic ossification, despite questions regarding its effectiveness due to the potential for complications. This study evaluated the clinical outcomes and complications of neurogenic heterotopic ossification (NHO) resection in stroke patients' ankylosed hips. We retrospectively analyzed nine hip NHO resections performed on seven patients from 2010 to 2018. The pre- and postoperative range of motion of the operated hip were compared. Analysis of postoperative complications, including infection, recurrence, iatrogenic fracture, and neurovascular injury was performed. The mean operative time was 132.78±21.08 minutes, with a mean hemoglobin drop of 3.06±0.82 g/dL within the first postoperative week. The mean duration of postoperative follow-up was 52.08±28.72 months for all patients. Postoperative range of motion showed improvement from preoperative. Flexion and external rotation (mean, 58.89±30.60° and 16.67±18.03°, respectively) showed the greatest gain of motion of the operated hip joint. Postoperative infections resolved in two cases through surgical debridement, and one case required conversion to total hip arthroplasty due to instability. There were no recurrences, iatrogenic fractures, or neurovascular injuries. Resection is a beneficial intervention for restoring the functional range of motion of the hip in order to improve the quality of life for patients with NHO and neurological disorders. We recommend performance of a minimal resection to achieve a targeted functional arc of motion in order to minimize the risk of postoperative complications.

Can a self-inspection programme improve compliance with professional standards in a hospital pharmacy?

Abstract Introduction Pharmacies must comply with professional standards to provide high-quality services. However, gaining assurance of compliance can be challenging and self-inspection was investigated as a means of consistently achieving this. Aim This project aimed to develop and implement a self-inspection programme to assess compliance with professional standards in a hospital pharmacy. Through the self-inspections, we aimed to identify required improvements and maintain achieved compliance through effective reporting, evaluation, and communication of results. Methods Standards from Royal Pharmaceutical Society professional guidance1, standards2 and General Pharmaceutical Council standards3 were used to create 41 self-inspection questions. These assessed different aspects of medicines management, including the receipt, storage, dispensing, delivery, disposal, and security of medicines. They also assessed compliance with health and safety measures and service quality indicators taken from the monthly quality report, health and safety report, cleaning logs, expiry date checks and stock checks in the department. Self-inspections were conducted monthly over a 12-month period by members of the Pharmacy Senior Leadership Team. Self-inspections were recorded using the Tendable accreditation application. Training in using the application and a standard operating procedure was in place to support this. Questions in the self-inspection were only answered as “Yes” or “No”. Additional information, images or actions taken were required for any question that was negatively scored. Following self-inspections, results were calculated by the application and a summary generated. A full report was also produced by the application. These were analysed by the Pharmacy Quality Assurance Team and included in the monthly departmental quality report for review by the Pharmacy Senior Leadership Team. Any identified actions were communicated by e-mail to the relevant team leader and an inspection summary later displayed in the department. This study did not require ethics approval. Results Compliance with standards increased steadily from 75% on the first self-inspection to 95%, with an average of 89% over the 12 months. During the self-inspections, non-compliance with 14 different standards was identified. 3 concerned non-compliance of staff with processes, which was addressed and not repeated. 11 concerned non-compliance that was repeated, including delays in updating essential documents, delays in completing essential tasks, medicines storage not complying with requirements, a correct responsible pharmacist notice not displayed and building work disrupting services. All of these have now been resolved, except deficiencies in the storage of bulk fluids, where risks have been mitigated and a long-term plan is in place. Discussion/Conclusion Compliance with professional standards in the pharmacy has been improved through the implementation of a self-inspection programme. Questions in the self-inspection defined the required standards and guidance on conducting self-inspections ensured consistent assessment, enabling both compliance and non-compliance to be identified. Processes for reporting, evaluating and communicating results from the self-inspections directed how non-compliance was resolved. This promoted awareness of required standards and helped maintain achieved compliance. Limitations of the study included failing to assess compliance with standards not covered in the self-inspection questions. A regular review of self-inspection questions, standards and results is therefore required to maintain reliability and continued improvement.

Analysis of the Risk of Infection Stratified By Absolute Neutrophil Counts during Deferiprone-Associated Severe Neutropenia or Agranulocytosis

