Serious Adverse Events In Patients Research Articles

Immediate hypersensitivity reactions to parenteral cyclosporine in patients with thalassemia major undergoing hematopoietic stem cell transplantation: a case report and review of the literature.

Allogeneic hematopoietic stem cell transplantation is a definitive cure for eligible patients with thalassemia major, and calcineurin inhibitors are essential for preventing graft-versus-host disease. Although invaluable, there are few reports of life-threatening hypersensitivity reactions associated with calcineurin inhibitors. These reactions are generally rare but seem to be more prevalent among patients with thalassemia. Herein, we retrospectively report four cases of patients with thalassemia major who developed hypersensitivity reactions to parenteral cyclosporine. The cases include one 19-year-old Caucasian female and three Caucasian males, aged 17, 10, and 20years, respectively. The patients exhibited symptoms of varying severity, necessitating different management strategies. The reactions occurred either immediately or within a few minutes after the onset of cyclosporine infusion and were often worsened by rechallenge. In all cases, cyclosporine was eventually replaced with tacrolimus or sirolimus. A comprehensive literature review was conducted to investigate the basis of severe immunoglobulin E-mediated hypersensitivity reactions to calcineurin inhibitors in patients with thalassemia major undergoing hematopoietic stem cell transplantation. Several immunogenic factors may potentially increase the susceptibility of these patients to hypersensitivity reactions to Cremophor-containing medications. While severe reactions to calcineurin inhibitors remain rare, clinicians should be aware of the potential for serious adverse events in patients with thalassemia.

Right ventricular to pulmonary artery coupling credicts poor outcomes after interatrial shunting in heart failure

Abstract Background Left atrial decompression is under investigation for heart failure (HF) with the potential to improve symptoms and potentially clinical outcomes. However, heterogeneous outcomes have been observed in randomized controlled studies. Purpose This study aimed to explore whether right ventricular (RV) -pulmonary artery (PA) coupling, as assessed from the tricuspid annular plane systolic excursion (TAPSE) /systolic PA pressure ratio, can be useful in predicting outcomes after implantation of the interatrial shunting device. Methods A total of 106 HF patients, n=62 with reduced ejection fraction (HFrEF), n=44 with preserved ejection fraction (HFpEF), were prospectively enrolled in the PRELIEVE registry with the Atrial Flow Regulator (AFR) implantation. Serious adverse events included cardiovascular mortality and HF worsening (W). Results Serious adverse events (SAEs) occurred in a total of 19 (18%) patients. There were no differences in baseline comorbidities, KCCQ scores, the 6-minute walking distance between patients with and without SAEs (Table). Patients with SAEs showed higher systolic pulmonary arterial pressure, NT-proBNP, serum creatinine and lower TAPSE/PASP ratio. Incidence of SAEs was higher in patients within the first TAPSE/PASP vs the third tertile (59% vs 12%, p=0.026), respectively. A TAPSE/PASP of <0.55 was identified to bear the most optimal sensitivity to predict the event (AUC=0.683, CI95% (0.533-0.833). Conclusion The reduced TAPSE/PASP ratio was associated with higher rates of serious adverse events in patients with heart failure undergoing controlled inter-atrial shunting. The hypothesis generating finding that reduced RV-PA coupling may identify potential clinical non-responders to left atrial decompression should be further prospectively validated.

Efficacy and safety of fexuprazan in patients with symptoms and signs of laryngopharyngeal reflux disease: a randomized clinical trial.

Laryngopharyngeal reflux disease (LPRD) is mainly treated with proton pump inhibitors (PPI) such as esomeprazole, which have shortcomings like delayed absorption and increased osteoporosis. Fexuprazan is a novel potent potassium-competitive acid blocker that inhibits gastric acid secretion with rapid onset and long duration of action. To assess the efficacy and safety of fexuprazan compared to esomeprazole in patients with LPRD. This prospective, randomized, double-blinded, multicenter, active-controlled trial was conducted in nine otolaryngologic clinics. Patients with reflux symptom index (RSI) ≥ 13 and reflux finding score (RFS) ≥ 7 were randomly assigned to the fexuprazan or esomeprazole groups, and received fexuprazan 40-mg or esomeprazole 40-mg once daily for 8weeks. The outcomes were (1) mean change, change rate, and valid rate in RSI, RFS, and LPR-related questionnaires; and (2) adverse events. A total of 136 patients (fexuprazan n = 68, esomeprazole n = 68) were followed up for ≥ 1month. Each parameter significantly improved after 4 and 8weeks in each group, with no significant differences between the two groups. For those with severe symptoms (RSI ≥ 18), the fexuprazan group (n = 32) showed more improvement in the mean change and change rate in the RSI than esomeprazole group (n = 31) after 4weeks (p = .036 and .045, respectively). This phenomenon was especially observed in hoarseness and troublesome cough. Fexuprazan improved symptoms and signs without no serious adverse events in patients with LPRD. In patients with severe symptoms, fexuprazan resulted in a faster symptom improvement than PPI. KCT0007251, https://cris.nih.go.kr/cris/search/detailSearch.do?seq=22100 .

