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Purpose: To examine the adherence to risk minimization measures (RMMs) in newly treated patients with anti‐tumor necrosis factor‐alpha (anti‐TNF‐α) medications at one of the largest tertiary care hospitals in Saudi Arabia. Methods: We included patients who had at least one prescription of infliximab or adalimumab. The index date was the first recorded date of infliximab or adalimumab prescription. New users of anti‐TNF‐α were divided into pre‐ and post‐RMM implementation groups. The outcome of interest was the proportion of patients that received tuberculosis (TB) screening, including a chest X‐ray (CXR) or a QuantiFERON test within 1 month prior to the index date. Results: A pre‐post RMM implementation comparison of TB screening among infliximab users showed a significant increase in the rates of CXR tests (from 7.5% before RMM implementation to 13.8% after RMM implementation, p < 0.001) and the rates of QuantiFERON tests (4.5% before RMM implementation to 24.1% after RMM implementation, p < 0.001). RMMs were introduced to the study site at the same time as adalimumab was approved and the proportion of patients receiving TB screening was 25.2%. Conclusion: TB screening prior to initiation of infliximab or adalimumab was not optimal. However, we noted an improvement in TB screening after the implementation of RMMs for infliximab. Future research may address reasons for low adherence to testing requirements for TB prior to initiation of anti‐TNF‐α medications. [ABSTRACT FROM AUTHOR]

Background: The combinations of BRAF + MEK inhibitors—encorafenib (ENC) + binimetinib (BIN), cobimetinib (COB) + vemurafenib (VEM), and dabrafenib (DAB) + trametinib (TRA)—are recommended for the treatment of BRAF-mutated advanced melanoma. Objective: To assess the cost-effectiveness and cost-utility of ENC + BIN versus COB + VEM versus DAB + TRA from a US payer perspective. Methods: A Markov model was constructed to simulate a hypothetical cohort over a time horizon of 10 years. The overall survival (OS) and progression-free survival (PFS) curves were independently digitized from a randomized controlled trial for ENC + BIN and fitted using R software. Published and indirectly estimated hazard ratios were used to fit OS and PFS curves for COB + VEM and DAB + TRA. Costs, life-year gains, and quality-adjusted life years (QALYs) associated with the 3 treatment combinations were estimated. A base case analysis and probabilistic sensitivity analysis (PSA) were conducted to estimate the incremental cost-utility ratio (ICUR). A discount rate of 3.5% was applied on cost and outcomes. Results: The ENC + BIN versus COB + VEM comparison was associated with an ICUR of $656 233 per QALY gained. The ENC + BIN versus DAB + TRA comparison was associated with an ICUR of $3 135 269 per QALY gained. The DAB + TRA combination dominated COB + VEM. The base case analysis estimates were confirmed by the PSA estimates. ENC + BIN was the most cost-effective combination at a high willingness-to-pay (WTP) threshold of $573 000 per QALY and $1.5 million/QALY when compared to COB + VEM and DAB + TRA, respectively. Conclusion and Relevance: Given current prices and acceptable WTP thresholds, our study suggests that DAB + TRA is the optimum treatment. In this study, ENC + BIN was cost-effective only at a very high WTP per QALY threshold. [ABSTRACT FROM AUTHOR]

Biopharmaceuticals have emerged as a cornerstone of modern medicine, offering targeted and effective treatments for a diverse array of medical conditions. This review provides an overview of the key applications, challenges, and opportunities in biopharmaceutical development. Key applications include cancer immunotherapy, rare genetic disorders, autoimmune diseases, infectious diseases, and neurological disorders. Challenges such as complex manufacturing processes, regulatory requirements, and high costs are discussed, alongside opportunities arising from advances in biotechnology, personalized medicine, and collaborative partnerships. The importance of prioritizing patient safety, accessibility, and affordability is emphasized. By embracing innovation and collaboration, the biopharmaceutical industry can continue to revolutionize healthcare and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Summary: Tirzepatide is a new glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) that has shown promising results for weight loss. A Bayesian network meta‐analysis was conducted to compare the efficacy and safety of GLP‐1RAs for obesity management. Embase and MEDLINE were searched looking for randomized clinical trials (RCTs) that evaluated the efficacy of GLP‐1RAs for weight loss in patients without diabetes. The main efficacy outcomes evaluated were the mean change in actual and percentage weight loss and the proportion of patients with weight loss of ≥5%–20%. Main safety outcomes evaluated include nausea, vomiting, diarrhea, constipation, loss of appetite, pancreatitis, gallbladder‐related disorders, and withdrawal due to adverse events. Seven RCTs with more than 12,300 patients were analyzed, including patients with body mass index (BMI) ≥ 30 kg/m2, or BMI ≥ 27 kg/m2 with comorbidities. Weekly tirzepatide 10 and 15 mg resulted in more weight loss than weekly semaglutide 2.4 mg, daily semaglutide 0.4 mg, or liraglutide 3 mg. Tirzepatide and weekly semaglutide demonstrated comparable results but with significantly higher odds of achieving ≥5%–20% weight loss compared with liraglutide. GLP‐1RAs triggered more gastrointestinal adverse events than placebo, with no in‐between difference. Although all GLP‐1RAs lead to significant weight reduction, tirzepatide was associated with better efficacy outcomes while having a comparable safety profile. [ABSTRACT FROM AUTHOR]

