Internal Medicine

Review: Enteral Nutrition in Hospitalized Adults

21 Apr, 2025 | 13:23h | UTC

Introduction:
This is a summary of a new review published in the New England Journal of Medicine discussing the rationale, evidence, and practical considerations for administering enteral nutrition to hospitalized adults. The main objective is to provide guidance on identifying patients with disease-related malnutrition, initiating enteral feeding, and differentiating strategies for critically ill versus non–critically ill patients who require nutritional support.

Key Recommendations:

1. Identify Malnutrition Early:

   • Screen all hospitalized patients for malnutrition (e.g., using the Malnutrition Screening Tool) on admission.

   • Confirm high-risk cases with a comprehensive nutrition assessment (e.g., GLIM or AAIM criteria).

2. Optimize Oral Intake First:

   • Whenever possible, use strategies such as dietary modifications and oral nutritional supplements before initiating enteral nutrition.

   • Implement medical nutrition therapy with the goal of meeting at least 75% of estimated energy and protein requirements orally; consider EN/PN if this goal is not reached within approximately 5 days.

3. Initiate Enteral Nutrition if Oral Intake Is Inadequate:

   • Consider enteral feeding for patients who fail to meet energy and protein goals and do not have contraindications (e.g., intestinal obstruction, severe shock, intestinal ischemia, or active gastrointestinal hemorrhage).

   • Dosing considerations differ significantly by patient population and clinical phase:

     • In critical illness (acute phase, first week), evidence suggests potential harm from early full caloric feeding or high protein doses (e.g., ≥2.2 g/kg/day), particularly in patients with shock or organ failure. A more “trophic” or hypocaloric approach (<70% of estimated energy needs) is often appropriate, especially if there is acute kidney injury or multiorgan dysfunction.

     • In contrast, for non–critically ill medical or surgical patients at risk of malnutrition, studies show that underfeeding is associated with worse outcomes, making it important to achieve closer to full nutritional requirements sooner.

4. Select the Appropriate Route and Timing:

   • For short-term use (up to 6 weeks), place a nasoenteric tube.

   • For anticipated long-term support, consider a gastrostomy or jejunostomy tube.

   • Postpyloric feeding (duodenal or jejunal) may reduce aspiration risk in certain patients.

5. Adjust Dose According to Clinical Phase:

   • In the ICU acute phase, avoid early full feeding; consider “trophic” or hypocaloric regimens.

   • As the patient recovers from critical illness, gradually increase caloric and protein delivery to meet estimated needs if tolerated, though exact targets remain under investigation.

   • In non–critically ill patients, aim to meet estimated requirements unless specific clinical issues necessitate lower delivery.

6. Mitigate Complications:

   • Use continuous pump-assisted infusion, though volume-based feeding can improve goal attainment.

   • Monitor regularly for refeeding syndrome (e.g., hypophosphatemia, hypokalemia, hypomagnesemia) and correct electrolyte abnormalities.

   • Employ glucose management strategies to avoid hyperglycemia.

7. Coordinate Interdisciplinary Care:

   • Engage dietitians, nursing staff, pharmacists, and other professionals to tailor therapy and optimize patient acceptance.

   • Involve patients in shared decision-making, particularly regarding personal values and treatment goals.

Conclusion:
These recommendations underscore enteral nutrition’s essential role in preventing and treating disease-related malnutrition. However, the direct impact on major outcomes (e.g., mortality, complications) varies by patient population, feeding strategy, and timing. In critically ill patients, especially during the first week of ICU care, lower-dose or “trophic” enteral feeding may be safer, whereas non–critically ill patients generally benefit from achieving nutritional targets more fully. Our understanding of optimal feeding approaches continues to evolve, particularly with regard to feeding dose during different phases of illness and recovery.

Reference:
Gramlich L, Guenter P. Enteral Nutrition in Hospitalized Adults. New England Journal of Medicine. 2025;392:1518-1530. DOI: https://doi.org/10.1056/NEJMra2406030

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Non-inferiority RCT: Reduced-Dose vs Full-Dose Direct Oral Anticoagulants for Extended VTE Treatment

8 Mar, 2025 | 17:46h | UTC

Background: Venous thromboembolism (VTE) carries a high risk of recurrence once anticoagulation is stopped, particularly in those with unprovoked events or persistent risk factors. Extended anticoagulation is therefore recommended for patients at high risk, but optimal dosing remains uncertain. Reduced-dose direct oral anticoagulants (DOACs) may lower bleeding risk compared with full-dose regimens. However, prior trials that tested reduced-dose anticoagulation enrolled patients with less definitive indications for continuation and were not powered for head-to-head efficacy comparisons.