Ketamine for Critically Ill Patients with Severe Acute Brain Injury: A Systematic Review with Meta-analysis and Trial Sequential Analysis of Randomized Clinical Trials.

Patients with severe acute brain injury have a high risk of a poor clinical outcome due to primary and secondary brain injury. Ketamine reportedly inhibits cortical spreading depolarization, an electrophysiological phenomenon that has been associated with secondary brain injury, making ketamine potentially attractive for patients with severe acute brain injury. The aim of this systematic review is to explore the current literature regarding ketamine for patients with severe acute brain injury. We systematically searched international databases for randomized clinical trials comparing ketamine by any regimen versus placebo, no intervention, or any control drug for patients with severe acute brain injury. Two authors independently reviewed and selected trials for inclusion, extracted data, assessed risk of bias, and performed analysis using Review Manager and Trial Sequential Analysis. Evidence certainty was assessed using Grading of Recommendations Assessment, Development and Evaluation. The primary outcomes were the proportion of participants with an unfavorable functional outcome, the proportion of participants with one or more serious adverse events, and quality of life. We identified five randomized trials comparing ketamine versus sufentanil, fentanyl, other sedatives, or saline (total N = 149 participants). All outcomes were at overall high risk of bias. The proportions of participants with one or more serious adverse events did not differ between ketamine and sufentanil or fentanyl (relative risk 1.45, 95% confidence interval 0.81-2.58; very low certainty). Trial sequential analysis showed that further trials are needed. The level of evidence regarding the effects of ketamine on functional outcome and serious adverse events in patients with severe acute brain injury is very low. Ketamine may markedly, modestly, or not at all affect these outcomes. Large randomized clinical trials at low risk of bias are needed.

Efficacy and safety of immune checkpoint inhibitors in recurrent or metastatic nasopharyngeal carcinoma: A systematic review and meta-analysis.

e14612 Background: Treatment options for recurrent or metastatic nasopharyngeal carcinoma (NPC) are limited. Recently, the introduction of Immune Checkpoint Inhibitors (ICIs), either as single agents or combined with other treatment options, has emerged as a potential treatment for NPC. Hence, we performed a systematic review and meta-analysis to evaluate the efficacy and safety of ICIs compared to standard chemotherapy. Methods: We systematically searched PubMed, EMBASE, and Cochrane databases for randomized controlled trials (RCTs) comparing ICIs versus standard chemotherapy in patients with NPC. The main outcomes were progression-free survival (PFS), overall survival (OS) and adverse events rate. All analyses used a random-effects model, with 95% confidence intervals (CIs) and were conducted on Review Manager 5.4. Results: A total of 1,188 patients from 5 RCTs were included, of which 634 (53.3%) received PD-1 inhibitors. In a pooled analysis of all studies, treatment with ICIs demonstrated a statistically significant benefit in OS (HR 0.73; 95% CI 0.61-0.87; p<0.01). In trials evaluating ICI monotherapy versus chemotherapy (617 patients), PFS was not significantly different between groups (p=0.91). However, pooling two studies evaluating ICI combined with chemotherapy vs. chemotherapy (541 patients) demonstrated higher PFS for the ICI group (HR 0.53; 95% CI 0.42-0.67; p<0.01). Overall pooled PFS was non-significant (HR 0.75; 95% CI 0.49-1.16; p=0.20). In all subgroup analyses, patients treated with ICI achieved greater PFS than chemotherapy: low EBV DNA level (HR 0.61; 95% CI 0.42-0.87; p=0.007) or high EBV DNA level (HR 0.44; 95% CI 0.35-0.56; p<0.01), without liver metastasis (HR 0.68; 95% CI 0.47-0.98; p=0.04), and with liver metastasis (HR 0.56; 95% CI 0.38-0.83; p=0.04). Moreover, ICIs were well tolerated and not associated with an increased risk of serious adverse events (HR 0.96; 95% CI 0.82-1.11; p=0.56). The frequency of hypothyroidism increased in the ICI group (HR 2.07; 95% CI 1.63-2.63; p<0.01). Other adverse events had similar rates in both groups, such as AST and ALT levels, diarrhea, pruritus, rash, stomatitis, and vomiting. Conclusions: This meta-analysis demonstrated that immune checkpoint inhibitors significantly enhanced overall survival without substantially increasing serious adverse events in patients with M/R NPC. Further studies are needed to identify the patients who benefit the most from ICI monotherapy or combination therapies. [Table: see text]

