Although Adverse Events Research Articles

Safety of Empagliflozin: An Individual Participant-Level Data Meta-Analysis from Four Large Trials.

Empagliflozin is a sodium-glucose co-transporter-2 inhibitor used to treat type 2 diabetes (T2D) to improve glycemic control, reduce risk of cardiovascular death in patients with T2D, and treat patients with symptomatic chronic heart failure (HF) and chronic kidney disease (CKD). The safety profile of empagliflozin is well documented, although adverse events (AEs) remain of interest to clinicians. This study provides an up-to-date safety evaluation of empagliflozin. Data were pooled from four long-term trials which included: patients with T2D and established cardiovascular disease (EMPA-REG OUTCOME), patients with HF, with/without diabetes (EMPEROR-Reduced and EMPEROR-Preserved), and patients with CKD, with/without diabetes (EMPA-KIDNEY). Since three of the four trials evaluated empagliflozin 10mg, the meta-analysis was restricted to this dose. Total trial medication exposure was 19,727 patient-years for patients who received empagliflozin (n = 10,472) and 19,447 patient-years for placebo (n = 10,461). The percentages of patients with serious AEs, fatal AEs, and AEs leading to discontinuation were similar for both groups. The incidences of serious urinary tract infection and serious pyelonephritis or urosepsis were similar for both groups but higher for women taking empagliflozin versus placebo. Serious genital infections were not increased with empagliflozin versus placebo. There was a slight increase in ketoacidosis and serious volume depletion in patients who received empagliflozin versus placebo. The occurrence of serious acute kidney injury was lower with empagliflozin versus placebo. Empagliflozin was not associated with an increased incidence of severe hypoglycemia, bone fractures, or lower limb amputations. Empagliflozin is therefore considered safe in people without diabetes, the elderly, patients with very low estimated glomerular filtration rate, low body mass index, and HF. Safety is unaltered by blood pressure, concomitant medication for hypertension, HF, and immunosuppression. This meta-analysis of long-term safety data extends current knowledge and confirms the safety and tolerability of empagliflozin.

A Brief, Just-in-Time Sedation Training in the Pediatric Emergency Department Improves Performance During Adverse Events Encountered in Simulated Procedural Sedations.

Procedural sedation (PS) is commonly performed in emergency departments (EDs) by nonanesthesiologists. Although adverse events (AEs) are rare, providers must possess the clinical skills to react in a timely manner. We previously described residents' experience and confidence in PS as part of a needs assessment. We found that their ability to perform important clinical tasks as a result of the usual training experience demonstrates educational needs. We developed an educational intervention to address the deficiencies uncovered during our needs assessment. To evaluate the effectiveness of an educational intervention on pediatric residents' clinical performance and confidence when faced with an AE during a simulated PS. This was a prospective observational cohort study of residents at a tertiary care children's hospital. All ED attending physicians and fellows were trained in uniform delivery of the educational intervention, which was delivered extemporaneously at the bedside ("Just-in-Time" [JIT]) to all residents performing PS on actual patients in the pediatric ED, over the course of 1 year. Subjects completed the following both before and after the educational intervention: a survey pertaining to confidence in PS, followed by a standardized, video-recorded simulated PS complicated by apnea and desaturation. Clinical performance was evaluated and assessed both in real time and by a video-rater blinded to participants' year of training. We summarized baseline resident characteristics, confidence questionnaire item rankings and success in both the preparation and AE tasks. We compared successful task completion and time to task completion before and after intervention. Forty residents completed both the PRE and POST phases of the study. There was significant improvement in the proportion of residents who completed both preparation and AE tasks after the JIT training. Specifically, there was a significant improvement in the proportion of residents who performed positive-pressure ventilation to treat an apneic event associated with desaturation during the PS (P = 0.007). Residents' confidence scores also significantly improved after the training. A brief JIT training in the pediatric ED improves resident clinical performance and confidence when faced with an AE during a simulated PS. Future direction includes correlating this improved performance with patient outcomes in PS.

A 10-year follow-up of infliximab monotherapy for refractory uveitis in Beh\xe7et\u2019s syndrome

Infliximab (IFX) was the first biologic introduced for refractory uveitis treatment in Behçet’s syndrome (BS). However, there have been few reports on the safety and efficacy of IFX monotherapy over follow-up periods of more than 10 years. This retrospective study evaluated the 10-year safety and efficacy of IFX monotherapy compared to IFX combination therapies with colchicine or corticosteroid for refractory uveitis in BS patients. Monotherapy was performed in 30 eyes of 16 patients while combination therapies were performed in 20 eyes of 11 patients. Continuation of IFX occurred in 70.3% of enrolled patients for 10 years without any significant difference noted in the retention rate between the monotherapy and combination therapies (p = 0.86). Reduction of ocular inflammatory attacks and improvement of best corrected visual acuity occurred in the monotherapy group after 10 years, which was equivalent to that for the combination therapies. Although adverse events (AEs) or therapy discontinuation occurred during the initial 5 years in both therapies, no AEs were observed for either therapy after 6 years. Our results suggested that IFX monotherapy proved to be effective and not inferior to combination therapies over a 10-year follow-up. Although loss of response and AEs may be noticed during the initial 5-year period, a safe and effective continuation can be expected thereafter.

