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28 Jan, 2025 | 00:54h | UTC

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Cohort Study: GLP-1 Receptor Agonists Demonstrate Wide-Ranging Benefits but Elevate Gastrointestinal, Renal, and Musculoskeletal Risks

31 Jan, 2025 | 10:30h | UTC

Background: GLP-1 receptor agonists (GLP-1RAs) are widely prescribed for type 2 diabetes and obesity due to their robust effects on glycemic control and weight reduction. Recent evidence indicates that these agents may exert broader cardiometabolic and neurocognitive benefits. However, uncertainties remain regarding their overall safety profile, prompting a need for large-scale, systematic investigation across multiple organ systems.

Objective: This study aimed to systematically map the associations of GLP-1RA use with 175 clinical outcomes, including cardiovascular, renal, gastrointestinal, musculoskeletal, and neuropsychiatric endpoints, compared to several active antihyperglycemic therapies and to usual care.

Methods: A retrospective cohort analysis was conducted using US Department of Veterans Affairs databases (2017–2023). Adults with type 2 diabetes (n=215,970) who initiated GLP-1RA therapy were compared to individuals starting sulfonylureas, DPP4 inhibitors, SGLT2 inhibitors, a combined active-control cohort, and a usual care group (total >1.9 million controls). Those with key contraindications were excluded. The primary analysis employed inverse probability weighting to adjust for demographics, comorbidities, and medication use. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using weighted Cox models, with Benjamini–Hochberg correction for multiple comparisons.

Results: Compared with usual care, GLP-1RA use was associated with reduced risks of cardiac arrest, myocardial infarction, heart failure, stroke, acute kidney injury, and chronic kidney disease, as well as decreased rates of neuropsychiatric disorders (including substance use disorders, psychotic disorders, suicidal ideation, and dementia). Notably, the risk of Alzheimer’s disease was also lower (HR 0.88). At the same time, GLP-1RAs increased risks for several gastrointestinal events (nausea, vomiting, gastroesophageal reflux disease), hypotension, syncope, and renal conditions such as nephrolithiasis and interstitial nephritis. A key finding was drug-induced acute pancreatitis (HR 2.46). Additionally, musculoskeletal complications emerged, including arthritis and arthralgia, both with HR 1.11.

Conclusions: While significant benefits—spanning cardiovascular, metabolic, and neuropsychiatric domains—were observed, clinicians should remain vigilant regarding gastrointestinal, renal, and musculoskeletal adverse events. In particular, drug-induced pancreatitis and arthritic disorders may pose important safety considerations.

Implications for Practice: GLP-1RAs appear beneficial for patients with type 2 diabetes or obesity who require improved cardiometabolic control and may gain additional neuropsychiatric advantages. However, these drugs can be costly and demand careful monitoring, especially for pancreatitis, renal complications, and arthritis. Tailored patient selection, combined with other lifestyle or pharmacologic measures, will likely optimize clinical outcomes.

Study Strengths and Limitations: Strengths include a large, diverse cohort and robust comparative analyses with multiple active controls. Limitations involve residual confounding typical of observational designs and a predominantly male, veteran population that may affect generalizability. Absolute event rates for certain outcomes require further clarification to gauge clinical relevance.

Future Research: Randomized trials and post-approval pharmacovigilance are warranted to further delineate mechanistic pathways, within-class variations, and cost-effectiveness. Studies focusing on subpopulations (e.g., women, younger adults, and different racial groups) and head-to-head comparisons of specific GLP-1RAs are also needed.

Reference: Xie, Y., Choi, T. & Al-Aly, Z. Mapping the effectiveness and risks of GLP-1 receptor agonists. Nature Medicine (2025). DOI: https://doi.org/10.1038/s41591-024-03412-w

RCT: Albendazole–Ivermectin Co-Formulation Achieves Higher Cure Rates for T. trichiura and Hookworms

22 Jan, 2025 | 12:41h | UTC

Background: Soil-transmitted helminthiases (STH) affect an estimated 1.5 billion people worldwide, with Trichuris trichiura and hookworms remaining particularly challenging to treat. Although single-dose albendazole or mebendazole is standard in mass deworming programs, these agents show limited efficacy against T. trichiura and often leave Strongyloides stercoralis under-treated. Ivermectin has demonstrated broad activity against multiple parasites, suggesting that a combined albendazole–ivermectin regimen might enhance treatment outcomes, simplify protocols, and potentially curb emerging drug resistance.

Objective: This trial aimed to evaluate the safety, efficacy, and acceptability of a novel fixed-dose co-formulation (FDC) tablet containing albendazole (400 mg) plus a higher-than-standard, fixed dose of ivermectin (9 mg or 18 mg), administered once daily (FDC×1) or for three consecutive days (FDC×3). Investigators compared these regimens against single-dose albendazole alone for the treatment of T. trichiura, hookworms, and S. stercoralis in children and adolescents.

Methods: In this adaptive, randomized, parallel-group, phase 2/3 trial, 1001 participants aged 5–18 years were recruited from schools in Ethiopia, Kenya, and Mozambique. All were infected with at least one of T. trichiura, hookworms, or S. stercoralis. Eligible participants were allocated (by computer-generated block randomization) to either a single dose of albendazole 400 mg (control), a single-dose FDC of albendazole–ivermectin (FDC×1), or a three-day FDC regimen (FDC×3). Primary endpoints included safety (phase 2) and efficacy (phase 3), determined by cure rates at day 21 using the Kato–Katz and Baermann methods. Laboratory staff were blinded to treatment assignment.

Results: No serious adverse events were reported; mild-to-moderate gastrointestinal symptoms were the most frequent treatment-related events, resolving spontaneously within 48 hours. Cure rates for T. trichiura were 35.9% (95% CI 27.7–44.1) in the albendazole group, 82.9% (78.2–87.5) in FDC×1, and 97.2% (95.2–99.3) in FDC×3. For hookworms, cure rates were 65.1% (56.0–74.2) with albendazole, 79.8% (72.8–86.9) with FDC×1, and 95.0% (91.1–98.9) with FDC×3. Egg reduction rates in FDC arms consistently surpassed those of albendazole alone, especially for multi-day dosing. The sample size for S. stercoralis was insufficient to power a definitive efficacy conclusion, though ivermectin-containing arms trended toward favorable results. Palatability questionnaires indicated the orodispersible FDC was well accepted in taste, texture, and overall ease of administration.

Conclusions: A new co-formulation of albendazole plus ivermectin delivered at higher, fixed doses demonstrated an excellent safety profile and superior efficacy against T. trichiura and hookworms compared with albendazole monotherapy. This approach may streamline programmatic control of multiple STH species, including S. stercoralis, while contributing to reduced transmission in endemic communities.

Implications for Practice: For mass deworming initiatives, a single-dose FDC offers improved cure rates over albendazole alone while preserving simplicity. Where higher efficacy is critical—such as programs targeting near-elimination goals or in clinical settings—the three-day regimen may be preferable. Nonetheless, implementation feasibility, cost considerations, and further confirmation of efficacy against S. stercoralis and other co-endemic parasites remain important next steps.

Study Strengths and Limitations: Strengths include a multicenter design across three countries and a rigorous adaptive protocol that assessed both safety and efficacy. Limitations include the lack of blinding for participants and care providers (though outcome assessors were blinded), the underpowered sample size for S. stercoralis, and reliance on single-stool diagnostics, which may underestimate residual infections.

Future Research: Additional large-scale studies should confirm these findings in varied geographic regions and evaluate the cost-effectiveness of both single-dose and multi-day FDC strategies. Integrating albendazole–ivermectin with treatment programs for other neglected tropical diseases (e.g., onchocerciasis) could further amplify public health benefits. Genomic and pharmacokinetic analyses will clarify resistance patterns and optimize dosing regimens for broader implementation.

Reference: Krolewiecki A, Kepha S, Fleitas PE, van Lieshout L, Gelaye W, Messa A Jr, et al. “Albendazole–ivermectin co-formulation for the treatment of Trichuris trichiura and other soil-transmitted helminths: a randomised phase 2/3 trial.” The Lancet Infectious Diseases. Published January 10, 2025. DOI: https://doi.org/10.1016/S1473-3099(24)00669-8

Review: Management of Alcohol Withdrawal Syndromes in General Hospital Settings

14 Jan, 2025 | 12:33h | UTC

Introduction:
This summary provides an overview of a state-of-the-art review on identifying, assessing, and treating alcohol withdrawal syndromes among patients in general hospital settings. The rising prevalence of heavy alcohol use—and the sharp increase in hospital admissions for alcohol withdrawal during and after the COVID-19 pandemic—underscores the need for clear, evidence-based guidance. This review addresses the epidemiology, pathophysiology, clinical features, screening tools, and pharmacologic options for managing alcohol withdrawal. It also highlights nutritional considerations and the importance of preventing relapse to reduce readmissions and improve patient outcomes.