To assess the cost-efficiency and expanded access of three rituximab biosimilars versus the reference rituximab from the perspective of the Jordanian national health payer. A 1-year cost-efficiency and expanded access model of conversion from reference rituximab (Mabthera) to the approved biosimilars (Truxima, Rixathon, and Tromax) to assess five metrics: total annual cost to treat a hypothetical patient; head-to-head cost comparison; changes in patients' access to rituximab; number-needed-to-convert (NNC) to provide an additional 10 patients access to a rituximab treatment; and relative amount of Jordanian Dinar (JOD) spent on rituximab options. The model included rituximab doses at 100 mg/10 ml and 500 mg/50 ml and considered both cost-saving and cost-wastage scenarios. Costs of treatments were based on the fiscal year 2022 tender prices received by the Joint Procurement Department (JPD). Rixathon was associated with the lowest average annual cost per patient (JOD2,860) across all six indications among all rituximab comparators, followed by Truxima (JOD4,240), Tromax (JOD4,365) and reference Mabthera (JOD11,431). The highest percentage of patient access to rituximab treatment (321%) was achieved when switching patients from Mabthera to Rixathon in the RA and PV indications. At four patients, Rixathon was associated with the lowest NNC to provide an additional 10 patients access to rituximab treatment. For each JOD1 spent on Rixathon, an additional JOD3.21 must be spent on Mabthera, an additional JOD0.55 on Tromax, and an additional JOD0.53 on Truxima. Rituximab biosimilars were associated with cost savings in all approved indications in Jordan compared to reference rituximab. Rixathon was associated with the lowest annual cost, the highest percentage of expanded patient access for all six indications, and the lowest NNC providing 10 additional patients with access. [ABSTRACT FROM AUTHOR]

Aim: To determine the incidence of chemotherapy-induced febrile neutropenia (FN) and related outcomes after same-day pegfilgrastim in lung cancer. Materials & methods: This single-center, retrospective study evaluated electronic health records of patients with lung cancer treated between 2013-2018. The main end points were incidence of FN and grade 3/4 neutropenia after the first and across all chemotherapy cycles. Results: A total of 114 patients received same-day pegfilgrastim in 384 cycles. The incidence of FN and grade 3/4 neutropenia was 2.3 and 25% after the first chemotherapy cycle and 1.6 and 10.4% across all cycles, respectively. Conclusion: Same-day prophylactic pegfilgrastim in patients with lung cancer may be a suitable option, owing to its low incidence of FN and related outcomes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Previous reports suggest that the Coronavirus Disease-2019 (COVID-19) pandemic might have affected incidences of diabetic ketoacidosis (DKA) and new diagnoses of type 1 diabetes. This systematic review and meta-analysis aimed to estimate the risk of DKA, including severe DKA, during the COVID-19 pandemic versus the prior-to-COVID-19 period among pediatric patients with type 1 diabetes. Methods: PubMed and EMBASE were searched for observational studies investigating the risk of DKA among pediatric patients with type 1 diabetes during the COVID-19 pandemic and the prior-to-COVID-19 period. A random meta-analysis model was performed to estimate the relative risk of DKA during the COVID-19 pandemic compared to before the pandemic. Subgroup analyses were conducted based on the type 1 diabetes status, established or newly diagnosed. In addition, sensitivity analysis was conducted for studies that reported results from adjusted analysis for potential confounders using fixed effect model. Results: A total of 20 observational studies reported the risk of DKA, of which 18 reported the risk of severe DKA. The risks of DKA and severe DKA were 35% (RR 1.35, 95%CI 1.2-1.53, I 2 = 71%) and 76% (RR 1.76, 95%CI 1.33-2.33, I 2 = 44%) higher in the during-COVID-19 group compared to the prior-to-COVID-19 group, respectively. Among patients with newly diagnosed type 1 diabetes, the risk of DKA was 44% higher for the during-COVID-19 group compared to the prior-to-COVID-19 group (RR 1.44, 95%CI 1.26-1.65; I 2 = 64%). Only two studies reported the risk of DKA among patients with established type 1 diabetes and the cumulative risk was not statistically significant. In the sensitivity analysis, four studies reported an adjusted odds ratio (aOR) of the risk of DKA during COVID-19 compared to the prior-to-COVID-19 period. The fixed estimate from the meta-analysis found an increase in the risk of DKA in the during-COVID-19 group compared to the prior-to-COVID-19 group (aOR 2.04, 95%CI 1.66-2.50). Conclusions: This study showed that DKA risk, especially the risk of severe DKA, has increased significantly during the pandemic. Healthcare systems must be aware and prepared for such an increase in DKA cases and take all necessary measures to prevent future spikes during the pandemic. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display%5frecord.php?RecordID=272775 , identifier PROSPERO [CRD42021272775]. [ABSTRACT FROM AUTHOR]