Prognostic and Immune-Related Factors for Response to Duvelisib in the Phase 2 DYNAMOTM Clinical Trial in iNHL

Prognostic and Immune-Related Factors for Response to Duvelisib in the Phase 2 DYNAMOTM Clinical Trial in iNHL

Side effects of corticosteroids in patients with advanced cancer: a systematic review.

Corticosteroids are commonly used in palliative care settings, but are associated with several side effects. Although adverse events (AEs) are highly distressing for patients, few data are available from prospective studies to look at incidence or predictors of such harms. The aim of this study is to identify AE reporting among studies of patients with advanced cancer receiving corticosteroids for any reason. A systematic review was conducted using the following data sources: PubMed, Medline, SCOPUS, Cochrane reviews, and CINAHL. Randomized controlled trials (RCTs) with patients with advanced cancer assessing the effect of corticosteroids were included. Consecutive cohort observational studies of corticosteroid toxicities in cancer patients were also included. Twenty-seven RCTs and 12 consecutive cohort observational studies were identified. The most frequently reported primary outcome of RCTs was nausea and vomiting (8/27). Dexamethasone was prescribed in almost half of RCTs (13/27). In consecutive cohort studies, the primary outcomes were a wide variety of symptoms. Dexamethasone was also the most common glucocorticoid used (7/12). In terms of quality of AE reporting, two RCTs and one consecutive cohort study used a validated AE assessment tool in their studies. Side effects of corticosteroids in advanced cancer patients were poorly reported with few data using validated tools. Researchers should be aware of the guideline of AE reporting to provide the best evidence of risk-benefit balance. Developing specific consensus guidelines about AE reporting in studies of glucocorticoids in studies of people with advanced cancer would be useful.

P1.03-010 Efficacy and Safety of Anaplastic Lymphoma Kinase (ALK) Tyrosine Kinase Inhibitors in ALK-Positive Non-Small Cell Lung Cancer

Anaplastic lymphoma kinase (ALK) gene rearrangements occur in 3-5% of non-small cell lung cancer (NSCLC) cases. ALK tyrosine kinase inhibitors (ALK-TKIs), such as crizotinib and alectinib, are recommended for the treatment of ALK-positive NSCLC. However, acquired resistance to the ALK-TKIs develops after treatment with these agents. Therefore, it is necessary to consider the alteration of the therapeutic approach against ALK-positive NSCLC. This investigation, reviewed patients with ALK-positive NSCLC treated at Hiratsuka Kyosai Hospital in 2016, to determine the efficacy and safety of ALK-TKIs in this setting. The medical data of 11 patients who had been diagnosed with ALK-positive advanced NSCLC and treated with ALK-TKIs at Hiratsuka Kyosai Hospital in 2016 were reviewed retrospectively. A total of 11 patients (3 males and 8 females; mean age: 62 years) with ALK-positive NSCLC were investigated. All the pathological types were adenocarcinomas. Eight patients were treated with crizotinib as first-line therapy, and 3 out of those patients were treated with alectinib as second-line therapy. The remaining 3 patients were treated with alectinib as first-line therapy. The overall response rate was 87.5%, and the median progression-free survival was not reached. Four patients had developed PD while receiving crizotinib. Two out of those patients have developed brain metastasis, and were administered local radiotherapy to the brain. Patients who progressed following treatment with ALK-TKIs, were treated with pemetrexed-based chemotherapy. Although adverse events (AEs) of crizotinib were more than those of alectinib, most of them were of Grade 1 to 2 severity. Most common AEs of crizotinib included vision disorder (62.5%), diarrhea (50%), elevated aminotransferases (50%), and nausea (37.5%). Grade 3 to 4 adverse events were reported in 4 cases. However, all of them were controlled by withdrawal of treatment or reduction of dosage. ALK-TKIs demonstrate good efficacy and safety in patients with ALK-positive NSCLC.

Body size-adjusted dose analysis of pirfenidone in patients with interstitial pneumonia.

Pirfenidone is an effective anti-fibrotic agent for idiopathic pulmonary fibrosis (IPF). Although adverse events (AE) sometimes prevent patients from continuing treatment, current dose adjustment guidance does not consider patient body size or weight (BW). The aim of this study was to evaluate the importance of pirfenidone dose adjustment by body surface area (BSA) or BW for preventing AE and permitting continuous treatment in patients with interstitial pneumonia (IP). Sixty-seven Japanese patients with IP including 46 patients with IPF treated with pirfenidone between 2009 and 2015 were retrospectively evaluated. Pirfenidone doses were adjusted by BSA or BW and were compared with clinical parameters. Forty-two of 67 patients (62.7%) with IP showed AE, most commonly gastrointestinal symptoms (77.5%). Patients having AE received significantly higher adjusted doses of pirfenidone by both BSA and BW (P = 0.024 and P = 0.010, respectively), while unadjusted doses did not differ. BSA-adjusted dose discriminated patients with AE from those without (area under the curve = 0.666 at 1085 mg/m2 ). Six of seven patients (85.7%) who discontinued pirfenidone due to AE took ≥1085 mg/m2 of pirfenidone. In a subgroup with IPF, patients taking a medium dose (median: 876 median-1085 mg/m2 ) showed a lower annual decline in % forced vital capacity than patients taking a lower dose (P = 0.025). BSA-adjusted pirfenidone dosing may be useful to prevent AE whilst achieving a long-term treatment effect in patients with IP.

