Indirect comparison of various lumen-apposing metal stents for EUS-guided biliary and gallbladder drainage: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Studies assessing EUS-guided biliary drainage (EUS-BD) or gallbladder drainage (EUS-GB) using lumen-apposing metal stents (LAMSs) have shown variable results based on the type of LAMS. We performed a meta-analysis of the available data. METHODS: Multiple online databases were searched for studies using LAMSs (Axios [Boston Scientific, Marlborough, Mass, USA] or Spaxus [Taewoong Medical Co, Gimpo, Korea]) for EUS-BD and EUS-GB. The outcomes of interest were technical success, clinical success, and adverse events. Pooled proportions along with 95% confidence intervals were calculated. RESULTS: A total of 18 observational studies were included: 11 for the Axios stent (433 patients; mean age, 72 years; 54% male) and 7 for the Spaxus stent (242 patients; mean age, 74 years; 50% male). The respective pooled outcomes for the Axios stent (EUS-BD and EUS-GB, respectively) were technical success, 96.2% and 96.2%; clinical success, 92.8% and 92.7%; total adverse events, 10.1% and 23.6%; and bleeding, 3.7% and 4.8%. The respective pooled outcomes for the Spaxus stent (EUS-BD and EUS-GB, respectively) were technical success, 93.8% and 95.9%; clinical success, 90.1% and 94.2%; total adverse events, 12.6% and 9.5%; and bleeding, 3.1% and 1.8%. CONCLUSIONS: Axios and Spaxus stents demonstrate similar pooled technical and clinical success rates. Adverse events occurred in 23.6% of patients (Axios stent) and 9.5% of patients (Spaxus stent) during EUS-GB.

Conventional Versus Traction Endoscopic Submucosal Dissection for Colorectal Tumors: A Meta-analysis of Randomized Controlled Trials.

INTRODUCTION: Compared with conventional endoscopic submucosal dissection (C-ESD) for colorectal lesions, the traction method (T-ESD) allows the lesion to be stabilized with easier dissection. However, randomized controlled trials (RCTs) have reported conflicting results on the clinical outcomes of T-ESD as compared with C-ESD. We conducted a meta-analysis to compile the data. METHODS: Multiple databases were searched for RCTs evaluating C-ESD versus T-ESD for colorectal tumors. The end points of interest were procedure time (min), resection speed (mm²/min), R0 resection, en bloc resection, delayed bleeding, and perforation. Standard meta-analysis methods were employed using the random-effects model. RESULTS: Six RCTs with a total of 566 patients (C-ESD n=284, T-ESD n=282) were included. The mean age was 67±10 y and 60% were men. As compared with the T-ESD technique, the C-ESD group was associated with longer procedure time (SMD 0.91, 95% CI 0.58 to 1.23, P<0.00001) and lesser resection speed (SMD -1.03, 95% CI -2.01 to -0.06, P=0.04). No significant difference was found in the 2 groups with respect to R0 resection rate (RR 1.00, 95% CI 0.94 to 1.06, P=0.87), en bloc resection (RR 0.99, 95% CI 0.97 to 1.01, P=0.35), delayed bleeding (RR 0.66, 95% CI 0.17 to 2.59, P=0.55) and perforation (RR 2.16, 95% CI 0.75 to 6.27, P=0.16). DISCUSSION: On meta-analysis, pooled procedure time was significantly faster with T-ESD compared with C-ESD. The clinical outcomes, however, were comparable.

Meta-Analysis of Endoscopic Full-Thickness Resection Versus Endoscopic Submucosal Dissection for Complex Colorectal Lesions.