Introduction Patients with transfusional iron overload receiving iron chelation therapy with deferiprone may experience a decrease in absolute neutrophil counts (ANC) that range from mild (ANC &amp;lt;1.5 x 10 9/L) to severe neutropenia/agranulocytosis (typically defined as ANC &amp;lt;0.5 x 10 9/L), and which put them at risk for infections. In patients taking deferiprone, the risk of infection and/or mortality associated with ANC of &amp;lt;0.2 or &amp;lt;0.1 x 10 9/L is unknown. Our objective was to analyze data from patients taking deferiprone in clinical trials and the postmarketing setting to determine the incidence and severity of infection stratified by ANC levels. s Methods The clinical trial setting involved patients with systemic iron overload who had thalassemia, sickle cell disease, or other anemias and received deferiprone across 15 clinical trials. Data associated with episodes of severe neutropenia/agranulocytosis in patients who had been treated with at least 1 dose of deferiprone were reviewed. For the postmarketing setting, all individual case safety reports since the first market approval of deferiprone on August 25, 1999 to August 31, 2021, were reviewed; cases coded to agranulocytosis were extracted; cases without any reported ANC were removed; and cases with at least 1 ANC value were analyzed. Obtaining confirmed ANC value was not always possible in the postmarketing setting. All infections occuring within ±2 weeks of agranulocytosis onset were identified, graded for severity, and classified as serious, including fatal or life-threatening. Serious events were defined as any event that resulted in death, was life-threatening, required hospitalization or prolonged existing hospitalization, caused disability or permanent damage, caused congenital anomaly, or was classified as an important medical event. Infection events associated with ANC values were categorized into 3 groups based on the nadir ANC (all x 10 9/L): Group A, ANC ≥0.2 to &amp;lt;0.5; Group B, ANC ≥0.1 to &amp;lt;0.2; or Group C: ANC &amp;lt;0.1. Results A total of 977 patients with systemic iron overload received deferiprone in sponsored clinical trials. Among those, 9 patients were in Group A, 3 in Group B, and 10 in Group C. Of the 12 patients in Groups A and B, none had serious, severe, or fatal infections ( Table 1). Three of the 10 (30.0%) patients in Group C experienced serious or severe infections that included (1) parvovirus infection accompanied by diarrhea, a maculopaular rash, and pyrexia resulting in hospitalization; (2) a severe but nonserious respiratory tract infection with esophageal candidiasis in a patient with a history of neutropenia prior to initiating deferiprone; and (3) a fatal case of Pseudomonal sepsis in a patient who had a history of multiple cardiac and pulmonary comorbidities. Deferiprone was permanently discontinued in all 3 patients. From postmarketing data, of a total of 238 adverse reactions that were coded as agranulocytosis, 176 had at least 1 ANC value. Among those, 65 reactions were in Group A, 20 in Group B, and 91 in Group C. Among the reactions in Group A, 5/65 (7.7%) had serious infections and 3 of them (4.6%) had fatal outcomes due to sepsis ( Table 2). Among the reactions in Group B, 2/20 (10.0%) had serious infections, with a fatal outcome in one of them (5.0%); the death was from sepsis and the life-threatening infection involved pneumonia with multiple pulmonary complications. Among the reactions in Group C, 12/91 (13.2%) had serious infections and 8 of them (8.8%) had fatal outcomes; the 8 deaths were associated with sepsis. The 4 serious non-fatal infections involved sepsis; pancytopenia with ANC nadir of 0 accompanied by oropharyngeal pain, fever, and diarrhea that required hospitilization; angioinvasive mucormycosis; and disseminated herpes simplex accompanied by sepsis, resulting in hospitalization. Conclusion Patients receiving deferiprone who become neutropenic are generally at a higher risk of infections or mortality with lower neutrophil levels (ie, ANC &amp;lt;0.2 or &amp;lt;0.1 x 10 9/L compared with ANC ≥0.2 to &amp;lt;0.5 x 10 9/L). Our findings are consistent with the recently published guidelines from the European Hematology Association and the European Network for Innovative Diagnosis and Treatment of Chronic Neutropenias that used agranulocytosis to describe events with ANC of ≤0.2 x 10 9/L in association with a high risk of severe and life-threatening infections.

Cumulative Review of Hypertension in Patients with Chronic Lymphocytic Leukemia (CLL) and Other Hematologic Malignancies Treated with Acalabrutinib