Background: Venous thromboembolism (VTE) is a common complication among patients with cancer and is one of the most common causes of increased morbidity and mortality. The use of direct oral anticoagulants (DOACs) for thromboprophylaxis and treatment of cancer-associated venous thromboembolism (CA-VTE) has been evaluated in several randomized clinical trials (RCTs). The aim of this meta-analysis was to assess efficacy and safety of using DOACs for thromboprophylaxis and treatment of CA-VTE and provide a summary for available guidelines' recommendations. Methods: MEDLINE was searched to identify studies evaluating the use of DOACs for thromboprophylaxis or treatment in patients with cancer. Search was limited to peer-reviewed studies published in English. Studies were excluded if they were not RCTs or subgroup analyses of data derived from RCTs, if they did not report efficacy and safety data on patients with active cancer, or if they were published as an abstract. New VTE or VTE recurrence, and major or clinically relevant non-major bleeding (CRNMB) were used to assess the efficacy and safety, respectively. The Mantel-Haenszel random-effects model risk ratios (RRs) and the corresponding 95% confidence intervals (CIs) were calculated to estimate the pooled treatment effects of DOACs. Results: Four studies evaluating DOACs use for thromboprophylaxis and four – for treatment of CA-VTE were included. Thromboprophylaxis with DOACs was associated with a significant reduction in the risk of symptomatic VTE (RR = 0.58; 95%CI 0.37,0.91) but with an incremental risk of major bleeding or CRNMB (RR = 1.57; 95%CI 1.10,2.26). CA-VTE treatment with DOACs was linked with a significant reduction in VTE recurrence (RR = 0.62; 95%CI 0.44,0.87) but with an incremental risk of CRNMB (RR = 1.58; 95%CI 1.11,2.24). Conclusions: The DOACs are associated with a lower risk of symptomatic VTE and VTE recurrence, but the risk of bleeding remains a considerable concern. Clinical decisions should be made by assessing individual patient's risk of VTE and bleeding. [ABSTRACT FROM AUTHOR]

Purpose: The main objective of this study was to evaluate the effectiveness and safety of apixaban versus warfarin in patients with venous thromboembolism (VTE) in a "real-world" setting. Patients and Methods: A retrospective cohort study was conducted using data from a large tertiary hospital in Saudi Arabia. Patients were included if they were adults (≥ 18 years), diagnosed with VTE, and treated with either apixaban or warfarin between January 2016 and September 2018. Patients who had received anticoagulation therapy within three months of the date of the index event were excluded. The effectiveness outcomes were incidence of VTE recurrence (ie, deep vein thrombosis DVT or pulmonary embolism [PE]), while the safety outcome was incidence of any major bleeding (MB) event within 90 days of follow-up. Results: Among the 492 patients included for study, 212 (43.1%) received apixaban and 280 (56.1%) received warfarin. The mean age of patients was 53.6± 19.1 years and 62% of the cohort was female. Comparable rates of VTE recurrence were observed for apixaban and warfarin treatment groups during follow-up (adjusted odds ratio (AOR) =0.95; 95% CI 0.53– 1.68), including DVT (AOR=1.06; 95% CI 0.52– 2.17) and PE (AOR=0.78; 95% CI 0.31– 1.96). However, apixaban was associated with significantly fewer MB events than warfarin (AOR=0.18; 95% CI 0.04– 0.83). Conclusion: The use of apixaban for the treatment of Saudi patients with acute VTE is associated with a VTE recurrence rate comparable to that of warfarin, with significantly fewer MB events. [ABSTRACT FROM AUTHOR]

