Comparing the efficacy and safety of faecal microbiota transplantation with bezlotoxumab in reducing the risk of recurrent Clostridium difficile infections:a systematic review and Bayesian network meta-analysis of randomised controlled trials

The risk of recurrent Clostridium difficile infections (RCDIs) is high when treated with standard antibiotics therapy (SAT) alone. It is suggested that the addition of faecal microbiota transplantation (FMT) or bezlotoxumab after SAT reduces the risk of RCDI. In the absence of head-to-head randomised controlled trials (RCTs), this review attempts to compare the efficacy and safety of bezlotoxumab with FMT in reducing the risk of RCDI in hospitalised patients.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Immune-Related Adverse Events (irAEs) of Immune Checkpoint Inhibitors (ICIs) in Advanced Melanoma Patients

Abstract (1): Background: The use of ipilimumab, nivolumab, and pembrolizumab as monotherapies or in combination has transformed the management of advanced melanoma even though these drugs are associated with a new profile of immune-related adverse events (irAEs). The incidence of irAEs from clinical trials of these agents is an important factor for clinicians when treating patients with advanced melanoma. In the current study, we aimed to profile the incidence of potential irAEs of these agents when used as monotherapy and as combination therapy. Methods: We searched the Medline, Embase, and Cochrane databases; clinicaltrials.gov; and websites of regulatory agencies in the USA, Europe, Australia, and Japan for phase 1-3 trials of ipilimumab, nivolumab, and pembrolizumab for advanced melanoma. Random effect meta-analysis was utilized to profile the incidence of potential irAEs. Results: A total of 58 reports of 35 trials including 6331 patients with advanced melanoma and reporting irAE data were included in the meta-analyses. We found higher incidences of potential irAEs in combination therapies versus monotherapies for most of the types of irAEs. Among the monotherapies, ipilimumab users had the most frequent incidence of potential irAEs related to the gastrointestinal system (diarrhea, 29%; and colitis, 8%) and skin (rash, 31%; pruritus, 27%; and dermatitis, 10%), with hypophysitis in 4% of the patients. The most frequent potential irAEs among nivolumab users were maculopapular rash (13%), erythema (4%), hepatitis (3%), and infusion-related reactions (3%), while they were arthralgia (12%), hypothyroidism (8%), and hyperglycemia (6%) among pembrolizumab users. Conclusion: Especially the combination therapies tend to elevate the incidence of potential irAEs. Clinicians should be vigilant about irAEs following combination therapy as well as gastrointestinal and skin irAEs following ipilimumab therapy, in addition to being aware of potential irAEs leading to hyperglycemia, thyroid, hepatic, and musculoskeletal disorders following nivolumab and pembrolizumab therapy. Abstract (2): Importance Anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) antibody (ipilimumab) and anti-programmed cell death 1(anti-PD1) antibodies (nivolumab and pembrolizumab), have been shown to have a beneficial effect in treating melanoma but their risk of immune-related hypothyroidism (ir-hypothyroidism) in elderly patients from a real-world setting is limited. Objective To estimate the risk of ir-hypothyroidism in elderly with advanced melanoma treated with anti-CTLA4 or anti-PD1 in real-world setting. Design, Setting, and Participants SEER-Medicare data was used to identify elderly patients (≥65 years) diagnosed with advanced melanoma between 2011 and 2015 who were de novo users of anti-CTLA4 or anti-PD1. We estimated the risk of ir-hypothyroidism between users of anti-PD1 