Development of a rapid HPLC-fluorescence method for monitoring warfarin metabolites formation: In vitro studies for evaluating the effect of piperine on warfarin metabolism and plasma coagulation

Warfarin, a widely prescribed anticoagulant, is highly effective for various coagulation disorders. However, its efficacy is limited by a narrow therapeutic index and frequent drug interactions, especially those involving metabolism by Cytochrome P450 (CYP450) enzymes. Piperine, found in black and long pepper, possesses blood-thinning properties and has been observed to inhibit CYP3A and CYP2C enzymes linked to warfarin metabolism. This study investigated the effect of piperine on warfarin metabolism in liver microsomes using a rapid and sensitive HPLC-Fluorescence method. The use of PFP (pentafluorophenyl) column with core shell particles provided the selectivity and resolution to resolve warfarin and its 4-, 6-, 7-, and 10-hydroxy metabolites in addition to the internal standard naproxen in less than 3 min. This is the fastest analytical assay for warfarin and its major metabolites reported to date, making it ideal for metabolic studies. The applicability of the method was demonstrated by monitoring the metabolism of S-warfarin in human and rat liver microsomes, and evaluating the inhibitory effect of piperine on metabolite formation. The results showed that piperine inhibited the formation of the major metabolite, 7-hydroxywarfarin, with half-maximal inhibitory concentration (IC50) 14.2 μM and 3.2 μM in human and rat liver microsomes, respectively. Furthermore, coagulation studies in vitro using rat plasma showed that piperine does not affect prothrombin time (PT) and activated partial thromboplastin time (aPTT). This study suggested that piperine may present a potential drug interaction with warfarin at the metabolism level, but has no direct effect on the activation of the extrinsic or intrinsic coagulation cascades. Further clinical investigation is therefore required, as piperine may increase the bioavailability of warfarin, thus increasing risk of serious adverse events in patients.

Abstract 3560: Quantified kinematics and wearable sensors to predict serious adverse events in patients undergoing cancer therapy trials

Abstract Background: Serious adverse events (SAEs) are a critical determinant of drug toxicity in clinical trials. However the drivers of toxicity may be related to patient factors as much or more than drug related factors. Prior studies have shown that time in non-sedentary activity predicted toxicity in cancer patients receiving highly emetogenic chemotherapy. SAEs are a critical determinant of drug toxicity in clinical trials. However, predicting SAEs using conventional PS scales measurements, such as ECOG is challenging because measurements can vary among observers. Prior studies have used activity trackers to measure physical activity and showed that time spent in non-sedentary activity predicted toxicity in cancer patients receiving highly emetogenic chemotherapy. Here, we sought to extend these findings to early phase clinical trial participants by examining data collected in two single-arm, observational, prospective studies at USC Keck and MD Anderson centers. We explored the use of out-of-clinic wearable sensors as an objective metric of frailty so as to identify patients at risk for therapy complications. Methods: Adult patients diagnosed with cancer and enrolled in early stage clinical trials across USC Keck and MD Anderson centers were included in parallel single-arm, observational, prospective studies. Patients used a consumer grade wearable activity tracker (Fitbit) and the study examined associations between the number of severe adverse events to activity levels measured by metabolic equivalents (METs) and get-up-go times across the first 30 days. Trends were assessed using t-tests. Results: 36 eligible patients were included in METs activity analysis. There was a total of 16 recorded incidences of SAEs within the first 30 study days, with 10 patients experiencing at least one SAE. The median non-sedentary time for patients with no SAEs was 27.5 hours above 1.5 METs per week, compared to 21.5 hours for those with at least one SAE occurrence (p-value=0.0146, r2=0.1629). The median get-up-go times for those without SAEs was 10.0 seconds (n=26) and with SAEs was 9.8 seconds (n=10), (p-value=0.828, r2=0.0014). Conclusions: Non-sedentary time, as an objective measure of activity, can be used to identify those patients who are at greatest risk for SAEs in clinical trials. Widely available and inexpensive consumer grade sensors can be used as a stratification tool. Findings should be confirmed in larger patient cohorts across a wider variety of trial settings. Figure 1: Weekly non-sedentary hours vs. presence of SAE in first 30 days of trial enrollment Citation Format: Eli Tran, Luciano Nocera, Anand Kolatkar, Anthony El-Khoueiry, Jacob Thomas, Peter Kuhn, Andrew Zeng, Megumi Kai, Meghan Karuturi, Jorge Nieva. Quantified kinematics and wearable sensors to predict serious adverse events in patients undergoing cancer therapy trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3560.