Background: The cardiovascular outcome trials (CVOTs) have shown that glucagon like peptide-1 receptor agonists (GLP1RAs) have varying degrees of cardiovascular (CV) safety in patients with type 2 diabetes mellitus (T2DM.) The lack of any head-to-head comparative trials among GLP1RAs urged the need for an indirect comparison of these agents. Therefore, this study was conducted to indirectly compare the CV safety and mortality effects among different GLP1RAs in patients with T2DM using network meta-analysis (NMA). Methods: Medline was searched to identify GLP1RA CVOTs to date. The outcomes of interest were CV death, myocardial infarction (IM), stroke, and death from any cause. An NMA with binomial likelihood logit link model was used for the binary outcomes. We conducted both fixed effects and random effects models for each outcome, and selected the best model based on the deviance information and the average posterior residual deviance. This NMA was reported in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA-NMA). Results: A total of seven GLP1RA CVOTs were included having 56,004 patients. The NMA results showed that oral semaglutide was statistically better than exenatide (OR 0.47, 95% CI 0.21–0.99), dulaglutide (OR 0.46, 95% CI 0.20– 0.97), albiglutide (OR 0.45, 95% CI 0.19–0.97), lixisenatide (OR 0.43, 95% CI 0.19–0.92) in reducing CV death events. No significant differences were detected between most of the treatments regarding reducing death from any cause, MI and stroke events. The ranking results showed that oral semaglutide had the highest probability to be ranked first (>90%) in reducing CV death and death from any cause. Moreover, once weekly semaglutide had the highest probability to be ranked first in reducing MI and stroke events. Conclusion: The GLP1RAs have shown significant benefits in terms of CV safety. The indirect comparison and ranking probability results have shown that one weekly semaglutide and oral semaglutide seems to be the preferred option in patients with T2DM and established or at high risk of CVD. This result can aid health care providers, pharmacy and therapeutics committees in hospitals, and insurance companies when deciding which GLP1RA to start or add to their formulary. [ABSTRACT FROM AUTHOR]

Background: Olanzapine, neurokinin-1-receptor-antagonists (NK-1-RA), and thalidomide added to palonosetron + dexamethasone (PALO-DEX) have been evaluated in separate studies as prophylaxis for chemotherapy-induced nausea and vomiting (CINV) due to highly emetogenic chemotherapy (HEC). We conducted a Bayesian network meta-analysis to compare the prophylactic efficacy of these agents in combination with PALO-DEX.Methods: PubMed, Medline/Ovid, Embase, and Clinicaltrials.gov were searched from inception through 22 Mar 2018. Study quality was assessed using the Cochrane methodology. A Bayesian network meta-analysis using random-effects models was used to asses complete response (CR) and rate of no nausea (RNN) in acute, delayed, and overall phases and were expressed as odds ratios (OR) and 95% credible interval (95% CrI). Ranking probabilities of treatments were calculated using the surface under the cumulative ranking curve (SUCRA) to identify the probability of a given treatment as the best option against the worst option.Results: Nine RCTs involving two thousand nine hundred fifty-nine patients were included. The olanzapine-based regimen showed greater CR in the acute, delayed, and overall-phases versus the PALO-DEX regimen (OR = 3.97, 95% CrI = 1.02-19.13; OR = 5.62, 95% CrI = 1.66-28.58; OR = 4.79, 95% CrI = 1.40-24.02, respectively). Additionally, it showed greater RNN than the NK-1-RA-based and the PALO-DEX regimens in the delayed phase only (OR = 2.90, 95% CrI = 1.34-5.15; OR = 4.53, 95% CrI = 1.89-10.55, respectively). Olanzapine-, NK-1-RA-, and thalidomide-based regimens did not differ in CR in the three phases. SUCRA probabilities ranked the olanzapine-based regimen as the best option in terms of CR and RNN, while ranking the NK-1-RA-based regimens as the second best option in terms of CR throughout the three phases.Conclusion: Based on the data included in the analyses, there is insufficient evidence to support adding thalidomide or NK-1-RA to PALO-DEX in preventing CINV induced by HEC. However, adding olanzapine to PALO-DEX achieves better CR and RNN. Olanzapine side-effects and the absence of direct comparisons explain why some guidelines are cautious in suggesting the use of olanzapine. [ABSTRACT FROM AUTHOR]