Key Recommendations:

Screening and Risk Stratification:
- Use brief, validated questionnaires (eg, Single Alcohol Screening Question or AUDIT-C) to identify at-risk alcohol use.
- Employ biomarker tests (eg, blood alcohol level, PEth, EtG) when possible to confirm recent intake and evaluate heavy use.
- Consider standardized risk scales (eg, PAWSS) to identify patients likely to develop severe withdrawal and guide treatment intensity.
Symptom Severity Assessment:
- Select a validated tool to monitor withdrawal progress (eg, CIWA-Ar).
- For patients with altered mental status or unreliable self-report, consider alternative scales (eg, BAWS or GMAWS) that rely more on objective signs.
Benzodiazepine Therapy:
- Continue to regard benzodiazepines (particularly long-acting agents like diazepam or chlordiazepoxide) as first-line therapy for prevention of seizures and delirium.
- In patients with liver dysfunction or advanced age, short-acting options (eg, lorazepam, oxazepam) may be safer.
- Symptom-triggered regimens can reduce total benzodiazepine exposure in lower-risk patients but require trained staff and structured protocols.
- Fixed-schedule or loading-dose regimens may be warranted in severe withdrawal cases or when symptom-triggered approaches prove insufficient.
Alternative and Adjunctive Pharmacotherapies:
- Phenobarbital: Offers GABA-enhancing and anti-glutamatergic effects, useful in severe or benzodiazepine-resistant withdrawal; consider ICU-level monitoring for high-risk patients.
- Alpha-2 Adrenergic Agonists (clonidine, dexmedetomidine): Adjunctive benefit for persistent autonomic instability (tachycardia, hypertension), but these agents do not prevent seizures or delirium if used alone.
- Antiseizure Medications (eg, carbamazepine, gabapentin, valproate): May aid in mild cases or adjunctively, but current evidence does not support them as stand-alone agents in severe withdrawal.
Nutritional Repletion and Thiamine Replacement:
- Aggressively treat thiamine deficiency (eg, IV thiamine 200–500 mg daily) to prevent or halt Wernicke-Korsakoff syndrome.
- Correct additional deficits (eg, folate, magnesium) for better overall recovery.
Relapse Prevention and Post-Acute Care:
- Initiate FDA-approved medications (eg, naltrexone or acamprosate) during admission to reduce relapse risk after discharge.
- Provide psychosocial support and referral to continuing addiction services (eg, specialty programs, peer support) to sustain recovery efforts.

Conclusion:
Effective management of alcohol withdrawal in hospital settings requires early recognition of at-risk patients, thoughtful risk stratification, and prompt pharmacologic intervention tailored to withdrawal severity and comorbid conditions. Benzodiazepines remain the mainstay therapy, though phenobarbital shows promise, particularly for resistant or severe cases. Adjunctive alpha-2 agonists help control hyperadrenergic symptoms, but do not replace core GABA-targeted therapies. By integrating nutritional repletion, addressing potential complications, and initiating relapse-prevention strategies, clinicians can reduce both the morbidity of acute withdrawal and the likelihood of future hospitalizations related to alcohol use.

Reference:
Kast KA, Sidelnik SA, Nejad SH, Suzuki J. Management of alcohol withdrawal syndromes in general hospital settings. BMJ 2025;388:e080461. https://doi.org/10.1136/bmj-2024-080461

Diagnosis and Management of Eosinophilic Esophagitis: Updated ACG Clinical Guideline Summary

14 Jan, 2025 | 13:46h | UTC

Introduction: This summary highlights the updated American College of Gastroenterology (ACG) Clinical Guideline on eosinophilic esophagitis (EoE), a chronic, immune-mediated disease of the esophagus characterized by esophageal eosinophilia and clinical symptoms of esophageal dysfunction. Over the last decade, the incidence and prevalence of EoE have increased significantly. This guideline incorporates new diagnostic strategies, therapeutic advances, and monitoring practices, aiming to improve patient outcomes and minimize disease complications such as strictures, food impactions, and impaired quality of life. The document underscores the importance of assessing both the inflammatory and fibrostenotic components of EoE through endoscopy, histopathology, and symptom evaluation.

Key Recommendations:

Diagnosis:
- Diagnose EoE when patients present with symptoms of esophageal dysfunction and at least 15 eosinophils per high-power field (eos/hpf) on esophageal biopsies, after exclusion of other causes of esophageal eosinophilia.
- Use a systematic scoring tool such as the EoE Endoscopic Reference Score (EREFS) to assess edema, rings, exudates, furrows, and strictures at every endoscopy.
- Obtain at least six esophageal biopsies from two or more levels (e.g., distal and proximal) to minimize diagnostic miss rates; quantify peak eosinophil counts in each specimen.
Pharmacologic Therapy:
1. Proton Pump Inhibitors (PPIs):
  - Consider high-dose PPIs (e.g., twice daily) as a first-line treatment option. Although originally used for acid suppression, PPIs also reduce eotaxin-3 expression and improve esophageal barrier function in EoE.
  - Maintain therapy long term in patients who respond, as discontinuation frequently leads to disease recurrence.
2. Topical Corticosteroids (Swallowed Steroids):
  - Budesonide or fluticasone can be delivered via specially formulated suspensions/tablets or by swallowing inhaler medication.
  - Expect histologic remission rates of around 60%–70%.
  - Oral/esophageal candidiasis is the most common adverse event. Routine adrenal suppression testing is generally not necessary for short-term use.
3. Dietary Elimination:
  - Empiric elimination diets (e.g., 2-food or 6-food elimination) help identify specific food triggers. Histologic remission rates can exceed 70%, particularly with the 6-food approach.
  - Less-restrictive diets (e.g., milk-only elimination) may be tried first (the “step-up” approach).
  - Do not rely on currently available skin prick or Ig-based tests to guide elimination diets, as these have poor predictive value for EoE triggers.
4. Biologic Therapy:
  - Dupilumab (anti–IL-4 receptor alpha) is recommended in adolescents and adults (≥12 years, ≥40 kg) and is now approved for children as young as 1 year (≥15 kg) with moderate to severe, PPI-refractory EoE. Expect significant histologic, endoscopic, and symptom improvements in most patients, along with an overall favorable safety profile.
  - Other biologics (e.g., cendakimab, benralizumab, mepolizumab) remain under investigation; current data are insufficient for routine clinical use.
5. Esophageal Dilation:
  - Perform endoscopic dilation to treat symptomatic strictures or narrow-caliber esophagi. Dilation reduces dysphagia promptly but does not alter the underlying inflammation.
  - Combine dilation with anti-inflammatory therapy to address the disease’s inflammatory component and help prevent recurrent stricture formation.
Maintenance and Monitoring:
- Because EoE is chronic, continue effective therapy over the long term. Abrupt cessation of treatment often leads to relapses in symptoms and inflammation.
- Evaluate treatment response by assessing symptoms, endoscopic findings (e.g., EREFS), and histopathology (peak eosinophil counts).
- A target of <15 eos/hpf and near-normal endoscopic appearance (EREFS ≤2) is commonly used to define remission, although some patients aim for histologic normalization.
- In children, ensure regular assessment of growth, development, and feeding behaviors. Referral to a nutritionist or feeding therapist is recommended if feeding difficulties or failure to thrive are present.

Conclusion: These updated ACG guidelines underscore the importance of a comprehensive, individualized approach to EoE that encompasses diagnosis, treatment of the inflammatory state, dilation of fibrotic strictures, and ongoing monitoring to maintain long-term remission. The introduction of biologics (particularly dupilumab) expands treatment options for patients nonresponsive to PPIs or topical steroids. Clinicians should adopt a structured assessment strategy—integrating clinical history, endoscopic scoring, and histological evaluation—to guide therapy selection, document treatment response, and prevent complications. With improved understanding of disease pathogenesis and evolving therapeutic tools, outcomes for patients with EoE are expected to continue to improve.

Reference: Dellon ES, Muir AB, Katzka DA, Shah SC, Sauer BG, Aceves SS, Furuta GT, Gonsalves N, Hirano I. ACG Clinical Guideline: Diagnosis and Management of Eosinophilic Esophagitis. The American Journal of Gastroenterology. 2025;120(1):31–59. DOI: https://doi.org/10.14309/ajg.0000000000003194

AGA Clinical Practice Update on Potassium-Competitive Acid Blockers for Foregut Disorders

14 Jan, 2025 | 11:20h | UTC

Introduction: This summary presents the key points of a recently published American Gastroenterological Association (AGA) Clinical Practice Update that reviews the role of potassium-competitive acid blockers (P-CABs) in managing acid-related foregut disorders. P-CABs offer a unique mechanism of action compared with proton pump inhibitors (PPIs) and histamine_2-receptor antagonists, potentially delivering more rapid and prolonged acid suppression. The aim of this review is to provide clinicians with evidence-based guidance on P-CAB use in gastroesophageal reflux disease (GERD), Helicobacter pylori (HP) infection, and peptic ulcer disease (PUD), clarifying their benefits, limitations, and potential place in therapy.