P543 Patients in trials of moderate-to-severe UC who are exposed to placebo are more likely to suffer harm than those receiving active treatment: The lack of clinical equipoise in traditional study designs

Abstract Background Ulcerative Colitis (UC) is a relapsing-remitting inflammatory disease of the colon and rectum. There are many challenges to the recruitment of eligible individuals into clinical trials for IBD, including the availability of multiple standard-of-care treatment options and patient refusal to participate in randomized placebo (PBO)-controlled trials due to fear of receiving PBO. Patient harm across clinical trials for moderate-to-severe UC has not been adequately examined. We sought to quantify the potential harm to patients recruited to PBO. Methods We reviewed phase 3 clinical trials of therapies for moderate-to-severe UC including anti-TNF-alpha (infliximab, adalimumab, golimumab), anti-integrin (vedolizumab), anti-interleukin (IL) 12/23 (ustekinumab), anti-IL23 (mirikizumab, guselkumab), Janus kinase inhibitors (tofacitinib, upadacitinib), and sphingosine-1 phosphate receptor modulators (ozanimod, etrazimod). We analyzed the proportions (# of pts. with events/cohort size) of adverse events (AEs), serious adverse events (SAEs), disease exacerbation AEs (DEAEs), and disease exacerbation SAEs (DESAEs). We calculated Number Needed to Harm (NNH = 1/Incidence rate in cohort) for PBO (NNHPBO) and experimental therapy (NNHRx) in each trial. Maintenance phase NNHs were categorized as treat-through (TT) or re-randomized (RR). Results We identified an increased probability of AEs in the PBO arm of 7/11 induction (NNHPBO= 2.18-11.06; NNHRx=2.47-16.52), 1/8 TT maintenance, and 5/11 RR maintenance (NNHTTPBO = 1.2-3.1; NNHTTRx =1.1-16.4; NNHRRPBO = 1.3-10.8). We identified an increased probability of SAEs for 8/11 induction (NNHPBO=14.5-58.0; NNHRx=22.13-101.0), 4/8 TT, and 5/11 RR (NNHTTPBO = 3.9-23.3; NNHTTRx =4.2-29.9; NNHRRPBO = 8.8-35.0). Patients were at increased probability of DEAEs in the PBO arm of 8/11 induction (NNHPBO=7.38-43.20; NNHRx=12.50-106.33), 7/8 TT, and 7/10 RR (NNHTTPBO = 3.0-11.1; NNHTTRx =4.3-15.0; NNHRRPBO = 2.7-25.2). DESAEs were at increased probability of harm in the PBO arm of 8/9 induction (NNHPBO=29.00-116.00; NNHRx=47.43-119.75), 3/5 TT, and 7/10 RR (NNHTTPBO = 14.4-52.0; NNHTTRx =13.2-230.0; NNHRRPBO = 11.2-25.2). Conclusion In PBO-controlled clinical trials of therapies for moderate-to-severe UC, there are increased AEs and SAEs for patients who receive PBO, especially for DEAEs and DESAEs. Induction treatment responders re-randomized for maintenance to PBO experienced greater harms (i.e. lower NNH) than TT PBO patients. These findings raise concern about clinical equipoise in moderate-to-severe UC clinical trials and support ongoing efforts to design trials with active comparator arms and adaptive or platform methodologies.

P798 Study of the concordance between the enzymatic activity of Thiopurine S-methyltransferase and polymorphisms in the TPMT gene in patients with Inflammatory Bowel Disease

Abstract Background Thiopurine therapy is associated with an increased risk of serious adverse events in patients with Inflammatory Bowel Disease (IBD). Thiopurine S-methyltransferase (TPMT) is the enzyme responsible for metabolism, and its determination helps identify patients at risk of toxicity. This study aims to explore the level of correspondence between the TPMT genotype and enzymatic activity (phenotype) with the objective of preventing adverse events prior to the commencement of thiopurine therapy. Methods Consecutive patients with IBD, Crohn’s Disease (CD) or Ulcerative Colitis (UC), were included. Genotype was conducted for the most prevalent TPMT variants (TPMT*2, TPMT*3B, TPMT*3C), TPMT enzymatic activity assessment, and quantification of 6-thioguanine nucleotide (6-TGN) levels. Adverse effects were documented, along with the administration of biologics, mesalazine, ACE inhibitors or allopurinol. The primary objective was to evaluate the concordance between TPMT genotype and phenotype. Secondary objectives included determining the prevalence of genotype and phenotype within our patient cohort, 6-TGN serum levels, the prevalence of adverse events and identifying potential pharmacological inducers of the phenotype. Results A total of 218 patients were included (131 with CD and 81 with UC). Thirteen patients did not initiate thiopurines, and 34.63% (71/205) had discontinued treatment. The most observed adverse events were myelotoxicity (15.12%), gastrointestinal toxicity (12.20%), and hepatic toxicity (5.37%). TPMT activity exhibited a trimodal distribution, with 87.61% (191/218) having normal activity, 11.47% having intermediate activity, and 1% having low activity. Genotypically, 90.83% (198/218) had a wild-type genotype, 8.72% (18/218) had a heterozygous genotype, and 0.5% (1/218) had a homozygous genotype. The concordance index between phenotype and genotype was calculated at 0.57. Significantly, myelotoxicity was associated with the presence of genotypic variants (p=0.004). 6-TGN levels did not correlate with TPMT activity and concurrent medications did not affect TPMT activity . Conclusion The proactive assessment of TPMT (phenotype or genotype) before initiating thiopurine therapy effectively mitigates the occurrence of myelotoxicity in IBD patients. Importantly, the level of concordance between TPMT activity and genotype is moderate, with genotyping serving as the more reliable approach for preselecting patients susceptible to myelotoxic reactions.