and anti-CTLA4. We used a propensity weighting approach by using the inverse probability of treatment weighting (IPTW) method to adjust for potential confounders. We utilized proportional hazards models to estimate the risk of ir-hypothyroidism and performed several sensitivity analyses to estimate the risk over ranges of follow-up periods as well as including patients with different stages of melanoma. Exposure Anti-CTLA4 or anti-PD1. Main Outcomes and Measures The risk of ir-hypothyroidism between the initiation of the treatment and up to 90 days from the last dose was measured as a hazard ratio (HR) and its 95% confidence interval (95%CI). Results Our sample had 210 elderly patients with advanced melanoma (164 anti-CTLA4, and 46 anti-PD1 (11 nivolumab, 35 pembrolizumab)). There was no statistical difference in the risk of ir-hypothyroidism between anti-PD1 and anti-CTLA4 (HR 2.15, 95%CI 0.83-5.53). Comparing the individual medications to each other showed a lower risk among users of ipilimumab versus nivolumab (HR 0.15, 95%CI 0.06-0.40) and pembrolizumab versus nivolumab (HR 0.13, 95%CI 0.03-0.55). Sensitivity analyses using a cohort of all-stages melanoma did not show a difference in the risk of ir-hypothyroidism between anti-CTLA4 and anti-PD1 and between individual medications. Conclusions and Relevance In our retrospective study of claims data of elderly patients diagnosed with melanoma, there was no statistical difference in the risk of ir-hypothyroidism between users of anti-CTLA4 or anti-PD1. However, advanced melanoma patients treated with ipilimumab or pembrolizumab may have a lower risk of ir-hypothyroidism compared to nivolumab users. Abstract (3): Purpose Melanoma treatment was advanced significantly by the approval of anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) agents (ipilimumab) and anti-programmed cell death 1 (anti-PD1) agents (nivolumab and pembrolizumab). However, these agents have been associated with gastrointestinal immune-related adverse events (irAEs) including colitis, which could lead to treatment discontinuation. We aimed to estimate the incidence and the risk of colitis in elderly patients with advanced melanoma treated with anti-CTLA4 and anti-PD1 in the real-world setting. Patients and Methods Elderly patients (age ≥ 65 years) diagnosed with advanced melanoma between 2011 and 2015 and treated with anti-CTLA4 or anti-PD1 agents were identified from the SEER-Medicare data. We estimated the risk of colitis from starting the treatment up to 90 days from the last dose of therapy. We used the log-rank test and logistic regression with adjustment for potential confounders using the inverse probability of treatment weighting (IPTW) method. Also, we conducted several sensitivity analyses using different follow-up periods and including all-stages of melanoma. Results A total of 274 elderly patients with advanced melanoma were included in our cohort. The risk of colitis was similar between the anti-PD1 users of and anti-CTLA4 groups based on log-rank test (p=0.17) and logistic regression model (OR 2.86, 95%CI 0.36-25). The 12-month cumulative incidence of colitis was 9.27% in the anti-CTLA4 vs. 4.64% in the anti-PD1 group. Sensitivity analyses for patients with all-stage melanoma showed a significantly lower risk of colitis in anti-PD1 compared to anti-CTLA4 treated patients based on a log-rank test (p=0.017) and logistic regression model (OR of 0.21, 95%CI 0.09-0.53). Conclusion Elderly with advanced melanoma who were treated with anti-CTLA-4 or anti-PD1 had a statistically similar risk of developing colitis. However, there was a statistical difference in the risk of colitis between anti-CTLA4 or anti-PD1 users among all-stages melanoma patients.Release after 03/27/202