BACKGROUND: Studies evaluating endoscopic full-thickness resection (EFTR) and endoscopic submucosal dissection (ESD) for complex colorectal lesions have shown variable results. We conducted a meta-analysis of the available data. METHODS: Online databases were searched for studies comparing EFTR versus ESD for complex colorectal lesions. The outcomes of interest were resection rates, procedure time (min), and complications. Pooled odds ratios (OR) and standardized mean difference (SMD) along with 95% CI were calculated. RESULTS: A total of 4 studies with 530 patients (n=215 EFTR, n=315 ESD) were included. The mean follow-up duration was 5 months. The mean age of the patients was 68 years and 64% were men. The EFTR and ESD groups had similar rates of en bloc resection (OR: 1.73, 95% CI: 0.60-4.97, P=0.31) and R0 resection (OR: 1.52, 95% CI: 0.55-4.14, P=0.42). The EFTR group had significantly reduced procedure time (SMD -1.87, 95% CI: -3.13 to -0.61, P=0.004), total complications (OR: 0.24, 95% CI: 0.13-0.44, P<0.00001), perforation (OR: 0.12, 95% CI: 0.03-0.39, P=0.0005) and postresection electrocoagulation syndrome (OR: 0.06, 95% CI: 0.01-0.48, P=0.008). Delayed bleeding was similar in the 2 groups (OR: 0.80, 95% CI: 0.30-2.12, P=0.66). Residual/recurrent lesions were significantly higher in the EFTR group (OR: 4.67, 95% CI: 1.39-15.66, P=0.01). DISCUSSION: This meta-analysis of small studies with high heterogeneity showed that EFTR and ESD have comparable resection rates for complex colorectal lesions. EFTR is faster and has fewer complications, but it increases residual or recurrent lesions.

Safety and efficacy of thalidomide in treatment of gastrointestinal bleeding secondary to angioectasias: a systematic review and meta-analysis.

BACKGROUND: Thalidomide has been used for angioectasia-associated refractory gastrointestinal bleeding (GIB), with studies showing variable efficacy and side effects profile. We conducted a meta-analysis to reconcile the data. METHODS: Online databases were searched for studies evaluating thalidomide in patients with refractory/recurrent GIB due to angioectasias. The outcomes of interest were cessation of bleeding, rebleeding, need for blood transfusion, hospitalization and adverse events. Pooled proportions for incidence, and odds ratios (OR) for comparison with control were calculated along with 95% confidence interval (CI). RESULTS: A total of seven studies with 346 patients (n = 269 thalidomide, n = 77 control) were included. Thalidomide dose was usually started at 50-100mg/day. The mean age was 65 years, 45% patients were men, and mean follow-up was 1.8 years. The pooled clinical outcomes with thalidomide were: cessation of bleeding 42.2% (95% CI 36.02 to 48.41), rebleeding 30%, need for blood transfusion 20.1%, hospitalization 40% and adverse events 55.9%. When compared with the control group in 2 studies, patients on thalidomide had significantly higher odds of cessation of bleeding (OR 21.40, 95% CI 5.78 to 79.29, p < 0.00001) and adverse events, with lower need for blood transfusion and hospitalization. DISCUSSION: In patients with angioectasias-related refractory/recurrent GIB, the use of thalidomide results in significantly decreased bleeding risk and may play a role in the management of such patients.

Groove pancreatitis: From enigma to future directions-A comprehensive review.

Groove pancreatitis (GP) is a rare and clinically distinct form of chronic pancreatitis affecting the pancreaticoduodenal groove comprising the head of the pancreas, duodenum, and the common bile duct. It is more prevalent in individuals in their 4-5th decade of life and disproportionately affects men compared with women. Excessive alcohol consumption, tobacco smoking, pancreatic ductal stones, pancreatic divisum, annular pancreas, ectopic pancreas, duodenal wall thickening, and peptic ulcers are significant risk factors implicated in the development of GP. The usual presenting symptoms include severe abdominal pain, nausea, vomiting, diarrhea, weight loss, and jaundice. Establishing a diagnosis of GP is often challenging due to significant clinical and radiological overlap with numerous benign and malignant conditions affecting the same anatomical location. This can lead to a delay in initiation of treatment leading to increasing morbidity, mortality, and complication rates. Promising research in artificial intelligence (AI) has garnered immense interest in recent years. Due to its widespread application in diagnostic imaging with a high degree of sensitivity and specificity, AI has the potential of becoming a vital tool in differentiating GP from pancreatic malignancies, thereby preventing a missed or delayed diagnosis. In this article, we provide a comprehensive review of GP, covering the etiology, pathogenesis, clinical presentation, radiological and endoscopic evaluation, management strategies, and future directions. This article also aims to increase awareness about this lesser known and often-misdiagnosed clinical entity amongst clinicians to ultimately improve patient outcomes.