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 6,331 patients with advanced melanoma and reporting irAE data were included in the meta-analyses. We found higher incidences of potential irAEs in combination therapies vs. 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 FROM AUTHOR]

Objectives 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. Design A systematic review and Bayesian network meta-analysis. Data source A comprehensive search from inception to 30 February 2019 was conducted in four databases (Medline/PubMed, Embase, Scopus, ClinicalTrials. gov). Eligibility criteria RCTs reporting the resolution of diarrhoea associated with RCDI without relapse for at least 60 days after the end of treatments as the primary outcome. Data extraction and synthesis We extracted author, year of publication, study design and binomial data that represented the resolution of diarrhoea or adverse events of monoclonal antibodies and FMT infusion. Random-effects models were used for resolution rate of RCDI and adverse events. The Cochrane Risk of Bias tool was used to assess the quality of included RCTs. Results Out of 1003 articles identified, seven RCTs involving 3043 patients contributed to the review. No difference was reported between single or multiple infusions of FMT and bezlotoxumab in resolving RCDI, (OR 1.53, 95% credible interval (CrI) 0.39 to 5.16) and (OR 2.86, 95% CrI 1.29 to 6.57), respectively. Patients treated with SAT alone or bezlotoxumab with SAT showed significantly lower rates of diarrhoea than FMT (OR 0, 95% CrI 0 to 0.09) and (OR 0, 95% CrI 0 to 0.19), respectively. There was no difference in terms of other adverse events. Conclusions This is the first network meta-analysis that has compared the recently Food and Drug Administration-approved monoclonal antibody bezlotoxumab with FMT for resolving RCDI. The quality of the included RCTs was variable. The findings of this study suggested no difference between single or multiple infusions of FMT and bezlotoxumab. However, FMT was associated with a higher rate of non-serious diarrhoea as opposed to SAT used alone or in combination with bezlotoxumab. [ABSTRACT FROM AUTHOR]

Objective: To indirectly compare glucagon like peptide-1 receptor agonists (GLP-1RA) cardiovascular outcome trials (CVOTs) using network meta-analysis (NMA). Methods: We searched Medline to retrieve CVOTs that involved GLP-1RA. We conducted NMAs using binomial likelihood logit link model for the following outcomes: CV death, myocardial infarction (IM), stroke, and death from any cause. After running both fixed effects and random effects models for each outcome, we identified the best fit model that has the smallest deviance information and the average posterior residual deviance. We followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA-NMA) in reporting this NMA. Results: After screening, a total of seven GLP-1RA CVOTs were included. The NMA results showed that oral semaglutide was statistically better than exenatide (HR 0.47, CI: 0.21-0.99), dulaglutide (HR 0.46, CI: 0.20-0.97), albiglutide (HR 0.45, CI: 0.19-0.97), and lixisenatide (HR 0.43, CI: 0.19-0.92) in reducing CV death events. No significant differences were detected between most of the treatments regarding reducing death from any cause, MI and stroke events. The ranking results showed that oral semaglutide had the highest probability to be ranked first (>90%) in reducing CV death and death from any cause. Moreover, once weekly semaglutide had the highest probability to be ranked first in reducing MI and stroke events. Conclusion: The indirect comparison of GLP-1RAs using CVOTs data showed that oral semaglutide is preferred over most of the GLP-1RAs in reducing CV death and death from any cause events. The ranking probability showed that once weekly semaglutide and oral semaglutide are the most likely to be ranked first in reducing the outcomes of interest. Disclosure: O. Alfayez: None. O. Alkhezi: None. A.R. Almutairi: None. [ABSTRACT FROM AUTHOR]