Background: Patients (pts) with CLL have a high rate of comorbidities, including cardiovascular disease (CVD). Comorbid CVD is correlated with higher mortality in this pt population. Hypertension (HTN) is the most common concurrent CVD in pts with CLL and is associated with development of complications such as stroke and heart failure. The incidence of new or worsening HTN in treatment-naive CLL pts receiving placebo within the CLL12 trial was 8.3% over a 69.3-month observation period (Langerbeins et al. Hematol Oncol. 2023). New and/or worsening HTN has been observed in pts with CLL treated with Bruton tyrosine kinase inhibitor (BTKi) therapy. Studies have shown new or worsening HTN with ibrutinib (7−30%) and zanubrutinib (11−20%) (Christensen et al. Expert Rev Hematol. 2022). Acalabrutinib (acala), a selective, second-generation BTKi, demonstrated a lower rate of HTN (8.6%) vs ibrutinib (22.8%) in the head-to-head ELEVATE-RR study at a median follow-up of 40.9 months (Byrd et al. J Clin Oncol. 2021). Here, we performed a cumulative analysis of new or worsening HTN from the acala global development program and compared these data against real-world prevalence and incidence of HTN for pts with CLL prior to treatment initiation using claims data. Methods: Safety reports of new or worsening HTN were obtained from 11 clinical trials with acala (the safety database analysis comprised 2034 pts from studies in CLL [86.3%] and mantle cell lymphoma [6.1%], with the remainder from other B-cell malignancies). The clinical trials analyzed included therapy with acala (monotherapy or in combination with obinutuzumab) and active comparator groups (described in Table 1). Using the narrow Standardized MedDRA Query and the related MedDRA preferred terms for “HTN,” exposure-adjusted incidence rates in events/100 person-years were determined, and as a comparison, HTN prevalence was assessed at median treatment exposure for acala monotherapy. HTN prevalence (proportion of pts with HTN 6 months before treatment initiation) and incidence rates (number of new cases of HTN per 100 person-years during the 5 years before any treatment initiation) were also assessed based on ICD-10 codes from 3 adjudicated closed claims databases (Optum, MarketScan, and IQVIA). Results: In the claims database analysis, prevalence of HTN ranged from 47.3% to 66.1% in pts with TN CLL prior to treatment initiation. HTN prevalence with acala monotherapy at median treatment exposure (45.5 months) was 55.7%. Exposure-adjusted incidence rates of HTN were analyzed from 11 clinical trials; 1225 pts received acala monotherapy (947 pts with CLL), 223 pts received acala + obinutuzumab (all pts with CLL), 264 pts received ibrutinib as a comparator (all pts with CLL), and 322 pts received other comparators (all pts with CLL). Among the 1225 pts treated with acala monotherapy, 165 pts (147 with CLL) experienced a treatment-emergent adverse event of HTN (median age 66 years; 66.1% [n=109] male; 59.4% [n=98] with history of HTN at baseline). The exposure-adjusted incidence rates of HTN with acala monotherapy (3.844) and acala + obinutuzumab (3.926) were similar to that of other comparators (4.788 [excluding ibrutinib]) ( Table 1). In the ELEVATE-RR study specifically (subgroup of the current analysis), the exposure-adjusted incidence rate of HTN with acala (3.053) was approximately one-third that of ibrutinib (8.590). The exposure-adjusted incidence rate of HTN in pts treated with acala monotherapy without history of HTN was 3.239. Conclusions: Our data showed that HTN is a common comorbidity in pts with CLL as demonstrated in the claims database and clinical trial database analyses where 59.4% of pts who experienced HTN with acala monotherapy had history of HTN at baseline. The incidence rates of new or worsening HTN with acala monotherapy and acala + obinutuzumab were low (3.844 and 3.926, respectively). This is supported by similar incidence proportion of new or worsening HTN in pts receiving placebo (8.3%) from CLL12 (median follow-up 69.3 months) and acala monotherapy (8.9%) from ELEVATE-TN (median follow-up 58.2 months; Sharman et al. EHA. 2022), and similar HTN prevalence at median treatment exposure vs before treatment initiation in claims databases. Our analysis, conducted predominantly in patients with CLL, suggests that acala monotherapy did not worsen pre-existing HTN or increase the risk of new-onset HTN.

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

BackgroundHeart 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. MethodsWe 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. ResultsThe 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). ConclusionsIn 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.

Safety and Efficacy Report for the Use of Poly-4-Hydroxybutyrate as a Retropubic Mid-Urethral Sling (MUS) for Stress Urinary Incontinence: A Prospective 24 Months Follow-Up of New Poly-4-Hydroxybutyrate TephaFlex SUI Bioresorbable MUS

To investigate the feasibility and safety of the retropubic mid-urethral sling (MUS) procedure with a resorbable mesh implant made of poly-4-hydroxybutyrate (P4HB). A prospective clinical cohort study with 24 months follow-up. A tertiary academic hospital. Seventeen women with moderate to severe stress urinary incontinence (SUI). A retropubic MUS procedure with P4HB sling. Seventeen women underwent an uncomplicated MUS procedure with a new sling made of resorbable P4HB. Following safety criteria, there has been no need to stop the study before 24 months' end point. Three serious adverse events were reported during follow-up: (1) inability to void urine after 1 week postsurgery, (2) a hysterectomy and bilateral oophorectomy performed due to a precancerous endometrial lesion at 16 months after initial MUS procedure and (3) exposed mesh with a part of device sheath left behind. These participants underwent an uncomplicated reintervention with no additional and/or permanent harm. Reinterventions because of failure of cure contained 3 second MUS procedures and one admission of urethral bulking agent. Seventy-six percent and 47 percent of patients were objectively cured of SUI at 12 and 24 months, respectively. Preliminary evidence suggests that a sling made of P4HB can be safely used for MUS procedures and could be an alternative for permanent polypropylene slings in patients that prefer the use of nonpermanent material.