Early assessment of the pharmacokinetic and pharmacodynamic effects following acetylsalicylic acid loading: toward a definition for acute therapeutic response.

Despite decades of investigations, the optimal assessment of the "therapeutic response" to early after loading dose of acetylsalicylic acid (ASA) remains unclear. Limited information is available on the relation between pharmacodynamic (PD) and pharmacokinetic (PK) measurements assessed immediately after ASA administration. Serial PD and PK analyses were performed immediately after a single 162 or 650 mg dose of chewed and swallowed ASA in ten healthy adults. ASA response was defined as > 95% inhibition of serum thromboxane (Tx)B2, < 550 aspirin reaction units (ARU) by VerifyNow Aspirin (VN) test, and ≤ 20% arachidonic acid (AA)-induced platelet aggregation (PA). Correlation analyses between PK and PD measurements and receiver operating characteristic (ROC) curve analyses were performed. ASA response measured by VN test and AA-induced PA was achieved within 30 min of ASA administration. A correlation was observed between ARU and AA-induced maximum PA (r = 0.69, p < 0.001), serum TxB2 (r = 0.74 and p < 0.001), and serum TxB2 inhibition (r = 0.79, p < 0.001). In ROC curve analyses, ≤ 558 ARU and ≤ 7% AA-induced PA were associated with > 95% inhibition of TxB2. 686 ng/ml plasma ASA cut-off point was associated with > 95% inhibition of serum TxB2, ≤ 7% 1 mM AA-induced PA, and ≤ 585 ARU. A modest ~ 50% inhibition of TxB2 inhibition was associated with marked inhibition of 1 mM AA-induced platelet aggregation by LTA. Our analyses demonstrated important relationships between pharmacodynamic, and pharmacokinetic parameters measured immediately following oral ASA and cutoff values for ARU and AA-induced PA that is associated with > 95% inhibition of serum TxB2.

Utility of VerifyNow to assess the immediate pharmacodynamic response of chewed and swallowed aspirin: comparison with aggregometry.

VerifyNow (VN) test is a less laborious method to assess pharmacodynamics (PD) compared to light transmittance aggregometry (LTA). VN assay has not been used to study the immediate PD effects of acetylsalicylic acid (ASA). Ten healthy volunteers were randomly assigned to a single 162 or 650 mg dose of chewed and swallowed ASA. Pharmacodynamic and pharmacokinetic measurements were performed at baseline and serially up to 60 min after ASA administration. Onset by VN was 20 ± 7 min with 162 mg and 13 ± 7 min with 650 mg ASA (p = .07). Onset by 1 mM AA-induced PA was 13 ± 12 min with 162 mg and 7 ± 3 min with 650 mg ASA (p=NS). VN correlated with AA-induced PA (r = 0.80, p < .001) and serum TxB2 levels (r = 0.76, p < .001). 95% inhibition of serum TxB2 was achieved at 38 ± 22 min and 22 ± 8 min with the 162 and 650 mg ASA, respectively (p = .08). The onset and extent of the antiplatelet effect of 650 mg ASA is numerically faster and greater than the 162 mg dose. VN identifies the onset, extent, and dose response to ASA therapy. The ease of using VN should facilitate multicenter PD investigations of ASA.

Aspirin (acetylsalicylic acid) is an important drug widely used to prevent adverse ischemic events in patients with cardiovascular disease. Platelet aggregation and thromboxane B₂ levels in blood samples by complex laboratory methods are used to assess platelet response to aspirin. VerifyNow assay is a simple laboratory test that has not been used to assess the immediate effect of aspirin. In this study, conducted in 10 healthy volunteers, we compared the immediate platelet response to aspirin by serially assessing platelet aggregation by aggregometry and VerifyNow assay, and thromboxane B₂ levels. We also measured plasma levels of acetylsalicylic acid and salicylic acid. Our study demonstrated that the VerifyNow Aspirin test identifies the onset, extent, and dose-response to aspirin therapy. The ease of using the VerifyNow test should facilitate multicenter pharmacodynamic investigations of aspirin.

Renal denervation in hypertension: An updated meta-analysis of the randomized controlled trials.