Key Recommendations:

Overall Use of P-CABs: Clinicians should generally avoid using P-CABs as first-line therapy for acid-related conditions unless there is proven clinical superiority over PPIs. Factors such as higher costs, more limited availability, and less comprehensive long-term safety data often outweigh the advantages of P-CABs, particularly for milder disease.
Cost-Effectiveness: Current U.S. costs for P-CABs may not justify routine first-line use, even if modest clinical benefits exist compared with double-dose PPIs. Long-term data on cost-effectiveness and safety remain limited.
Nonerosive GERD: P-CABs are not recommended as initial treatment for heartburn without endoscopic findings (uninvestigated GERD) or nonerosive reflux disease. Clinicians may consider P-CABs for patients who have confirmed acid-related reflux and show inadequate response to twice-daily PPI therapy.
On-Demand Therapy: Rapid onset of P-CABs suggests potential utility in on-demand regimens for patients previously responsive to acid suppression. While limited data show efficacy compared to placebo, further trials against PPIs and histamine_2-receptor antagonists are needed before making firm recommendations.
Mild Erosive Esophagitis (LA Grade A/B): For Los Angeles classification (LA) grade A/B erosive esophagitis (EE), standard PPIs remain first-line treatment. P-CABs may be an option for patients whose esophagitis persists despite optimal PPI therapy, but initial evidence does not support routine, front-line use.
Severe Erosive Esophagitis (LA Grade C/D): In more advanced EE, P-CABs can be considered for healing and maintenance, as some data suggest superior efficacy compared with standard-dose PPI. However, the lack of comparative trials with high-dose PPIs and the higher cost of P-CABs complicate their routine use as first-line therapy in severe disease.
HP Eradication: P-CAB–based regimens for H pylori treatment often show higher or noninferior cure rates compared with PPI-based therapies, particularly in the presence of clarithromycin resistance. The more potent and prolonged acid suppression may enhance antibiotic efficacy, supporting the use of P-CABs in most patients with HP infection.
Peptic Ulcer Disease Treatment and Prophylaxis: Current evidence indicates that P-CABs are noninferior to PPIs for ulcer healing and prevention of recurrent ulcers in patients requiring aspirin or nonsteroidal anti-inflammatory drugs. However, in light of their higher cost and similar clinical outcomes, P-CABs should not replace PPIs as first-line therapy unless patients fail PPI regimens.
Ulcer Bleeding: Although data are preliminary, P-CABs may be useful following endoscopic hemostasis in high-risk ulcer bleeding. Their rapid and potent acid suppression suggests they could match or exceed high-dose PPI efficacy, but more robust comparative trials are needed.

Conclusion: Potassium-competitive acid blockers represent a valuable therapeutic option in selected patients who do not respond adequately to traditional PPIs or who have complex acid-related conditions (such as severe erosive esophagitis or antibiotic-resistant H pylori). While their more rapid onset of action and prolonged effect can be advantageous, the limited availability of long-term safety data, cost considerations, and lack of substantial clinical superiority over standard or double-dose PPIs in many indications currently limit widespread adoption. Further investigations are needed to establish cost-effectiveness, clarify safety profiles, and identify specific patient populations most likely to benefit from P-CABs.

Reference: Patel A, Laine L, Moayyedi P, Wu J. AGA Clinical Practice Update on Integrating Potassium-Competitive Acid Blockers Into Clinical Practice: Expert Review. Gastroenterology. 2024;167(6):1228–1238. https://doi.org/10.1053/j.gastro.2024.06.038

Phase 2b/3 QUASAR Program: Guselkumab for Induction and Maintenance Therapy in Moderate-to-Severe Ulcerative Colitis

7 Jan, 2025 | 13:00h | UTC

Background: Ulcerative colitis (UC) is a chronic inflammatory condition affecting the colon’s mucosal surface, frequently accompanied by debilitating symptoms such as bloody diarrhea, urgency, and abdominal discomfort. Despite the availability of corticosteroids, immunosuppressants, and advanced biologic or small-molecule therapies, many patients still experience suboptimal outcomes. Targeting interleukin (IL)-23, a critical cytokine in the inflammatory cascade, has gained increasing attention. Guselkumab, a human IgG1 monoclonal antibody against the IL-23p19 subunit, has shown clinical promise in psoriasis, psoriatic arthritis, and Crohn’s disease. This article reports findings from the phase 2b/3 QUASAR clinical development program evaluating guselkumab in UC.

Objective: To assess the efficacy and safety of intravenous (IV) guselkumab induction therapy (200 mg every 4 weeks) compared to placebo, followed by subcutaneous (SC) maintenance regimens (200 mg every 4 weeks or 100 mg every 8 weeks) compared to placebo (withdrawal) in adults with moderately to severely active UC who had inadequate responses or intolerance to at least one conventional or advanced therapy.

Methods: In these double-blind, randomized, placebo-controlled studies within the QUASAR program, adults with a baseline modified Mayo (mMayo) score of 5–9 (which excludes the physician’s global assessment) and evidence of active UC underwent IV induction with either guselkumab or placebo at Weeks 0, 4, and 8. The primary endpoint of the induction trial was clinical remission at Week 12 in the primary analysis population (patients with mMayo score 5-9), defined by improved stool frequency, rectal bleeding, and endoscopic findings. Responders from both the phase 2b and phase 3 induction studies then entered the maintenance study, randomized to SC guselkumab (either 200 mg Q4W or 100 mg Q8W) or placebo (withdrawal, meaning patients who had previously responded to guselkumab). The primary endpoint for the maintenance phase was clinical remission at Week 44 in the primary analysis population. Key secondary outcomes included endoscopic improvement, histological remission, corticosteroid-free remission, and patient-reported measures.

Results: A total of 701 patients with a baseline mMayo score of 5-9 (primary analysis population) were evaluated in the phase 3 induction study. By Week 12, a higher proportion of those receiving IV guselkumab (23%) achieved clinical remission compared to placebo (8%; p<0.0001). Patients also demonstrated improvement in endoscopic outcomes and had early symptomatic relief (notably a reduction in rectal bleeding as early as Week 1). In the subsequent maintenance phase, 568 guselkumab induction responders from both phase 2b and phase 3 studies (primary analysis population) were randomized. At Week 44, clinical remission was significantly more frequent in patients receiving guselkumab SC (50% on 200 mg Q4W, 45% on 100 mg Q8W) vs 19% on placebo (both p<0.0001). Endoscopic and histological indices indicated improved mucosal healing with active therapy. Most patients in remission were free of corticosteroids, highlighting a significant steroid-sparing effect.

Conclusions: Guselkumab induction (200 mg IV every 4 weeks) followed by either of the two SC maintenance regimens (200 mg Q4W or 100 mg Q8W) demonstrated substantial efficacy in adults with moderate-to-severe UC, with improved clinical, endoscopic, and histological endpoints relative to placebo. No new safety concerns were observed compared to the known safety profile of guselkumab.

Implications for Practice: Guselkumab offers a new therapeutic option for UC, particularly for individuals who have not responded to, or could not tolerate, other treatments. The study suggests that guselkumab can be considered for both biologic-naive and biologic-experienced patients. As with any novel therapy, careful patient selection and close follow-up are advisable.

Study Strengths and Limitations: Strengths include the rigorous, global, phase 2b/3 design with objective assessments of clinical, endoscopic, and histological response. The large population permitted detailed subgroup analyses (e.g., efficacy was observed in both biologic-naive and biologic-experienced populations). Limitations include the exclusion of certain therapy-refractory cases and lack of active comparator arms. The randomized-withdrawal maintenance design means only induction responders were evaluated further, potentially enhancing observed effect sizes.

Future Research: Extended follow-up will elucidate the durability of remission beyond one year and clarify long-term safety considerations. Head-to-head trials against other IL-23 antagonists or advanced therapies could further guide treatment algorithms. Real-world evidence evaluating diverse populations will be instrumental in determining broader applicability.

Reference: Rubin DT, Allegretti JR, Panés J, Shipitofsky N, Yarandi SS, Huang K-HG, Germinaro M, Wilson R, Zhang H, Johanns J, Feagan BG, Hisamatsu T, Lichtenstein GR, Bressler B, Peyrin-Biroulet L, Sands BE, Dignass A; QUASAR Study Group. Guselkumab in patients with moderately to severely active ulcerative colitis (QUASAR): phase 3 double-blind, randomised, placebo-controlled induction and maintenance studies. The Lancet. 2025;405(10472):33–49. DOI: http://doi.org/10.1016/S0140-6736(24)01927-5

AGA Clinical Practice Update on Managing Portal Vein Thrombosis in Cirrhotic Patients: Expert Review

3 Jan, 2025 | 10:00h | UTC

Introduction: This summary highlights key recommendations from an AGA expert review on portal vein thrombosis (PVT) in cirrhotic patients. PVT is common in cirrhosis, with an estimated five-year incidence of around 11%, and may worsen portal hypertension and elevate mortality. Management is challenging because of limited evidence, the potential complications of both PVT and anticoagulation, and significant heterogeneity regarding clot characteristics, host factors, and cirrhosis severity. This review presents the latest guidance on identifying clinically relevant PVT, selecting anticoagulation, and considering endovascular interventions, including TIPS (transjugular intrahepatic portosystemic shunt).