Combining the Nurse Intuition Patient Deterioration Scale with the National Early Warning Score provides more Net Benefit in predicting serious adverse events: A prospective cohort study in medical, surgical, and geriatric wards

ObjectivesThis prospective cohort study aimed to assess the predictive value of the Nurse Intuition Patient Deterioration Scale (NIPDS) combined with the National Early Warning Score (NEWS) for identifying serious adverse events in patients admitted to diverse hospital wards. Research methodology/designData was collected between December 2020 and February 2021 in a 350-bed acute hospital near Brussels, Belgium. The study followed a prospective cohort design, employing NIPDS alongside NEWS for risk assessment. Patients were monitored for 24 h post-registration, with outcomes recorded. SettingThe study was conducted in a hospital with a Rapid Response System (RRS) and electronic patient record wherein NEWS was routinely collected. Patients admitted to two medical, two surgical, and two geriatric wards were included. Main outcome measuresThe primary outcome included death, urgent code calls, or unplanned ICU transfers within 24 h after NIPDS registration. The secondary outcome comprised rapid response team activations or changes in Do-Not-Resuscitate codes. ResultsIn a cohort of 313 patients, 10/313 and 31/313 patients reached the primary and secondary outcome respectively. For the primary outcome, NIPDS had a sensitivity of 0.900 and specificity of 0.927, while NEWS had a sensitivity of 0.300 and specificity of 0.974. Decision Curve Analysis demonstrated that NIPDS provided more Net Benefit across various Threshold Probabilities. Combining NIPDS and NEWS showed potential for optimizing rapid response systems. Especially in resource-constrained settings, NIPDS could be used as a calling criterion. ConclusionThe NIPDS displayed strong predictive capabilities for adverse events. Integrating NIPDS into existing rapid response systems can objectify nurse intuition, enhancing patient safety. Implications for clinical practiceThe Nurse Intuition Patient Deterioration Scale (NIPDS) is a valuable tool for detecting patient deterioration. Implementing NIPDS alongside traditional scores such as NEWS can improve patient care and safety. The optimal NIPDS threshold to activate rapid response is ≥5.

Data-Based Opioid Risk Review in Patients with Chronic Pain: A Retrospective Chart Review

A retrospective, cohort, single center, chart review was conducted to compare rates of opioid-associated serious adverse events (SAEs) in a patient cohort 6 months before and 6 months after data-based opioid risk review. The primary objective was the composite reduction in opioid-related SAEs including suicide-related events and opioid overdoses. The impact of the reviews was assessed via multivariate logistic regression and a McNemar’s test to analyze difference in rates of opioid-associated SAEs. This study demonstrates that data-based opioid risk review can reduce opioid-related SAEs, opioid overdoses, and suicide-related events in the 6 months post-review. The primary outcome was not statistically significant with a p-value of 0.080. In the population that underwent opioid tapers, the hazard ratios (HR) for suicide-related events and opioid-related SAEs were 6.64 (1.09–40.53, p = 0.05) and 10.43 (0.48–226.80, p = 0.02) respectively when compared to non-tapered patients. The HR for suicide-related events and opioid-related SAEs when opioid therapy was discontinued were 9.95 (2.16–45.94, p = 0.009) and 15.64 (1.09–225.19, p = 0.001) respectively when compared to continuation of opioids. This study showed that data-based opioid risk review may reduce incidence of opioid-related SAEs in patients with chronic pain. Additionally, opioid tapers and discontinuations are significant risk factors for suicide-related events and opioid-related SAEs.