BACKGROUND: Radiofrequency or ultrasound renal denervation (RDN) has shown conflicting results when used as an adjunctive option for hypertension management in randomized controlled trials (RCTs). METHODS: We searched Pubmed, MEDLINE, and other online databases for RCTs comparing RDN versus sham-control procedures in patients with uncontrolled or resistant hypertension. The endpoints of interest were 24-h ambulatory (AMB) blood pressure (BP), daytime AMB BP, and office BP. We performed a random-effects meta-analysis using the inverse variance method to estimate mean difference (MD) with a 95% confidence interval (CI). RESULTS: Nine studies with 1643 patients were included in the final analysis. The mean follow-up was 5 months. As compared with the sham-controlled group, RDN was associated with a significant decrease in 24-h AMB BP (systolic [MD -4.20; 95% CI -5.36 to -3.03; p < 0.00001], diastolic [-2.38; -3.42 to -1.35]), and daytime AMB BP (systolic: -5.11; -6.75 to -3.47, diastolic: -2.88; -3.91 to -1.85). Similarly, office BP was reduced with RDN (systolic: -5.46; -7.12 to -3.81; diastolic: -3.17; -4.23 to -2.12) when compared with placebo. CONCLUSION: Our meta-analysis shows that RDN is associated with a significant reduction in the 24-h AMB BP, daytime AMB BP, and office BP.

Oxygen Targets After Cardiac Arrest: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Optimal oxygen saturation target in patients resuscitated after cardiac arrest is unknown. Previous randomized controlled trials (RCTs) comparing restrictive oxygen therapy with liberal therapy have shown conflicting results. STUDY QUESTION: We performed a meta-analysis of available RCTs to consolidate the contrasting findings regarding the oxygen targets after cardiac arrest. DATA SOURCES: We searched electronic databases for RCTs comparing restrictive versus liberal oxygen targets in patients resuscitated after cardiac arrest. STUDY DESIGN: End points of interest were mortality, unfavorable neurological outcomes, and rearrests. Random-effects meta-analysis was performed to estimate the risk ratio (RR) with a 95% confidence interval (CI). RESULTS: Eight RCTs with 1641 patients (restrictive n = 833, liberal n = 808) were included in the analysis. The oxygen targets were defined by either saturation, partial pressure (PaO2), or supplementation rates. The mean age and male percentage were 63 years and 80%, respectively. There was no significant difference observed in the 2 groups for overall mortality (RR = 0.91, 95% CI = 0.75-1.10, P = 0.33), unfavorable neurological outcomes (RR = 0.93, 95% CI = 0.74-1.18, P = 0.56), and rearrests (RR = 0.67, 95% CI = 0.22-1.98, P = 0.47). CONCLUSIONS: Overall, this meta-analysis shows no significant difference in mortality, unfavorable neurological outcomes, and rearrests when using restrictive or liberal oxygen targets in patients after cardiac arrest. The limitations in the newer trials should be kept in mind while interpreting the overall results.

Active-Site Tryptophan, the Target of Antineoplastic C-Terminal Binding Protein Inhibitors, Mediates Inhibitor Disruption of CtBP Oligomerization and Transcription Coregulatory Activities.

C-terminal binding proteins (CtBP1/2) are oncogenic transcriptional coregulators and dehydrogenases often overexpressed in multiple solid tumors, including breast, colon, and ovarian cancer, and associated with poor survival. CtBPs act by repressing expression of genes responsible for apoptosis (e.g., PUMA, BIK) and metastasis-associated epithelial-mesenchymal transition (e.g., CDH1), and by activating expression of genes that promote migratory and invasive properties of cancer cells (e.g., TIAM1) and genes responsible for enhanced drug resistance (e.g., MDR1). CtBP's transcriptional functions are also critically dependent on oligomerization and nucleation of transcriptional complexes. Recently, we have developed a family of CtBP dehydrogenase inhibitors, based on the parent 2-hydroxyimino-3-phenylpropanoic acid (HIPP), that specifically disrupt cancer cell viability, abrogate CtBP's transcriptional function, and block polyp formation in a mouse model of intestinal polyposis that depends on CtBP's oncogenic functions. Crystallographic analysis revealed that HIPP interacts with CtBP1/2 at a conserved active site tryptophan (W318/324; CtBP1/2) that is unique among eukaryotic D2-dehydrogenases. To better understand the mechanism of action of HIPP-class inhibitors, we investigated the contribution of W324 to CtBP2's biochemical and physiologic activities utilizing mutational analysis. Indeed, W324 was necessary for CtBP2 self-association, as shown by analytical ultracentrifugation and in vivo cross-linking. Additionally, W324 supported CtBP's association with the transcriptional corepressor CoREST, and was critical for CtBP2 induction of cell motility. Notably, the HIPP derivative 4-chloro-HIPP biochemically and biologically phenocopied mutational inactivation of CtBP2 W324. Our data support further optimization of W318/W324-interacting CtBP dehydrogenase inhibitors that are emerging as a novel class of cancer cell-specific therapeutic.