Key Recommendations:

No Routine Screening: Asymptomatic patients with compensated cirrhosis do not require regular screening for PVT in the absence of suggestive clinical changes.
Imaging Confirmation: When Doppler ultrasound reveals suspected PVT, contrast-enhanced CT or MRI is recommended to confirm the diagnosis, exclude malignancy, and characterize clot extent and occlusion.
Hypercoagulability Testing: Extensive thrombophilia workup is not indicated unless there is family or personal history of thrombotic events, or associated laboratory abnormalities.
Intestinal Ischemia Management: Patients who develop PVT with evidence of intestinal ischemia should receive prompt anticoagulation and, ideally, multidisciplinary team care involving gastroenterology, hepatology, interventional radiology, hematology, and surgery.
Observation of Minor or Recent Thrombi: In cirrhotic patients without ischemia, with recent (<6 months) thrombi that are <50% occlusive, close imaging follow-up every three months is a reasonable option to track potential spontaneous clot regression.
Anticoagulation for Significant PVT: Consider anticoagulation for more extensive or obstructive (>50%) recent PVT, especially if the main portal vein or mesenteric vessels are involved. Candidates for liver transplantation and those with inherited thrombophilia may derive additional benefit.
Chronic Cavernous PVT: Anticoagulation is generally not advised in patients with long-standing (>6 months) complete occlusion and well-formed collateral channels.
Variceal Screening: Perform endoscopic screening or ensure prophylaxis for varices. Avoid delays in initiating anticoagulation, as timeliness is essential for better recanalization outcomes.
Choice of Anticoagulant: Vitamin K antagonists, low-molecular-weight heparin, and direct oral anticoagulants (DOACs) are all viable options in cirrhosis. DOACs may be appropriate in well-compensated (Child-Turcotte-Pugh class A or certain class B) cirrhosis but should be avoided in class C. Treatment selection should consider patient preferences, monitoring feasibility, and risk of bleeding.
Duration of Therapy: Reassess clot status with cross-sectional imaging every three months. Continue anticoagulation for transplant-eligible individuals who show partial or complete recanalization, and consider discontinuation in nonresponders after six months if futility is evident.
TIPS Revascularization: Portal vein revascularization using TIPS may be pursued in patients who have other TIPS indications (like refractory ascites or variceal bleeding) or to improve transplant feasibility by recanalizing portal flow.

Conclusion: PVT in cirrhosis remains a complex clinical issue requiring careful evaluation of clot extent, timing, and the potential need for transplantation. The recommendations presented here underscore prompt imaging, timely anticoagulation for high-risk thrombi, and individualized therapy based on Child-Turcotte-Pugh classification and bleeding risk. When necessary, multidisciplinary collaboration is key to achieving optimal patient outcomes. Prospective randomized trials and standardized classifications of PVT will be instrumental in refining future guidelines.

Reference:
Davis JPE, Lim JK, Francis FF, Ahn J. AGA Clinical Practice Update on Management of Portal Vein Thrombosis in Patients With Cirrhosis: Expert Review. Gastroenterology. 2024. DOI: http://doi.org/10.1053/j.gastro.2024.10.038

Meta-analysis: One-day Low-residue Diet Achieves Comparable Bowel Cleansing Compared to Multi-day Regimens

26 Dec, 2024 | 18:21h | UTC

Background: Colorectal cancer remains a leading cause of cancer-related morbidity worldwide, making early detection through colonoscopy essential. Adequate bowel preparation is crucial to maximize mucosal visibility and detect lesions effectively. Although low-residue diets (LRDs) are commonly recommended before colonoscopy, guidelines vary regarding the optimal duration (one day versus multiple days). This systematic review and meta-analysis evaluated whether a one-day LRD regimen is non-inferior to multi-day protocols in achieving satisfactory bowel cleansing and lesion detection.

Objective: To compare the efficacy of 1-day versus >1-day LRD regimens for bowel preparation in adult patients undergoing elective colonoscopy, focusing on bowel cleanliness, polyp detection, and adenoma detection rates.

Methods: A comprehensive search of PubMed, Cochrane Central Register of Controlled Trials, ScienceDirect, Scopus, and ClinicalTrials.gov was conducted for randomized controlled trials (RCTs) comparing 1-day with >1-day LRD regimens. Six RCTs involving 2,469 participants met inclusion criteria. Patients were randomized to either a 1-day LRD (n=1,237) or a multi-day LRD (n=1,232). Adequate bowel preparation was primarily defined by a Boston Bowel Preparation Scale (BBPS) score ≥2 in each segment or total BBPS ≥6. Secondary outcomes included polyp detection rate (PDR), adenoma detection rate (ADR), withdrawal time, cecal intubation rate, and cecal intubation time.

Results: Both groups demonstrated similar rates of adequate bowel preparation (87.2% in the 1-day LRD vs. 87.1% in the multi-day group), with no significant difference (OR=1.03, 95% CI, 0.76–1.41; p=0.84; I2=0%). PDR was likewise comparable (OR=0.91, 95% CI, 0.76–1.09; p=0.29; I2=16%), as was ADR (OR=0.87, 95% CI, 0.71–1.08; p=0.21; I2=0%). Withdrawal time did not differ (MD=–0.01 minutes, 95% CI, –0.25 to 0.24; p=0.97; I2=63%), and cecal intubation parameters were also statistically similar. Across studies, the pooled mean global BBPS revealed minimal difference (MD=0.16, 95% CI, –0.02 to 0.34; p=0.08; I2=15%), confirming the non-inferiority of a shorter LRD protocol.

Conclusions: A one-day LRD achieves bowel cleansing outcomes comparable to those of multi-day LRDs, without compromising polyp or adenoma detection. This shorter regimen may help optimize patient adherence, reduce dietary restriction burden, and simplify procedural logistics, especially for busy endoscopy practices.

Implications for Practice: Adopting a 1-day LRD can streamline preparation, improve patient satisfaction, and maintain high-quality visualization. Clinicians should weigh individual patient factors such as chronic constipation or comorbidities but may generally favor a shorter dietary restriction period to enhance compliance and comfort.

Study Strengths and Limitations: This meta-analysis included only RCTs, strengthening its internal validity. Heterogeneity for primary outcomes was minimal. However, the included trials employed varied dietary protocols and bowel preparation solutions. Additionally, some studies lacked uniform reporting of cecal intubation endpoints, limiting direct comparisons. Future investigations with standardized outcome measures could offer more definitive guidance.

Future Research: Further large-scale RCTs should assess cost-effectiveness, patient-reported outcomes, and LRD composition in specific populations. Identifying optimal dietary instructions for individuals with slower colonic transit or specific nutritional needs would refine colonoscopy preparation guidelines and potentially increase detection of precancerous lesions.

Reference: Putri RD, et al. One-day low-residue diet is equally effective as the multiple-day low-residue diet in achieving adequate bowel cleansing: a meta-analysis of randomized controlled trials. Clinical Endoscopy. 2024. DOI: https://doi.org/10.5946/ce.2024.061

AGA Clinical Practice Update on Screening and Surveillance in High-Risk US Populations for Gastric Cancer: Expert Review

25 Dec, 2024 | 11:02h | UTC

Introduction:
This American Gastroenterological Association (AGA) Clinical Practice Update provides guidance on primary and secondary prevention strategies for gastric cancer (GC) among high-risk groups in the United States. GC disproportionately affects racial and ethnic minorities, certain first-generation immigrants from countries with elevated GC incidence, and individuals with specific hereditary syndromes or family histories of GC. Given ongoing disparities in diagnosis and outcomes, this document outlines best practices for recognizing at-risk individuals, performing high-quality endoscopic screening, and establishing surveillance protocols for gastric precancerous conditions.

Key Recommendations:

Identify High-Risk Groups: Consider screening among first-generation immigrants from high-incidence regions, people with a family history of GC in a first-degree relative, individuals with hereditary gastrointestinal syndromes, and patients with multiple risk factors (eg, chronic Helicobacter pylori infection, smoking, diets high in salt and processed meats).
Preferred Screening Modality: Upper endoscopy is considered the best method for detecting precancerous lesions (atrophic gastritis and intestinal metaplasia) and early malignancies. It allows direct visualization of the gastric mucosa, systematic biopsy, and accurate histologic staging.
High-Quality Endoscopic Examination: Essential elements include high-definition endoscopes, optimal mucosal cleansing and insufflation, adequate inspection time, systematic photodocumentation, and biopsy protocols (such as the updated Sydney System) to detect and characterize precancerous changes or early cancer.
H. pylori Eradication: Opportunistic screening for H. pylori and its eradication are key adjunctive measures in preventing GC development. Family-based testing—screening adult household members of H. pylori–positive individuals—may further reduce reinfection rates and disease progression.
Systematic Biopsy Protocols: When atrophic gastritis or intestinal metaplasia is suspected, obtain at least five biopsies (antrum/incisura and corpus in separate containers). Any suspicious lesion should be sampled independently.
Recognition of Metaplasia and Dysplasia: Endoscopists should be trained to accurately identify visual patterns associated with gastric intestinal metaplasia (GIM) and dysplasia. Artificial intelligence may hold promise, but current data are insufficient to recommend routine use.
Risk Stratification and Surveillance Intervals: Patients with confirmed GIM or dysplasia, especially those with severe or extensive metaplasia, may require follow-up endoscopy every three years. Individuals with multiple risk factors or severe metaplastic changes could benefit from shorter intervals.
Management of Dysplasia and Early GC: All dysplasia should be reviewed by an expert gastrointestinal pathologist. Visible high-grade dysplasia or early GC lesions generally warrant endoscopic submucosal dissection (ESD) at specialized centers to achieve en bloc, R0 resection and enable accurate pathology.
Post-Resection Surveillance: Individuals with successfully resected dysplasia or early cancer need ongoing endoscopic surveillance to detect metachronous lesions. Surveillance intervals vary depending on pathology results and patient-level factors.
De-Escalation of Screening: Discontinue screening or surveillance when the patient is no longer fit for potential endoscopic or surgical treatment.
Equity and Sustainability: To reduce GC mortality, it is crucial to address modifiable risk factors, enhance patient access to endoscopy and skilled practitioners, and integrate research advances, especially in noninvasive biomarker development and improved endoscopic technologies.