Association of immune-checkpoint inhibitors and the risk of immune-related colitis among elderly patients with advanced melanoma: real-world evidence from the SEER–Medicare database

Background: The use of anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) therapy (ipilimumab) and anti-programmed cell-death 1 (anti-PD1) agents (nivolumab and pembrolizumab) in advanced melanoma have been associated with immune-related adverse events (irAEs) including colitis. We aimed to estimate the incidence and the risk of colitis in elderly patients with advanced melanoma treated with anti-CTLA4 and anti-PD1 in the real-world setting. Methods: Elderly patients (age ⩾ 65 years) diagnosed with advanced melanoma between 2011 and 2015 and treated with anti-CTLA4 or anti-PD1 agents were identified from the Surveillance, Epidemiology, and End Results (SEER)–Medicare data. We estimated the risk of colitis from start of treatment up to 90 days from the last dose of therapy. We used the log-rank test and logistic regression with adjustment for potential confounders using the inverse probability of treatment weighting method. We conducted several sensitivity analyses. Results: A total of 274 elderly patients with advanced melanoma were included in our cohort. The risk of colitis was similar between anti-PD1 users and anti-CTLA4 users based on log-rank test (p = 0.17) and logistic regression [odds ratio (OR) = 0.35, 95% confidence interval (95%CI) 0.04–2.79]. Sensitivity analyses for patients with all-stage melanoma showed a significantly lower risk of colitis in anti-PD1 compared with anti-CTLA4 treated patients based on log-rank test (p = 0.017) and logistic regression (OR = 0.21, 95%CI 0.09–0.53). Conclusion: Elderly with advanced melanoma treated with anti-CTLA4 or anti-PD1 had a similar risk of developing colitis. However, there was a statistically significant difference in the risk of colitis between anti-CTLA4 or anti-PD1 users among all-stage-melanoma patients. Plain Language Summary: Risk of colitis (inflammation of the large intestine) in elderly patients with melanoma treated with immune-checkpoint inhibitors (a group of medications that uses the patient’s immune system to fight cancer) While the anti-cancer agents known as immune-checkpoint inhibitors have had a great impact on the treatment of melanoma, they may also have side effects. This study estimated the risk of colitis, a chronic inflammation of the colon, in elderly patients with melanoma treated with anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) or anti-programmed cell-death 1 (anti-PD1) agents, using data from the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked database. Overall, we found that the risk of colitis was not different between anti-PD1 users and anti-CTLA4 users with advanced-stage melanoma. However, after including patients across all stages of melanoma, we found a significantly lower risk of colitis with anti-PD1 compared with anti-CTLA4. © The Author(s), 2021.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Establishing the Validity and Reliability Evidence of Preceptor Assessment of Student Tool

Objective. To evaluate the validity and reliability evidence of the preceptor assessment of student tool (PAST) which was designed to assess doctor of pharmacy (PharmD) student rotation performance. Methods. Evaluation data were loaded into WINSTEPS software to conduct a Rasch rating scale analysis. Validity evidence was examined from construct and content validity perspectives, and reliability was assessed via student and item separation index and reliability coefficient. Data from 435 observations were included in the analysis. Results. All 19 items measured the same construct of interest and the five-point rating scale functioned appropriately and differentiated students' ability. However, the item/person map indicated an absence of items at the end of the measurement continuum. Conclusion. Although adding items at the end of the measurement continuum may be beneficial, PAST showed good validity and reliability evidence when used to evaluate PharmD student rotations and is suitable to assess mastery learning.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Economic Evaluation of Talimogene Laherparepvec Plus Ipilimumab Combination Therapy vs Ipilimumab Monotherapy in Patients With Advanced Unresectable Melanoma

IMPORTANCE. A phase 2 trial comparing talimogene laherparepvec plus ipilimumab vs ipilimumab monotherapy in patients with advanced unresectable melanoma found no differential benefit in progression-free survival (PFS) but noted objective response rates (ORRs) of 38.8% (38 of 98 patients) vs 18.0% (18 of 100 patients), respectively. OBJECTIVE To perform an economic evaluation of talimogene laherparepvec plus ipilimumab combination therapy vs ipilimumab monotherapy. DESIGN, SETTING, AND PARTICIPANTS For PFS, cost-effectiveness and cost-utility analyses using a 2-state Markov model (PFS vs progression or death) was performed. For ORRs, cost-effectiveness analysis of the incremental cost of 1 additional patient achieving objective response was performed. In this setting based on a US payer perspective (2017 US dollars), participants were patients with advanced unresectable melanoma. MAIN OUTCOMES AND MEASURES The PFS life-years and PF5 quality-adjusted life-years were determined, and the associated incremental cost-effectiveness ratios (ICERs) and incremental cost-utility ratios (ICURs) were estimated. Also estimated was the ICER per 1 additional patient (out of 100 treated patients) achieving objective response. Base-case analyses were validated by sensitivity analyses. RESULTS In PFS analyses, the cost of talimogene laherparepvec plus ipilimumab ($494 983) exceeded the cost of ipilimumab monotherapy ($132 950) by $362 033. The ICER was$2 129 606 per PFS life-years, and the ICUR was $2 262 706 per PFS quality-adjusted life-year gained. Probabilistic sensitivity analyses yielded an ICER of$1 481 208 per PFS life-year gained and an ICUR of $1 683 191 per PFS quality-adjusted life-year gained. In 1-way sensitivity analyses, the PFS hazard ratio and the utility of response were the most influential parameters. Talimogene laherparepvec plus ipilimumab has a 50$1 683 191 per PFS quality-adjusted life-year gained. In ORR analyses, talimogene laherparepvec plus ipilimumab ($474 904) vs ipilimumab alone ($132 810), a $342 094 difference, yielded an ICER of$1 629 019 per additional patient achieving objective response. In subgroup analyses by disease stage and BRAF(V600E) mutation status, ICERs ranged from $1 069 044 to$17 104 700 per 1 additional patient achieving objective response. CONCLUSIONS AND RELEVANCE The cost to gain 1 additional progression-free quality-adjusted life-year, 1 additional progression-free life-year, or to have 1 additional patient attain objective response is about $1.6 million. This amount may be beyond what payers typically are willing to pay. Combination therapy of talimogene laherparepvec plus ipilimumab does not offer an economically beneficial treatment option relative to ipilimumab monotherapy at the population level. This should not preclude treatment for individual patients for whom this regimen may be indicated.12 month embargo; published online: 21 November 2018This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Comparative Risk of Acute Kidney Injury Following Concurrent Administration of Vancomycin with Piperacillin/Tazobactam or Meropenem: A Systematic Review and Meta-Analysis of Observational Studies