Quantitative Tyrosine Phosphoproteomics of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor-treated Lung Adenocarcinoma Cells Reveals Potential Novel Biomarkers of Therapeutic Response.

Mutations in the Epidermal growth factor receptor (EGFR) kinase domain, such as the L858R missense mutation and deletions spanning the conserved sequence 747LREA750, are sensitive to tyrosine kinase inhibitors (TKIs). The gatekeeper site residue mutation, T790M accounts for around 60% of acquired resistance to EGFR TKIs. The first generation EGFR TKIs, erlotinib and gefitinib, and the second generation inhibitor, afatinib are FDA approved for initial treatment of EGFR mutated lung adenocarcinoma. The predominant biomarker of EGFR TKI responsiveness is the presence of EGFR TKI-sensitizing mutations. However, 30-40% of patients with EGFR mutations exhibit primary resistance to these TKIs, underscoring the unmet need of identifying additional biomarkers of treatment response. Here, we sought to characterize the dynamics of tyrosine phosphorylation upon EGFR TKI treatment of mutant EGFR-driven human lung adenocarcinoma cell lines with varying sensitivity to EGFR TKIs, erlotinib and afatinib. We employed stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative mass spectrometry to identify and quantify tyrosine phosphorylated peptides. The proportion of tyrosine phosphorylated sites that had reduced phosphorylation upon erlotinib or afatinib treatment correlated with the degree of TKI-sensitivity. Afatinib, an irreversible EGFR TKI, more effectively inhibited tyrosine phosphorylation of a majority of the substrates. The phosphosites with phosphorylation SILAC ratios that correlated with the TKI-sensitivity of the cell lines include sites on kinases, such as EGFR-Y1197 and MAPK7-Y221, and adaptor proteins, such as SHC1-Y349/350, ERRFI1-Y394, GAB1-Y689, STAT5A-Y694, DLG3-Y705, and DAPP1-Y139, suggesting these are potential biomarkers of TKI sensitivity. DAPP1, is a novel target of mutant EGFR signaling and Y-139 is the major site of DAPP1 tyrosine phosphorylation. We also uncovered several off-target effects of these TKIs, such as MST1R-Y1238/Y1239 and MET-Y1252/1253. This study provides unique insight into the TKI-mediated modulation of mutant EGFR signaling, which can be applied to the development of biomarkers of EGFR TKI response.

Assessment of Lipid Peroxidation Levels and Total Antioxidant Status in Chronic and Aggressive Periodontitis Patients: An in vivo Study.

INTRODUCTION: Periodontitis is a common problem affecting a significant population of the world. For the assessment of oxidative stress of an individual, total oxidation status (TOS) and total antioxidant capacity (TAOC) are the significant biomarkers. Hence, we planned the present study to assess malondialde-hyde (MDA), TOS, TAOC levels, and oxidative stress index (OSI) in generalized aggressive periodontitis (GP) and chronic periodontitis (CP) patients. MATERIALS AND METHODS: The present study included assessment of 40 CP patients, 40 GP patients, and 40 healthy controls. Clinical assessment of all the subjects was done by measuring the probing depth (PD), clinical attachment (CL), gingival index (GI), gingival bleeding index (GBI), and plaque index (PI). Salivary and serum samples were taken and assessed by standard procedures as described previously in the literature. All the values were assessed and compared. RESULTS: Significant results were obtained while comparing all the periodontal parameters in between various study groups. Mean serum MDA levels in the CP, GP, and control group were found to be 0.68, 0.65, and 0.61 µM respectively. Statistically nonsignificant results were obtained while comparing the serum MDA levels in between the three study groups. Significant results were obtained while comparing the mean serum and salivary TOS values, TAOC values, and OSI in between various study groups. CONCLUSION: In periodontitis patients, oxidative stress was significantly higher in comparison with healthy subjects. CLINICAL SIGNIFICANCE: Oxidative parameters do play a significant role in the pathologic profile of periodontitis.