Conclusion:
An effective US-based GC screening and surveillance program requires robust preprocedural identification of high-risk individuals, intraprocedural adherence to quality endoscopy standards, and consistent postprocedural follow-up to ensure equitable access to treatment. By refining these clinical practices and prioritizing research, meaningful reductions in GC incidence and mortality can be achieved, ultimately improving patient outcomes and addressing healthcare disparities.

Reference:
Shah SC, Wang AY, Wallace MB, Hwang JH. AGA Clinical Practice Update on Screening and Surveillance in Individuals at Increased Risk for Gastric Cancer in the United States: Expert Review. Gastroenterology. Published online December 23, 2024.
https://doi.org/10.1053/j.gastro.2024.11.001

RCT: Nivolumab Plus Ipilimumab Extends Progression-Free Survival in MSI-H or dMMR Metastatic Colorectal Cancer

4 Dec, 2024 | 11:51h | UTC

Background: Patients with microsatellite-instability–high (MSI-H) or mismatch-repair–deficient (dMMR) metastatic colorectal cancer typically experience poor outcomes with standard chemotherapy. Previous nonrandomized studies suggested that combining nivolumab with ipilimumab may offer clinical benefits in this population.

Objective: To evaluate the efficacy and safety of nivolumab plus ipilimumab compared with chemotherapy in patients with MSI-H or dMMR metastatic colorectal cancer who had not received prior systemic treatment for metastatic disease.

Methods: In this phase 3, open-label, randomized trial, 303 patients with unresectable or metastatic MSI-H or dMMR colorectal cancer were assigned in a 2:2:1 ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy with or without targeted therapies. The primary endpoint assessed in this interim analysis was progression-free survival (PFS) of nivolumab plus ipilimumab versus chemotherapy in patients with centrally confirmed MSI-H or dMMR status.

Results: At a median follow-up of 31.5 months, nivolumab plus ipilimumab significantly improved PFS compared to chemotherapy (P<0.001). The 24-month PFS was 72% (95% CI, 64–79) with nivolumab plus ipilimumab versus 14% (95% CI, 6–25) with chemotherapy. The restricted mean survival time at 24 months was 10.6 months longer with the combination therapy. Grade 3 or 4 treatment-related adverse events occurred in 23% of patients receiving nivolumab plus ipilimumab and 48% of those receiving chemotherapy.

Conclusions: First-line treatment with nivolumab plus ipilimumab significantly prolonged progression-free survival compared to chemotherapy in patients with MSI-H or dMMR metastatic colorectal cancer, with a lower incidence of high-grade treatment-related adverse events.

Implications for Practice: The combination of nivolumab and ipilimumab may represent a new standard of care for first-line treatment in MSI-H or dMMR metastatic colorectal cancer. However, clinicians should weigh the benefits against potential immune-related adverse events, and long-term survival benefits remain to be fully established.

Study Strengths and Limitations: Strengths include the randomized, phase 3 design and central confirmation of MSI-H or dMMR status. Limitations involve the open-label design, potential bias in patient-reported outcomes, underrepresentation of certain populations, and immature overall survival data.

Future Research: Further studies are needed to compare nivolumab plus ipilimumab directly with nivolumab monotherapy and to assess long-term overall survival benefits and quality of life in diverse patient populations.

Reference: Andre T, et al. Nivolumab plus Ipilimumab in Microsatellite-Instability–High Metastatic Colorectal Cancer. New England Journal of Medicine. 2024;391(21):2014–2026. DOI: http://doi.org/10.1056/NEJMoa2402141

Phase 3 RCT: Resmetirom Significantly Improves NASH Resolution and Liver Fibrosis

16 Nov, 2024 | 13:56h | UTC

Background: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatments. It significantly increases the risk of liver-related complications, especially in patients with type 2 diabetes. Resmetirom, a thyroid hormone receptor beta-selective agonist, is being investigated for its potential to treat NASH and liver fibrosis.

Objective: To evaluate the efficacy and safety of resmetirom in resolving NASH and improving fibrosis in adults with biopsy-confirmed NASH and fibrosis stages F1B to F3.

Methods: This double-blind, placebo-controlled phase 3 trial randomized 966 adults with NASH to receive once-daily resmetirom (80 mg or 100 mg) or placebo for 52 weeks. Primary endpoints included (1) NASH resolution with no fibrosis worsening and (2) fibrosis improvement by at least one stage without NAFLD activity score worsening. Secondary outcomes included changes in lipid profiles and liver biomarkers.

Results: At 52 weeks, NASH resolution occurred in 25.9% of patients receiving 80 mg and 29.9% receiving 100 mg of resmetirom, compared with 9.7% in the placebo group (P<0.001 for both doses vs. placebo). Fibrosis improved by at least one stage in 24.2% (80 mg) and 25.9% (100 mg) of resmetirom-treated patients versus 14.2% for placebo (P<0.001). LDL cholesterol reductions were −13.6% (80 mg) and −16.3% (100 mg) at 24 weeks versus 0.1% for placebo (P<0.001). Improvements were also noted in triglycerides, liver enzymes, and imaging biomarkers. Adverse events, primarily mild gastrointestinal symptoms, were more frequent with resmetirom. Serious adverse events were similar across groups (10.9%–12.7%).

Conclusions: Resmetirom significantly improved NASH resolution and fibrosis compared to placebo, demonstrating its potential as a treatment for NASH with liver fibrosis.

Implications for Practice: Resmetirom offers a promising treatment option for NASH, potentially altering the disease course and improving outcomes. Clinicians should monitor for regulatory approval and long-term safety data.

Study Strengths and Limitations: Strengths include robust biopsy-confirmed endpoints and a large sample size. Limitations include short follow-up and lack of clinical-outcome data.

Future Research: Long-term studies are needed to assess durability, safety, and effects on clinical outcomes like cirrhosis and liver-related mortality.

Reference: Harrison SA, Bedossa P, Guy CD, et al. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. New England Journal of Medicine. 2024;390(6):497-509. DOI: http://doi.org/10.1056/NEJMoa2309000

Cohort Study: GIP/GLP-1 Receptor Agonist Prescriptions Linked to Reduced Opioid Overdose and Alcohol Intoxication

20 Oct, 2024 | 18:36h | UTC

Background: Opioid use disorder (OUD) and alcohol use disorder (AUD) are prevalent conditions leading to significant morbidity and mortality, including overdose and intoxication. Current pharmacotherapies for OUD and AUD are underutilized due to barriers like access and stigma. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), used for type 2 diabetes and obesity, have shown potential in modulating reward pathways associated with substance use, suggesting a possible role in reducing substance-related harms.

Objective: To estimate the association between prescriptions of glucose-dependent insulinotropic polypeptide (GIP) and/or GLP-1 receptor agonists and the incidence of opioid overdose and alcohol intoxication in patients with OUD and AUD, respectively, and to assess this association among patients with comorbid type 2 diabetes and obesity.

Methods: This retrospective cohort study analyzed de-identified electronic health record data from 136 U.S. health systems in the Oracle Cerner Real-World Data, covering over 100 million patients from January 2014 to September 2022. Adults aged 18 years or older with a history of OUD (n = 503,747) or AUD (n = 817,309) were included. The exposure was defined as having one or more prescriptions of GIP/GLP-1 RAs after the first OUD or AUD diagnosis. The primary outcomes were the incidence rates of opioid overdose in the OUD cohort and alcohol intoxication in the AUD cohort.

Results: Patients with GIP/GLP-1 RA prescriptions had significantly lower rates of opioid overdose (aIRR in OUD patients: 0.60; 95% CI, 0.43–0.83) and alcohol intoxication (aIRR in AUD patients: 0.50; 95% CI, 0.40–0.63) compared to those without such prescriptions. The protective association remained significant among patients with comorbid type 2 diabetes and obesity.

Conclusions: Prescriptions of GIP and/or GLP-1 receptor agonists are associated with lower rates of opioid overdose and alcohol intoxication in patients with OUD and AUD. These protective effects persist across various subgroups, including those with comorbid type 2 diabetes and obesity.

Implications for Practice: GLP-1 RAs show promise for reducing substance-related harms in patients with OUD and AUD. Clinicians may consider the potential benefits of GIP/GLP-1 RA prescriptions in this population, while recognizing the need for further research to establish causality and understand underlying mechanisms.

Study Strengths and Limitations: Strengths include a large, diverse patient population and adjustment for multiple confounders. Limitations involve the retrospective observational design limiting causal inference and reliance on data from Cerner-affiliated health systems, which may affect generalizability.