Effects of MIdazolam versus MOrphine in acute cardiogenic pulmonary edema and chronic obstructive pulmonary disease: An analysis of MIMO trial

AimsChronic obstructive pulmonary disease (COPD) is an important comorbidity in heart failure. The MIMO trial showed that patients with acute cardiogenic pulmonary edema (ACPE) treated with midazolam had fewer serious adverse events than those treated with morphine. In this post hoc analysis, we examined whether the presence/ absence of COPD modifies the reduced risk of midazolam over morphine. MethodsPatients >18 years old clinically diagnosed with ACPE and with dyspnea and anxiety were randomized (1:1) at emergency department arrival to receive either intravenous midazolam or morphine. In this post hoc analysis, we calculated the relative risk (RR) of serious adverse events in patients with and without COPD. Calculating the CochranMantel-Haenszel interaction test, we evaluated if COPD modified the reduced risk of serious adverse events in the midazolam arm compared to morphine. ResultsOverall, 25 (22.5%) of the 111 patients randomized had a history of COPD. Patients with COPD were more commonly men with a history of previous episodes of heart failure, than participants without COPD. In the COPD group, the RR for the incidence of serious adverse events in the midazolam versus morphine arm was 0.36 (95%CI, 0.1–1.46). In the group without COPD, the RR was 0.44 (95%CI, 0.22–0.91). The presence of COPD did not modify the reduced risk of serious adverse events in the midazolam arm compared to morphine (p for interaction =0.79). ConclusionsThe reduced risk of serious adverse events in the midazolam group compared with morphine is similar in patients with and without COPD.

Medications for alcohol use disorder promote abstinence in alcohol-associated cirrhosis: Results from a systematic review and meta-analysis.

The role of medications for alcohol use disorder (MAUD) in patients with cirrhosis is not well established. Evidence on the efficacy and safety of these drugs in these patients is scarce. We performed a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol guidelines on the efficacy of MAUD in patients with cirrhosis. A search was conducted in PubMed, Embase, and Scopus, including all studies until May 2022. The population was defined as patients with AUD and cirrhosis. The primary outcome was alcohol abstinence. Safety was a secondary outcome. We performed a random-effect analysis and expressed the results as relative risk of alcohol consumption. Heterogeneity was measured by I2 . Out of 4095 unique references, 8 studies on 4 different AUD treatments [baclofen (n = 6), metadoxine (n = 1), acamprosate (n = 1), and fecal microbiota transplant (n = 1)] in a total of 794 patients were included. Four were cohort studies, and 4 were RCTs. Only RCTs were included in the meta-analysis. MAUD was associated with a reduced rate of alcohol consumption [relative risk = 0.68 (CI: 0.48-0.97), P = 0.03], increasing alcohol abstinence by 32% compared to placebo or standard treatment, despite high heterogeneity ( I2 = 67%). Regarding safety, out of 165 serious adverse events in patients treated with MAUD, only 5 (3%) were possibly or probably related to study medications. MAUD in patients with cirrhosis is effective in promoting alcohol abstinence and has a good safety profile. Larger studies on the effects of MAUD are needed, especially in patients with advanced liver disease.

ID: 222733 The Influence of Human Transcription Errors on Surgical Scheduling

Retrospective studies examining errors within a surgical scheduling setting do not fully represent the effects of human error involved in transcribing critical patient data. These errors can negatively impact patient care and reduce workplace efficiency, due to insurance claim denials and potential sentinel events. Previous reports underscore the high burdens physicians face associated with prior authorizations as it may lead to serious adverse events in patients or the abandonment of treatment due to these delays (1). This study simulates scheduling to examine the error rate of experienced schedulers when transcribing forms.

DIFFERENCES IN MORTALITY AND COMPLICATION RATES FOLLOWING REVISION KNEE ARTHROPLASTY PERFORMED FOR URGENT VERSUS ELECTIVE INDICATIONS

Revision knee arthroplasty is a complex procedure with the number and cost of knee revision procedures performed per year expected to rise. Few studies have examined adverse events following revision arthroplasty.The objective of this study was to determine rates of serious adverse events in patients undergoing revision knee arthroplasty with consideration of the indication for revision (urgent versus elective indications) and to compare these with primary arthroplasty and re-revision arthroplasty.Patients undergoing primary knee arthroplasty were identified in the UK Hospital Episode Statistics. Subsequent revision and re-revision arthroplasty procedures in the same patients and same knee were identified. The primary outcome was 90-day mortality and a logistic regression model was used to investigate factors associated with 90-day mortality and secondary adverse outcomes including infection (undergoing surgery), pulmonary embolism, myocardial infarction, stroke. Urgent indications for revision arthroplasty were defined as infection or fracture, and all other indications were included in the elective indications cohort.939,021 primary knee arthroplasty cases were included of which 40,854 underwent subsequent revision arthroplasty, and 9,100 underwent re-revision arthroplasty. Revision surgery for elective indications was associated with a 90-day rate of mortality of 0.44% (135/30,826; 95% CI 0.37-0.52) which was comparable to primary knee arthroplasty (0.46%; 4,292/939,021; 95% CI 0.44-0.47). Revision arthroplasty for infection, however, was associated with a much higher mortality of 2.04% (184/9037; 95% CI 1.75-2.35; odds ratio [OR] 3.54; 95% CI 2.81-4.46), as was revision for periprosthetic fracture at 5.25% (52/991; 95% CI 3.94-6.82; OR 6.23; 95% CI 4.39-8.85). Higher rates of pulmonary embolism, myocardial infarction, and stroke were also observed in the infection and fracture cohort.These findings highlight the burden of complications associated with revision knee arthroplasty. They will inform shared decision-making for patients considering revision knee arthroplasty for elective indications. Patients presenting with infection of a knee arthroplasty or a periprosthetic fracture are at very high risk of adverse events. It is important that acute hospital services and tertiary referral centres caring for these patients are appropriately supported to ensure appropriate urgency and an anticipation for increased care requirements.