Role of endoscopic ultrasound-guided biliary drainage for palliation of malignant biliary obstruction.

Endoscopic ultrasound-guided biliary drainage (EUS-BD) directs bile flow into the digestive tract and has been mostly used in patients with malignant biliary obstruction (MBO) where endoscopic retrograde cholangiopancreatography-guided biliary drainage was unsuccessful or was not feasible. Lumen apposing metal stents (LAMS) are deployed during EUS-BD, with the newer electrocautery-enhanced LAMS reducing procedure time and complication rates due to the inbuilt cautery at the catheter tip. EUS-BD with electrocautery-enhanced LAMS has high technical and clinical success rates for palliation of MBO, with bleeding, cholangitis, and stent occlusion being the most common adverse events. Recent studies have even suggested comparable efficacy between EUS-BD and endoscopic retrograde cholangiopancreatography as the primary approach for distal MBO. In this editorial, we commented on the article by Peng et al published in the recent issue of the World Journal of Gastrointestinal Surgery in 2024.

Impact of glucagon-like peptide receptor agonists on endoscopy and its preoperative management: Guidelines, challenges, and future directions.

Glucagon-like peptide receptor agonists (GLP-1RA) are used to treat type 2 diabetes mellitus and, more recently, have garnered attention for their effectiveness in promoting weight loss. They have been associated with several gastrointestinal adverse effects, including nausea and vomiting. These side effects are presumed to be due to increased residual gastric contents. Given the potential risk of aspiration and based on limited data, the American Society of Anesthesiologists updated the guidelines concerning the preoperative management of patients on GLP-1RA in 2023. They included the duration of mandated cessation of GLP-1RA before sedation and usage of "full stomach" precautions if these medications were not appropriately held before the procedure. This has led to additional challenges, such as extended waiting time, higher costs, and increased risk for patients. In this editorial, we review the current societal guidelines, clinical practice, and future directions regarding the usage of GLP-1RA in patients undergoing an endoscopic procedure.

Meta-analysis of immediate complete vs staged complete revascularization in patients with acute coronary syndrome and multivessel disease.

BACKGROUND: Randomized controlled trials (RCTs) have shown varying results between immediate and staged complete percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) and multivessel disease (MVD). We conducted a meta-analysis to reconcile the findings. METHODS: Online databases were searched for RCTs comparing immediate vs staged complete PCI in patients presenting with ACS. The outcomes of interest were major adverse cardiovascular events (MACE), all cause death, myocardial infarction (MI), cardiovascular death, stent thrombosis, target vessel revascularization (TVR), cerebrovascular events, bleeding and acute kidney injury (AKI)/contrast induced nephropathy (CIN). Risk ratios (RR) with 95 % confidence intervals (CI) were calculated using the random-effects model. RESULTS: Nine RCTs with a total of 3637 patients - 1821 in the immediate PCI group and 1816 in the staged PCI group, were included. The mean age was 64 years, 78 % of patients were men and the mean duration of follow up was 1 year. As compared with staged complete PCI, the immediate PCI group was associated with significant reduction of MI (RR 0.53, 95 % CI 0.36-0.77) and TVR (RR 0.69, 95 % CI 0.53-0.90). The risks of all-cause death, cardiovascular death, MACE, cerebrovascular events, stent thrombosis, bleeding and AKI/CIN were similar in the two groups. CONCLUSIONS: In ACS patients selected for complete revascularization strategy, multivessel PCI during the index procedure may be associated with significant reduction in the risk of MI and TVR without harm when compared with a staged PCI strategy.

Safety and efficacy of glucagon-like peptide-1 receptor agonists on cardiovascular events in overweight or obese non-diabetic patients.