Future Research: Prospective clinical trials are needed to validate these findings, elucidate underlying mechanisms, and assess the efficacy and safety of GIP/GLP-1 RAs as treatments for substance use disorders.

Reference: Qeadan F, et al. (2024). The association between glucose-dependent insulinotropic polypeptide and/or glucagon-like peptide-1 receptor agonist prescriptions and substance-related outcomes in patients with opioid and alcohol use disorders: A real-world data analysis. Addiction. DOI: http://doi.org/10.1111/add.16679

RCT: Granulocyte Colony-Stimulating Factor (GCSF) Enhances 90-Day Survival and Reduces Complications in Severe Alcohol-Associated Hepatitis

20 Oct, 2024 | 17:23h | UTC

Study Design and Population: This randomized trial evaluated 126 patients with severe alcohol-associated hepatitis (SAH) eligible for steroid treatment, with discriminant function scores between 32 and 90. Patients were randomized into three groups: prednisolone alone, GCSF alone, and combined GCSF plus prednisolone (GPred). Prednisolone was administered at 40 mg/day, while GCSF was given at 150-300 mcg/d for 7 days, then every third day for up to 12 doses over a month.

Main Findings: The GPred group showed significantly higher 90-day survival (88.1%) compared to prednisolone alone (64.3%, P = 0.03) and GCSF alone (78.6%). The 28-day survival was similar across groups. The GPred group also had more steroid responders by day 7 and showed greater improvements in discriminant function and MELDNa scores. Additionally, patients in the GPred group had significantly lower rates of infections, acute kidney injury, hepatic encephalopathy, and rehospitalizations.

Implications for Practice: Adding GCSF to prednisolone improves survival and reduces the risk of infections and complications in patients with severe alcohol-associated hepatitis. This combination therapy could be considered for improving outcomes in steroid-eligible patients with SAH.

Reference: Mishra AK et al. (2024). Granulocyte Colony-Stimulating Factor Improves Prednisolone Responsiveness and 90-Day Survival in Steroid-Eligible Severe Alcohol-Associated Hepatitis: The GPreAH Study a Randomized Trial. Am J Gastroenterol. doi: 10.14309/ajg.0000000000003038

RCT: Low-Dose Amitriptyline Effective as Second-Line Treatment for Irritable Bowel Syndrome

20 Oct, 2024 | 15:56h | UTC

Background: Most patients with irritable bowel syndrome (IBS) are managed in primary care. When first-line therapies—such as dietary changes and antispasmodic drugs—are ineffective, the UK National Institute for Health and Care Excellence (NICE) recommends considering low-dose tricyclic antidepressants as second-line treatment. However, their effectiveness in primary care is uncertain, and they are infrequently prescribed in this setting.

Objective: To determine whether titrated low-dose amitriptyline is effective as a second-line treatment for IBS in primary care.

Methods: In a randomized, double-blind, placebo-controlled, phase 3 trial (ATLANTIS) conducted at 55 general practices in England, 463 adults aged 18 years or older with Rome IV IBS and ongoing symptoms despite first-line therapies were randomized 1:1 to receive low-dose oral amitriptyline (10 mg once daily) or placebo for 6 months. Dose titration over 3 weeks up to 30 mg once daily was allowed according to symptoms and tolerability. The primary outcome was the IBS Severity Scoring System (IBS-SSS) score at 6 months. Secondary outcomes included subjective global assessment (SGA) of relief of IBS symptoms, adequate relief for at least 50% of weeks, and adverse events.

Results: Among 463 participants (mean age 48.5 years; 68% female), low-dose amitriptyline was superior to placebo at 6 months, with a significant mean difference in IBS-SSS score between groups (–27.0; 95% CI, –46.9 to –7.1; P = .0079). More participants reported relief of IBS symptoms with amitriptyline compared to placebo (61% vs 45%; odds ratio [OR] 1.78; 95% CI, 1.19–2.66; P = .0050). Adequate relief of IBS symptoms for at least 50% of weeks was higher with amitriptyline (41% vs 30%; OR 1.56; 95% CI, 1.20–2.03; P = .0008). Adverse events were more frequent with amitriptyline, mainly related to anticholinergic effects such as dry mouth (54%) and drowsiness (53%), but most were mild. Withdrawals due to adverse events were slightly higher with amitriptyline (13% vs 9%).

Conclusions: Low-dose amitriptyline was superior to placebo as a second-line treatment for IBS in primary care and was safe and well tolerated.

Implications for Practice: General practitioners should consider prescribing low-dose amitriptyline to patients with IBS whose symptoms do not improve with first-line therapies, providing appropriate support for patient-led dose titration.

Study Strengths and Limitations: Strengths include the large sample size, primary care setting, and extended treatment duration. Limitations involve underrepresentation of patients with IBS with constipation, potential unblinding due to side effects, and a predominantly White participant population.

Future Research: Further trials assessing amitriptyline as a first-line therapy for IBS in primary care and studies on long-term outcomes are recommended.

Reference: Ford AC, Wright-Hughes A, Alderson SL, et al. Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment in Primary Care (ATLANTIS): a Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial. Lancet. 2023; DOI: http://doi.org/10.1016/S0140-6736(23)01523-4

Cohort Study: Ondansetron Initiation Linked to Increased 10-Day Sudden Cardiac Death Risk in Hemodialysis Patients

20 Oct, 2024 | 14:05h | UTC

Background: Individuals undergoing maintenance hemodialysis have a markedly elevated risk of sudden cardiac death, attributed to structural heart disease, electrolyte imbalances, and polypharmacy. Ondansetron, a commonly used antiemetic known to prolong the QT interval, has been associated with fatal arrhythmias when administered intravenously in the general population. However, its cardiac safety profile in the hemodialysis population remains unclear.

Objective: To assess whether initiation of oral ondansetron, compared to antiemetics with lesser QT-prolonging potential, is associated with a higher 10-day risk of sudden cardiac death among patients receiving maintenance hemodialysis.

Methods: This new-user, active-comparator cohort study analyzed data from the United States Renal Data System between 2012 and 2019. A total of 119,254 patients receiving in-center hemodialysis who initiated either oral ondansetron or comparator antiemetics (promethazine, metoclopramide, or prochlorperazine) were included. Inverse probability of treatment-weighted survival models estimated adjusted hazard ratios (aHR) and risk differences (aRD), using an intention-to-treat approach with non-sudden cardiac death as a competing event.

Results: Among the patients, 64,978 (55%) initiated ondansetron, while 54,276 (45%) initiated comparator antiemetics. Ondansetron initiation was associated with a higher 10-day risk of sudden cardiac death compared to comparator drugs (aHR 1.44; 95% CI, 1.08–1.93; aRD 0.06%; 95% CI, 0.01%–0.11%). The number needed to harm was 1,688. Secondary analyses of additional cardiac outcomes, including ventricular arrhythmias and cardiovascular mortality, yielded consistent findings.

Conclusions: Initiation of oral ondansetron is associated with an increased short-term risk of sudden cardiac death among patients on maintenance hemodialysis compared to initiation of antiemetics with lesser QT-prolonging potential.

Implications for Practice: Clinicians should exercise caution when prescribing ondansetron to hemodialysis patients and consider alternative antiemetics with lower QT-prolonging risks. If ondansetron is necessary, monitoring for cardiac arrhythmias and performing electrocardiograms may be advisable to mitigate potential risks.

Study Strengths and Limitations: Strengths include a large, nationally representative cohort and an active-comparator design that minimizes confounding. Limitations involve potential residual confounding inherent in observational studies, possible misclassification of outcomes, and inability to assess dose-response relationships due to power constraints.

Future Research: Further studies are warranted to confirm these findings, elucidate the underlying mechanisms of increased cardiac risk, and evaluate the safety of ondansetron across different dosages and patient subgroups within the hemodialysis population.

Reference: Ismail S., Funk M.J., Flythe J.E. (2024). Ondansetron and the Risk of Sudden Cardiac Death among Individuals Receiving Maintenance Hemodialysis. Journal of the American Society of Nephrology, 35(6), 761–771. DOI: http://doi.org/10.1681/ASN.0000000000000336

Management of Ascites in Cirrhosis: Key Recommendations from the British Society of Gastroenterology Guidelines

12 Oct, 2024 | 18:23h | UTC

Introduction: Ascites, the pathological accumulation of fluid within the peritoneal cavity, is a common and serious complication of cirrhosis, indicating advanced liver disease and portending increased morbidity and mortality. Recognizing the need for updated clinical guidance, the British Society of Gastroenterology (BSG), in collaboration with the British Association for the Study of the Liver (BASL), has issued comprehensive guidelines. These aim to standardize the diagnosis and management of ascites in cirrhotic patients, incorporating recent advances to optimize patient outcomes.