Incidence, predictors, and prognostic impact of in-hospital serious adverse events in patients ≥75 years of age undergoing elective endovascular aneurysm repair.

This study sought to identify the factors associated with the occurrence of in-hospital serious adverse events after elective endovascular aortic repair (EVAR) in older patients within the Global Registry for Endovascular Aortic Treatment. Consecutive patients ages ≥75 years who received GORE EXCLUDER AAA Endoprosthesis (W.L. Gore & Associates, Inc, Flagstaff, AZ) for elective EVAR. Based on the age at index elective EVAR, patients were categorized into 3 groups for subsequent analyses: those ages 75 to 79, 80 to 84, and ≥85 years. The primary end points for this study were the incidence of serious adverse events and all-cause mortality. In-hospital complications were defined according to the International Organization for Standardization 14155 standard (https://www.iso.org/standard/71690.html) and considered serious adverse events if they led to any of the following: (1) a life-threatening illness or injury, (2) a permanent impairment of a body structure or a body function, (3) in-patient or prolonged hospitalization, or (4) medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function. Overall, 1,333 older patients (ages 75-79: n= 601; 80-84: n= 474; and ≥85: n= 258) underwent elective EVAR in the Global Registry for Endovascular Aortic Treatment data set and were included in the present analysis. In total, 12 patients (0.9%) died perioperatively, and 103 patients (7.7%) experienced ≥1 in-hospital serious adverse event, with 18 patients (1.3%) experiencing >1 in-hospital complications. No significant differences were seen between the age groups in the rates of in-hospital serious adverse events (7.3% vs 8.2% vs 7.8%; P= .86). In logistic regression analysis, a history of chronic obstructive pulmonary disease (odds ratio= 2.014; 95% confidence interval, 1.215-3.340; P= .006) and prior requirement for dialysis (odds ratio= 4.655; 95% confidence interval, 1.087-19.928; P= .038) resulted as predictors for occurrence of in-hospital serious adverse events. In the whole cohort, the 5-year survival was 63% for patients who did not experience any in-hospital serious adverse events compared with 51% for those who experienced any complications (P= .003). Using multivariable Cox proportional hazards models, it was found that the occurrence of in-hospital serious adverse events (hazard ratio= 6.2; 95% confidence interval, 1.8-21.317; P= .003) and being underweight (hazard ratio= 7.0; 95% confidence interval, 1.371-35.783; P= .019) were the only independent predictors of death in ≤30 days from the initial intervention. Although age did not independently affect the risk for all-cause mortality in ≤180 days after the initial intervention, increasing age was associated with a higher risk for long-term death (ie, ≥181 days from index elective EVAR) in the multivariable analysis (ages 75-79: hazard ratio= 0.379; 95% confidence interval, 0.281-0.512; P < .001; and 80-84: hazard ratio= 0.562; 95% confidence interval, 0.419-0.754; P < .001). After elective EVAR in older patients (ie, ≥75 years), the occurrence of in-hospital serious adverse events appears to increase the risk of death, particularly in ≤180 days after the initial elective EVAR intervention, and might be related to patient baseline characteristics, including history of pulmonary and renal disease.

Analysis of Serious Adverse Event Reporting for Patients Enrolled in Cancer Clinical Trials During the COVID-19 Pandemic

This cross-sectional study assesses whether a change occurred in reporting of serious adverse events for patients in oncology clinical trials in the US during the COVID-19 pandemic.