Long-Term Efficacy and Safety of Atazanavir/Ritonavir Treatment in a Real-Life Cohort of Treatment-Experienced Patients with HIV Type 1 Infection

Atazanavir-based regimens have established efficacy and safety in both antiretroviral (ARV)-naive and -experienced patients. However, data evaluating effectiveness beyond 2 years is sparse. Therefore, we assessed the long-term outcomes of ritonavir-boosted atazanavir (ATV/r)-containing regimens in ARV-experienced patients in a clinical setting in a noncomparative, retrospective, observational study collecting data from three European HIV databases on ARV-experienced adults with HIV-1 infection starting an ATV/r-based regimen. Data were extracted every 6 months (maximum follow-up 5 years). Primary outcome was the proportion of patients remaining on ATV/r by baseline HIV-1 RNA (<500 or ≥500 copies/ml). Secondary outcomes included time to virologic failure, reasons for discontinuation, and long-term safety profile. The duration of treatment and time to virologic failure were analyzed using the Kaplan-Meier method. Data were analyzed for 1,294 ARV-experienced patients (male 74%; mean ART exposure 5.7 years). After 3 years, 56% (95% CI: 52%, 60%) of patients with baseline HIV-1 RNA <500 copies/ml and 53% (95% CI: 49%, 58%) of those with HIV-1 RNA ≥500 copies/ml remained on ATV/r. After 3 years, 75% (95% CI: 69%, 80%) of patients with baseline HIV-1 RNA <50 copies/ml remained suppressed and 51% (95% CI: 47%, 55%) of those with baseline HIV-1 RNA ≥50 copies/ml achieved and maintained virologic suppression. Although adverse events (AEs) were the main known reason for discontinuation, no unexpected AEs were observed. In a real-life setting ATV/r-based regimens demonstrated sustained virologic suppression in ARV-experienced patients. After long-term therapy the majority of patients remained on treatment and no unexpected AEs were observed.

Assessment of safety of bevacizumab (bev) use for metastatic colorectal cancer (mCRC) in elderly patients treated at the Centre Hospitalier de l’Université de Montréal (CHUM): A retrospective study.

677 Background: A 2004 randomized study showed a meaningful improvement in survival with bev added to chemotherapy (CT) for patients with mCRC. This combination is now widely used and generally well tolerated although adverse events (AEs) are described associated with the use of bev, some of which may be increased in incidence in an elderly population. In this study, we assessed these AEs in a population of elderly patients treated with bev in a major center in Montréal. Methods: Patients with mCRC who received bev at our institution outside a clinical trial were retrieved from the pharmacy registry. Medical records were sought from patients who qualified for the inclusion criteria: ≥ 65 years, bev therapy at 5mg/kg every two weeks, combination with CT, period 2007-2011. A retrospective analysis of specific AEs was done and grade according to NCI-CTC (version 4.0) was assessed: febrile neutropenia, hypertension, proteinuria, diarrhea, venous thromboembolic event (VTE), arterial thromboembolic event (ATE), bleeding and gastrointestinal perforation. Results: 47 patients received a total of 486 cycles of bev. Out of these cycles, 210 were given with FOLFOX, 199 with FOLFIRI and 77 with other combinations. Median age of the patients was 69 years. 3 episodes of febrile neutropenia were noted. Grade 3 or 4 arterial hypertension occurred in 4 patients of which 2 had to definitively stop bev. Grade 3 proteinuria was reported with definitive cessation of bev in 2 patients. Grade 3 or 4 diarrhea was observed in 2 cases. We reported 1 cerebral ATE leading to discontinuation of bev and grade 2 VTE in two patients. One grade 5 gastrointestinal perforation was reported. No major bleeding was noted. Conclusions: The number of adverse events observed in this population of elderly patients is comparable to other studies. Thus, age should not be an exclusion criteria for treatment with bev and CT.

Preventing Medical Injury

Although adverse events (AEs) are not uncommon in hospitalized patients, they are by no means inevitable. A review of records from a population-based study in New York revealed that nearly 4% of hospitalized patients suffered AEs. Two-thirds of those events were considered to be caused by errors in management, most of which were not because of negligence. A large part of the reason preventable AEs occur is that today's medical care is extremely complex, involving a variety of personnel, equipment, and procedures. By seeking to eliminate errors in the system of providing care and raising the awareness of health care providers about the potential for AEs, programs can be established to address and possibly remedy this serious problem.