The study aims to comparatively assess the nephrotoxicity of vancomycin when combined with piperacillin-tazobactam (V + PT) or meropenem (V + M) in adult patients hospitalized in general wards or intensive care units. We searched MEDLINE, Google Scholar, and Web of Science for observational studies evaluating incidences of AKI in adult patients receiving V + PT or V + M for at least 48 h in general wards or intensive care units. The primary outcome was AKI events, while the secondary outcomes were hospital length of stay, need for renal replacement therapy (RRT), and mortality events. The odds ratio (OR), or mean difference for the hospital length of stay, with a corresponding 95% confidence interval (CI) from the inverse variance weighting random-effects model were estimated for the risk of AKI, RRT, and mortality. Of the 112 studies identified, twelve observational studies were included in this meta-analysis with a total of 14,511 patients. The odds of having AKI were significantly higher in patients receiving V + PT compared with V + M (OR = 2.31; 95%CI 1.69–3.15). There were no differences between V + PT and V + M in the hospital length of stay, RRT, or mortality outcomes. Thus, clinicians should be vigilant while using V + PT, especially in patients who are at high risk of AKI

Safety and efficacy of dual versus triple antithrombotic therapy (DAT vs TAT) in patients with atrial fibrillation following a PCI: a systematic review and network meta-analysis

Objective Creating an appropriate antithrombotic therapy for patients with atrial fibrillation (AF) who have undergone percutaneous coronary intervention (PCI) remains a dilemma. Several clinical trials compared the use of a dual antithrombotic therapy (DAT) regimen with a direct oral anticoagulants including (apixaban, dabigatran, edoxaban or rivaroxaban) and a P2Y12 inhibitor versus a triple antithrombotic therapy (TAT) that includes a vitamin K antagonist plus aspirin and a P2Y12 inhibitor in patients with AF who have undergone PCI. However, there are no head-to-head trials comparing the DAT regimens to each other. We aimed to compare the efficacy and safety of DAT regimens using a network meta-analysis (NMA) approach.Design A systematic review and NMA of randomised clinical trials.Methods We conducted a systematic literature review to identify relevant randomised clinical trials and performed a Bayesian NMA for International Society on Thrombosis and Haemostasis (ISTH) major or clinically relevant non-major (CRNM) bleeding, all-cause mortality, stroke, myocardial infarction (MI) and stent thrombosis outcomes. We used NetMetaXL V.1.6.1 and WinBUGS V.1.4.3 for the NMA and estimated the probability of ranking the treatments based on the surface under the cumulative ranking curve.Results The comparison between DAT regimens showed no significant difference in the safety or efficacy outcomes. Apixaban regimen was ranked first as the preferred therapy in terms of ISTH major or CRNM bleeding and stroke, with a probability of 52% and 54%, respectively. Rivaroxaban regimen was the preferred therapy in terms of MI and stent thrombosis, with a probability of 34% and 27%, respectively. Dabigatran regimen was ranked first in terms of all-cause mortality, with a probability of 28%.Conclusion The DAT regimens are as safe and effective as TAT regimens. However, ranking probabilities for the best option in the selected outcomes can be used to guide the selection among these agents based on different patients’ conditions