BACKGROUND: Randomized controlled trials (RCTs) have shown variable cardiovascular (CV) outcomes in overweight or obese patients without diabetes mellitus (DM) who are treated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) vs. placebo. We conducted a meta-analysis of the available studies. METHODS: Online databases were searched for RCTs comparing GLP-1 RA to placebo in overweight or obese non-diabetic patients. The clinical endpoints of interest were major adverse CV events (MACE), CV death, all cause death, myocardial infarction (MI), stroke, revascularization, total adverse events and their subtypes. Pooled odds ratios (OR) and 95 % confidence intervals (CI) were calculated using a random-effects model. RESULTS: A total of 10 RCTs with 29,325 patients (n = 16,900 GLP-1 RA, n = 12,425 placebo) were included. The mean age was 48 years and 34 % of patients were men. As compared with placebo, the GLP-1 RA group was associated with significant reduction of MACE (OR 0.79, 95 % CI 0.71-0.89, p < 0.0001), all cause death (OR 0.80, 95 % CI 0.70-0.92, p = 0.002), MI (OR 0.72, 95 % CI 0.61-0.85, p = 0.0001) and revascularization (OR 0.76, 95 % CI 0.67-0.86, p < 0.0001), without any differences in CV death or stroke. Total adverse events, gastrointestinal and gallbladder-related disorders were higher in the GLP-1 RA group, with a similar rate of renal adverse events, malignant neoplasms and acute pancreatitis to placebo. CONCLUSION: In overweight or obese patients without DM, patients treated with GLP-1 RAs had significantly reduced MACE, all cause death, MI and revascularization when compared with placebo.

An overview of the utility of prasugrel hydrochloride as a treatment option for ischemic stroke.

INTRODUCTION: Prasugrel, a potent P2Y12 receptor inhibitor, is not currently recommended in patients with stroke due to a higher rate of recurrent stroke. Prasugrel was associated with comparable efficacy to clopidogrel in reducing the risk of ischemic stroke in a recent phase III study. AREAS COVERED: The authors provide an overview of the potential role of prasugrel in the management of ischemic stroke. The authors searched PUBMED, MEDLINE, and clinicaltrials.org and recently presented trials at the conferences for clinical trials of prasugrel therapy in patients with stroke and TIA, and important original investigations are reviewed. EXPERT OPINION: The recent PRASTRO-trials demonstrated comparable outcomes of lower maintenance dose (3.5 mg daily dose) with clopidogrel in East Asian stroke patients, thus can be a credible option as a P2Y12 receptor inhibitor. It can also be considered as a credible option in other races and ethnicities and in other clinical situations that may require DAPT, such as intracranial or carotid stenting. Since prasugrel is associated with a superior antiplatelet effect and is not influenced by genetic polymorphisms, there is no need for platelet function or genetic testing. More work is needed to establish the safety and efficacy of low-dose prasugrel plus aspirin in comparison with currently used clopidogrel plus aspirin in non-East Asian populations.

Milvexian: evaluating the factor XIa inhibitor for the treatment of acute coronary syndrome.

INTRODUCTION: Balancing the prevention of thrombosis with bleeding risk when combining anticoagulants and platelet antagonists remains a concern among clinicians, particularly in patients with acute coronary syndrome (ACS) who are treated with potent antiplatelet therapy. This may be because the available antiplatelet and anticoagulants are unable to uncouple physiological hemostasis and pathological thrombosis. Therefore, their use is associated with an unavoidable elevated risk of bleeding. AREAS COVERED: Evidence available from studies evaluating FXIa inhibitors and milvexian was collected from a selective literature search. In this review, the authors describe the potential role of FXI/XIa in experimental thrombosis, evidence for FXIa inhibition in the treatment of clinical thrombotic events, and highlight the current evidence supporting the role of milvexian, a novel FXIa inhibitor, in patients with ACS. EXPERT OPINION: The ongoing LIBREXIA-ACS trial is a large-scale study currently investigating milvexian in patients with ACS. This study may support the proof of concept of differentiating physiological hemostasis and pathological thrombosis and achieving maximum antithrombotic efficacy with minimum bleeding risk when used on top of dual antiplatelet therapy with potent P2Y12 receptor blockers.