Key Recommendations:

Diagnostic Paracentesis: It is strongly recommended that all patients with new-onset ascites undergo diagnostic paracentesis to measure total protein concentration and calculate the serum-ascites albumin gradient (SAAG). (Quality of evidence: moderate; Recommendation: strong)
Spontaneous Bacterial Peritonitis (SBP): Prompt diagnostic paracentesis should be performed in hospitalized patients with ascites, especially those with gastrointestinal bleeding or signs of infection, to rule out SBP. An ascitic neutrophil count >250/mm³ confirms SBP, necessitating immediate empirical antibiotic therapy tailored to local resistance patterns. (Quality of evidence: moderate; Recommendation: strong)
Dietary Salt Restriction: Patients should restrict dietary sodium intake to no more than 5–6.5 grams per day (87–113 mmol), equivalent to a no-added-salt diet, to manage fluid accumulation effectively. (Quality of evidence: moderate; Recommendation: strong)
Diuretic Therapy: For initial moderate ascites, spironolactone monotherapy is recommended. In cases of recurrent severe ascites, combination therapy with spironolactone and furosemide is advised. Regular monitoring for adverse events such as electrolyte imbalances and renal impairment is essential. (Quality of evidence: moderate; Recommendation: strong)
Large Volume Paracentesis (LVP): LVP is a safe and effective treatment for refractory ascites. Informed consent is required, and routine coagulation studies or prophylactic blood product infusions before the procedure are not recommended. (Quality of evidence: moderate; Recommendation: strong)
Use of Human Albumin Solution (HAS): After LVP exceeding 5 liters, infusion of HAS at 8 grams per liter of ascites removed is strongly recommended to prevent circulatory dysfunction. (Quality of evidence: high; Recommendation: strong)
Transjugular Intrahepatic Portosystemic Shunt (TIPSS): TIPSS should be considered for patients with refractory ascites not responding to medical therapy, with caution exercised in patients over 70 years or those with significant comorbidities. (Quality of evidence: high; Recommendation: strong)
Non-Selective Beta-Blockers (NSBBs): The presence of refractory ascites is not a contraindication for NSBB therapy. Patients should be closely monitored, and dose adjustments made in cases of hypotension or renal dysfunction. (Quality of evidence: moderate; Recommendation: strong)
Palliative Care: Patients unsuitable for liver transplantation should be offered palliative care referral to focus on symptom management and quality of life improvement. Alternative interventions for refractory ascites may also be considered. (Quality of evidence: weak; Recommendation: strong)

Conclusion: Implementation of these evidence-based guidelines is expected to enhance patient care by promoting early diagnosis, preventing complications, and standardizing management strategies for ascites in cirrhosis. Adherence to these recommendations can improve clinical outcomes, reduce hospitalizations, and enhance the quality of life for affected patients.

Reference: Aithal GP, Palaniyappan N, China L, et al. Guidelines on the management of ascites in cirrhosis. Gut. 2021;70(1):9–29. DOI: http://doi.org/10.1136/gutjnl-2020-321790

RCT: H. pylori Screening Added to Fecal Immunochemical Testing Did Not Reduce Gastric Cancer Incidence or Mortality

4 Oct, 2024 | 11:00h | UTC

Background: Gastric cancer is a leading cause of cancer-related mortality worldwide, particularly in East Asia. Helicobacter pylori infection is a well-established risk factor for gastric cancer development. While eradication therapy may prevent gastric cancer, the effectiveness of community-based H. pylori screening on gastric cancer incidence and mortality remains uncertain.

Objective: To determine whether adding H. pylori stool antigen (HPSA) testing to fecal immunochemical test (FIT) screening reduces gastric cancer incidence and mortality compared to FIT screening alone.

Methods: In a pragmatic randomized clinical trial conducted in Changhua County, Taiwan (2014–2018), 152,503 residents aged 50 to 69 years eligible for biennial FIT screening were randomized to receive an invitation for HPSA testing plus FIT (n = 63,508) or FIT alone (n = 88,995). Participants in the HPSA + FIT group with positive HPSA results were offered antibiotic eradication therapy. Primary outcomes were gastric cancer incidence and mortality, assessed via national cancer and death registries.

Results: Participation rates were higher in the HPSA + FIT group (49.6%) than in the FIT-alone group (35.7%). In the HPSA + FIT group, 38.5% tested positive for HPSA, and 71.4% of these received antibiotic treatment, achieving a 91.9% eradication rate. Over a median follow-up of approximately 5 years, gastric cancer incidence did not differ significantly between the HPSA + FIT and FIT-alone groups (0.032% vs 0.037%; mean difference –0.005%; 95% CI, –0.013% to 0.003%; P = .23). Gastric cancer mortality rates were also similar (0.015% vs 0.013%; mean difference 0.002%; 95% CI, –0.004% to 0.007%; P = .57). Adjusted analyses accounting for participation rates, follow-up duration, and baseline characteristics showed a lower gastric cancer incidence in the HPSA + FIT group (RR 0.79; 95% CI, 0.63–0.98; P = .04), but no difference in mortality (RR 1.02; 95% CI, 0.73–1.40; P = .91). Adverse effects from antibiotics were mild, with abdominal pain or diarrhea occurring in 2.1%.

Conclusions: An invitation to HPSA testing combined with FIT did not significantly reduce gastric cancer incidence or mortality compared to FIT alone over a median follow-up of about 5 years. Adjusted analyses suggest a potential reduction in gastric cancer incidence but not mortality when accounting for participation rates and follow-up duration.

Implications for Practice: Adding H. pylori screening to existing FIT programs may not significantly reduce gastric cancer incidence or mortality in the short term, possibly due to low participation rates, incomplete eradication, and limited follow-up. Clinicians should consider these factors when implementing community-based H. pylori screening and weigh the benefits against resource utilization and patient adherence.

Study Strengths and Limitations: Strengths include a large sample size and integration of HPSA testing into an existing FIT screening infrastructure. Limitations encompass differences in participation rates and baseline characteristics between groups, a relatively short follow-up period, and only 71.4% of HPSA-positive participants receiving eradication therapy, which may have reduced the ability to detect significant effects.

Future Research: Longer-term studies with higher participation and eradication rates are needed to assess the long-term benefits of H. pylori screening on gastric cancer incidence and mortality. Research should explore strategies to improve screening uptake and treatment adherence.

Reference: Lee Y-C, et al. (2024) Screening for Helicobacter pylori to Prevent Gastric Cancer: A Pragmatic Randomized Clinical Trial. JAMA. DOI: http://doi.org/10.1001/jama.2024.14887

RCT: Olanzapine Improves Nausea and Vomiting Control in Moderately Emetogenic Chemotherapy but Increases Somnolence

7 Sep, 2024 | 19:28h | UTC

Study Design and Population: This phase 3, multicenter, open-label randomized clinical trial involved 560 chemotherapy-naive patients aged 18 years or older with solid malignant tumors. The trial, conducted at three institutes in India, compared the efficacy of adding olanzapine to standard antiemetic therapy in patients receiving moderately emetogenic chemotherapy (MEC) based on oxaliplatin, carboplatin, or irinotecan.

Main Findings: The group receiving olanzapine in addition to standard antiemetic therapy showed significantly higher complete response (CR) rates (91% vs 82%, P = .005) compared to the observation group. The olanzapine group also demonstrated superior control of nausea (96% vs 87%, P < .001) and chemotherapy-induced nausea and vomiting (CINV) (96% vs 91%, P = .02). The use of rescue medications was significantly lower in the olanzapine group. Grade 1 somnolence occurred in 10% of patients receiving olanzapine but was absent in the observation group.

Implications for Practice: The results support the inclusion of olanzapine in antiemetic regimens for MEC to improve CINV outcomes. However, mild somnolence should be considered when prescribing olanzapine as part of antiemetic prophylaxis. Further research could explore dose optimization to minimize adverse effects.

Reference: Ostwal, V. et al. (2024). Olanzapine as antiemetic prophylaxis in moderately emetogenic chemotherapy: a phase 3 randomized clinical trial. JAMA Network Open. DOI: http://doi.org/10.1001/jamanetworkopen.2024.26076

Link: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2822027

RCT: Cold Snare EMR Reduces Major Adverse Events but Increases Residual Adenoma in Large Nonpedunculated Colorectal Polyps – Gastroenterology

25 Aug, 2024 | 11:45h | UTC

Study Design and Population: This multicentric randomized controlled trial (RCT) involved 19 centers in Germany and included 363 patients with 396 large nonpedunculated colorectal polyps (≥20 mm). Participants were randomly assigned to undergo either cold snare endoscopic mucosal resection (EMR) or the traditional hot snare EMR. The study aimed to compare the safety and effectiveness of cold versus hot snare EMR.

Main Findings: Cold snare EMR significantly reduced the incidence of major adverse events (AEs), with a major AE rate of 1.0% compared to 7.9% in the hot snare group. This included significant reductions in perforation and postendoscopic bleeding rates. However, cold snare EMR was associated with a higher rate of residual adenoma at follow-up, with 23.7% of cases compared to 13.8% in the hot snare group. The increased rate of residual adenoma was particularly noted in larger lesions (≥4 cm) and those with high-grade dysplasia.

Implications for Practice: Cold snare EMR offers a safer alternative to hot snare EMR for resecting large nonpedunculated colorectal polyps, particularly in terms of reducing major AEs. However, the higher rate of residual adenoma indicates that cold snare EMR should be used selectively, especially for smaller polyps or less likely to have advanced histology. Further research is needed to refine lesion selection criteria and to explore technical modifications that could improve the efficacy of cold snare EMR.