Assessment of efficacy and safety of volanesorsen for treatment of metabolic complications in patients with familial partial lipodystrophy: Results of the BROADEN study: Volanesorsen in FPLD; The BROADEN Study

BackgroundVolanesorsen, an antisense oligonucleotide, is designed to inhibit hepatic apolipoprotein C-III synthesis and reduce plasma apolipoprotein C-III and triglyceride concentrations. ObjectiveThe present study assessed efficacy and safety of volanesorsen in patients with familial partial lipodystrophy (FPLD) and concomitant hypertriglyceridemia and diabetes. MethodsBROADEN was a randomized, placebo-controlled, phase 2/3, 52-week study with open-label extension and post-treatment follow-up periods. Patients received weekly subcutaneous volanesorsen 300 mg or placebo. The primary endpoint was percent change from baseline in fasting triglycerides at 3 months. Secondary endpoints included relative percent change in hepatic fat fraction (HFF), visceral adiposity, and glycated hemoglobin levels. ResultsForty patients (11 men, 29 women) were enrolled, majority of whom were aged <65 years (mean, 47 years) and White. Least squares mean (LSM) percent change in triglycerides from baseline to 3 months was −88% (95% CI, −134 to −43) in the volanesorsen group versus –22% (95% CI, −61 to 18) in the placebo group, with a difference in LSM of −67% (95% CI, –104 to –30; P=0.0009). Volanesorsen induced a significant LSM relative reduction in HFF of 53% at month 12 versus placebo (observed mean [SD]: 9.7 [7.65] vs. 18.0 [8.89]; P=0.0039). No statistically significant changes were noted in body volume measurements (fat, liver, spleen, visceral/subcutaneous adipose tissue) or glycated hemoglobin. Serious adverse events in patients assigned to volanesorsen included 1 case each of sarcoidosis, anaphylactic reaction, and systemic inflammatory response syndrome. ConclusionIn BROADEN, volanesorsen significantly reduced serum triglyceride levels and hepatic steatosis in patients with FPLD.

Mathematical Prediction of the Efficacy of Medicinal Products in Preclinical Studies

Generally, preclinical studies of medicines conducted in accordance with national and international regulatory recommendations allow minimising the risks of detecting serious adverse events in patients at the stage of clinical trials. Nevertheless, current analytical trends motivate the development of new prognostic approaches aimed at improving the reliability and accuracy of safety assessments.The aim of this study was to develop and test methodological approaches to comprehensive preclinical assessment of the key risk factors associated with the use of medicinal products in humans and to mathematical prediction of the corresponding benefits and risks.Materials and methods: the study combined information analysis and statistics; it used consolidated preclinical data on the protective properties of fabomotizole and national and international regulatory documents describing the principles and methods of evidence-based medicine, in particular, Bayesian statistics and prognostic research methods.Results: The article presents mathematical approaches developed to confirm the statistical reliability and prognostic significance of the results of preclinical assessment of the safety of medicines, based on Bayesian statistics, in particular, the concepts of weight of evidence (WoE), information value (IV), and normalised density (ND). Depending on the volume of the evaluated data, the WoE can be used to determine the weight of evidence of single variables, as well as entire groups of variables from individual tests or whole test panels, considered in the studies of general toxic effects, reproductive toxicity, genotoxicity and other studies characterising the condition of vital organs when evaluating the safety of medicines.Conclusions: The developed methodology allows evaluating the entire volume of information obtained in preclinical studies of medicinal products. The criteria in the form of WoE and IV in preclinical safety assessment of medicines can be used to estimate the benefits and risks of using medicines, including the products developed specifically for children and pregnant women.

Risk of serious adverse events associated with non-steroidal anti-inflammatory drugs in orthopaedic surgery. A protocol for a systematic review.

Postoperative pain is a common condition following orthopaedic surgeries and causes prolonged hospitalisation, delayed rehabilitation and hamper the quality of life. Non-steroidal anti-inflammatory drugs (NSAIDs) are effective analgesics and anti-inflammatory mediators in the treatment of postoperative pain. The association of NSAIDs with serious adverse events may however keep some clinicians and clinical decision makers from using NSAIDs perioperatively. The evidence regarding the risks of serious adverse events following perioperative use of NSAIDs in orthopaedic surgery is sparse and needs to be assessed in a systematic review. This is a protocol for a systematic review that aims to identify the risks of serious adverse events from perioperative use of NSAIDs in orthopaedic patients. Our methodology is based on the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols and the eight-step assessment procedure suggested by Jakobsen and colleagues. We wish to assess if NSAIDs versus placebo, usual care or no intervention, will influence the risks of serious adverse events in patients undergoing orthopaedic surgery. We will include all randomised trials assessing the use of NSAIDs perioperatively. To identify trials we will search the Medical Literature Analysis and Retrieval System Online, Excerpta Medica database, Cochrane Central Register, Science Citation Index Expanded on Web of Science and BIOSIS. Two authors will screen the literature and extract data. We will use the 'Risk of Bias 2 tool' to assess trials. Extracted data will be analysed using RStudio and Trial Sequential Analysis. We will create a 'Summary of Findings' table in which we will present our primary and secondary outcomes. We will assess the quality of evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE). This systematic review can potentially aid clinicians and clinical decision makers in the use of NSAIDs for treatment of postoperative pain following orthopaedic surgeries.