Reference: Steinbrück, I., et al. (2024). Cold Versus Hot Snare Endoscopic Resection of Large Nonpedunculated Colorectal Polyps: Randomized Controlled German CHRONICLE Trial. Gastroenterology, 167(4), 764–777. http://doi.org/10.1053/j.gastro.2024.05.013

Systematic Review: Nasogastric Feeding Increases Diarrhea and Pain Compared to Nasojejunal Feeding in Acute Pancreatitis – BMC Gastroenterol

18 Aug, 2024 | 19:23h | UTC

Study Design and Population: This systematic review and meta-analysis compared the safety and efficacy of nasogastric (NG) versus nasojejunal (NJ) feeding initiated within 48 hours of hospital admission in patients with moderate to severe acute pancreatitis. The analysis included four randomized controlled trials (RCTs) involving a total of 217 patients.

Main Findings: The review found no significant difference in mortality between NG and NJ feeding groups. However, NG feeding was associated with a higher incidence of diarrhea (RR 2.75, P = 0.02) and pain (RR 2.91, P = 0.002). The risk of infection was also higher in the NG group (6.67% vs. 3.33%, P = 0.027). No significant differences were observed in the need for surgical intervention, the requirement for parenteral nutrition, or the success rates of feeding procedures.

Implications for Practice: The findings suggest that while NG feeding does not increase mortality in acute pancreatitis, it is associated with higher rates of certain complications, particularly diarrhea and pain. Clinicians should consider these risks when choosing a feeding strategy for patients with acute pancreatitis, especially within the critical early 48-hour period post-admission.

Reference: Wang M, Shi H, Chen Q, Su B, Dong X, Shi H, Xu S. (2024). Comparative safety assessment of nasogastric versus nasojejunal feeding initiated within 48 hours post-admission versus unrestricted timing in moderate or severe acute pancreatitis: a systematic review and meta-analysis. BMC Gastroenterology, 24(207), 1-11. DOI: 10.1186/s12876-024-03290-z.

Randomized Noninferiority Trial: Oral Vonoprazan Noninferior to IV Proton Pump Inhibitors in Preventing Rebleeding of High-Risk Peptic Ulcers – Gastroenterology

18 Aug, 2024 | 18:32h | UTC

Study Design and Population: This multicenter, randomized, open-label, noninferiority trial was conducted in Thailand across six centers, including both university and community hospitals. A total of 194 patients with high-risk peptic ulcer (PU) bleeding who had achieved successful endoscopic hemostasis were randomized to receive either vonoprazan or intravenous proton pump inhibitors (PPI). The study aimed to compare the efficacy of vonoprazan, a potassium-competitive acid blocker, with that of high-dose PPIs in preventing rebleeding.

Main Findings: The trial found that the 30-day rebleeding rate in the vonoprazan group was 7.1%, compared to 10.4% in the PPI group. This demonstrated noninferiority of vonoprazan within a 10% margin (risk difference: -3.3%, 95% CI: -11.2 to 4.7; P < .001). The 3-day and 7-day rebleeding rates were also noninferior. Secondary outcomes, including mortality rates, the need for rescue therapy, blood transfusion requirements, and length of hospital stay, were comparable between the two groups. Adverse events were similar in both groups.

Implications for Practice: Vonoprazan presents a viable alternative to intravenous PPIs for preventing rebleeding in patients with high-risk PU after endoscopic hemostasis. The availability of vonoprazan in oral form could potentially reduce hospital stays. However, further studies in multiethnic populations are needed to confirm these findings and assess the cost-effectiveness of vonoprazan in this setting.

Reference: Geeratragool T, Kaosombatwattana U, Boonchote A, et al. (2024). Comparison of Vonoprazan Versus Intravenous Proton Pump Inhibitor for Prevention of High-Risk Peptic Ulcers Rebleeding After Successful Endoscopic Hemostasis: A Multicenter Randomized Noninferiority Trial. Gastroenterology, -(-), 1-10. DOI: https://doi.org/10.1053/j.gastro.2024.03.036.

IDSA 2024 Guidelines for Managing Complicated Intra-abdominal Infections – Clin Infect Dis

10 Aug, 2024 | 22:10h | UTC

Introduction: The Infectious Diseases Society of America (IDSA) has updated its clinical practice guidelines for managing complicated intra-abdominal infections in adults, children, and pregnant individuals. The update focuses on risk assessment, diagnostic imaging, and microbiological evaluation, with recommendations grounded in systematic literature reviews and the GRADE approach for rating evidence.

Key Points:

1 – Risk Stratification:

– For adults with complicated intra-abdominal infections, the APACHE II score is recommended for risk stratification within 24 hours of hospital or ICU admission. The WSES Sepsis Severity Score is an acceptable alternative.

– No specific severity scoring system is recommended for pediatric patients.

2 – Diagnostic Imaging for Appendicitis:

– In non-pregnant adults, CT is suggested as the initial imaging modality for suspected acute appendicitis.

– For children, an abdominal ultrasound (US) is preferred initially, with MRI or CT recommended if the US is inconclusive.

– In pregnant individuals, US or MRI can be considered, with MRI suggested if initial US results are inconclusive.

3 – Imaging for Acute Cholecystitis and Cholangitis:

– For non-pregnant adults, US is recommended initially. If inconclusive, a CT scan is suggested.

– For pregnant individuals, US or MRI can be used, but the guidelines do not specify a preferred modality due to a knowledge gap.

4 – Blood Cultures:

– Blood cultures are recommended in adults and children with suspected intra-abdominal infections presenting with severe symptoms such as hypotension or tachypnea, especially when antibiotic-resistant organisms are a concern.

– Routine blood cultures are not recommended for patients without these risk factors.

5 – Intra-abdominal Fluid Cultures:

– In complicated intra-abdominal infections requiring source control procedures, obtaining intra-abdominal cultures is advised to guide antimicrobial therapy.

– In uncomplicated appendicitis cases, routine cultures are not recommended unless the patient is immunocompromised or complicated disease is suspected during surgery.

Conclusion: These guidelines provide evidence-based recommendations to improve the management of complicated intra-abdominal infections, emphasizing appropriate risk stratification, targeted diagnostic imaging, and the selective use of cultures to guide therapy.

Reference: Bonomo, R. A., et al. (2024). “2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Risk Assessment, Diagnostic Imaging, and Microbiological Evaluation in Adults, Children, and Pregnant People.” Clinical Infectious Diseases. DOI: 10.1093/cid/ciae346.

RCT: Tirzepatide Significantly Improves MASH Resolution Without Worsening Fibrosis Over 52 Weeks – N Engl J Med

10 Aug, 2024 | 19:53h | UTC

Study Design and Population: This phase 2, multicenter, double-blind, randomized, placebo-controlled trial evaluated the efficacy and safety of tirzepatide in 190 participants with biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH) and moderate to severe liver fibrosis (stage F2 or F3). Participants were assigned to receive subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo weekly for 52 weeks.

Main Findings: Tirzepatide significantly improved MASH resolution without worsening fibrosis compared to placebo. Resolution rates were 44% for 5 mg, 56% for 10 mg, and 62% for 15 mg, versus 10% for placebo. Improvement in fibrosis stage without worsening MASH was also higher in tirzepatide groups (51-55%) than in the placebo group (30%). The most common adverse events were mild to moderate gastrointestinal symptoms.

Implications for Practice: Tirzepatide shows promise as a treatment for MASH with moderate to severe fibrosis, significantly improving disease resolution without worsening fibrosis. However, further research with larger and longer trials is needed to confirm these findings and evaluate long-term safety.

Reference: Loomba, R., Hartman, M. L., Lawitz, E. J., et al. (2024). Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis. New England Journal of Medicine, 391(4), 299-310. DOI: 10.1056/NEJMoa2401943.

Phase 2 Trial: Survodutide Improves MASH Without Worsening Fibrosis, But Increases GI Side Effects – N Engl J Med

10 Aug, 2024 | 19:47h | UTC

Study Design and Population: This 48-week, phase 2 randomized trial evaluated the efficacy and safety of survodutide, a dual agonist of the glucagon and GLP-1 receptors, in 293 adults with biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis (F1-F3 stages). Participants were randomized to receive weekly injections of survodutide (2.4, 4.8, or 6.0 mg) or placebo.

Main Findings: Survodutide significantly improved MASH without worsening fibrosis compared to placebo, with 47% to 62% of participants in the survodutide groups achieving histologic improvement versus 14% in the placebo group. A reduction in liver fat content by at least 30% was observed in 57% to 67% of participants receiving survodutide, compared to 14% in the placebo group. However, adverse events such as nausea, diarrhea, and vomiting were more common with survodutide.

Implications for Practice: The findings suggest that survodutide could be a promising treatment for MASH, with potential benefits for liver histology and fat content. However, the increased gastrointestinal side effects warrant careful consideration in future phase 3 trials to better evaluate the drug’s safety profile and long-term efficacy.

Reference: Sanyal AJ, Bedossa P, Fraessdorf M, et al. (2024). A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. New England Journal of Medicine, 391(4), 311-319. DOI: 10.1056/NEJMoa2401755.

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