Objective: The RENOVE trial aimed to determine whether reduced-dose DOACs (apixaban 2.5 mg twice daily or rivaroxaban 10 mg once daily) are non-inferior to full-dose DOACs (apixaban 5 mg twice daily or rivaroxaban 20 mg once daily) in preventing VTE recurrence during extended treatment, while potentially reducing bleeding risk.

Methods: RENOVE was a non-inferiority, multicenter, randomized, open-label, blinded-endpoint trial conducted in 47 French hospitals. It included adult patients (n=2768) who had completed 6–24 months of uninterrupted full-dose anticoagulation for symptomatic pulmonary embolism or proximal deep vein thrombosis and were deemed at high risk for recurrence. Participants were randomly assigned 1:1 to a reduced-dose or a full-dose DOAC regimen. The primary outcome was symptomatic recurrent VTE (non-fatal or fatal). The main secondary outcomes included major bleeding or clinically relevant non-major bleeding, and a net clinical benefit composite of recurrent VTE plus major or clinically relevant non-major bleeding.

Results: After a median follow-up of 37.1 months, the primary outcome occurred in 19/1383 patients (5-year cumulative incidence 2.2%) in the reduced-dose arm and 15/1385 (1.8%) in the full-dose arm (adjusted HR 1.32; 95% CI 0.67–2.60; p=0.23 for non-inferiority). Major or clinically relevant non-major bleeding was significantly lower in the reduced-dose group (9.9% vs 15.2% at 5 years; HR 0.61; 95% CI 0.48–0.79). Major bleeding was 2.1% vs 4.0%, respectively. Net clinical benefit (recurrent VTE or clinically relevant bleeding) was 11.8% in the reduced-dose group versus 16.5% in the full-dose group (HR 0.67; 95% CI 0.53–0.86). Mortality and arterial events were similar between groups.

Conclusions: Reduced-dose DOACs did not meet the formal non-inferiority criterion for preventing VTE recurrence in patients requiring extended anticoagulation. Nonetheless, absolute recurrence rates were low in both arms. The reduced-dose strategy substantially lowered the risk of clinically relevant bleeding without increasing all-cause mortality. Although full-dose anticoagulation remains an option, these findings suggest that reduced-dose regimens may be clinically reasonable for many patients who need ongoing therapy.

Implications for Practice: Clinicians could consider a reduced-dose DOAC regimen for extended VTE treatment, especially in individuals at high bleeding risk, given the observed safety benefits. Treatment decisions should still account for patient-specific factors (e.g., obesity, history of severe VTE) where full-dose regimens might remain preferable.

Study Strengths and Limitations: Major strengths include the large sample size, well-defined endpoints adjudicated by a blinded committee, and extended follow-up. Limitations include the open-label design and the low rate of recurrence, which led to a sample size increase mid-study. Subgroup analyses may be underpowered to detect meaningful differences in specific populations.

Future Research: Further trials or pooled analyses are needed to clarify whether certain high-risk subgroups (e.g., those with severe obesity or active malignancy) might benefit more from continuing a full-dose regimen. Additional prospective studies could refine criteria for safe dose reductions.

Reference:

1. Couturaud F, Schmidt J, Sanchez O, et al. Extended treatment of venous thromboembolism with reduced-dose versus full-dose direct oral anticoagulants in patients at high risk of recurrence: a non-inferiority, multicentre, randomised, open-label, blinded endpoint trial. The Lancet. 2025;405(10480). DOI: https://doi.org/10.1016/S0140-6736(24)02842-3
2. Middeldorp S, Leentjens J. Anticoagulation for extended venous thromboembolism treatment: less is really more. The Lancet. 2025;405(10480). DOI: https://doi.org/10.1016/S0140-6736(25)00099-6

 

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2025 ACC/AHA/ Guideline for the Management of Patients With Acute Coronary Syndromes

3 Mar, 2025 | 18:02h | UTC

Introduction:

This summary highlights the key points from the 2025 ACC/AHA/ACEP/NAEMSP/SCAI Clinical Practice Guideline on the management of acute coronary syndromes (ACS). It covers both ST-segment elevation myocardial infarction (STEMI) and non–ST-segment elevation ACS (NSTE-ACS), emphasizing timely diagnosis, reperfusion strategies, risk stratification, and secondary prevention. The primary aim is to help clinicians provide evidence-based and up-to-date care to reduce mortality, complications, and long-term adverse outcomes in patients with ACS.

Key Recommendations:

• Early and Accurate Diagnosis

  • Obtain and interpret a 12-lead ECG within 10 minutes of first medical contact in suspected ACS.
  • Use high-sensitivity troponin testing to accelerate ruling in/out myocardial infarction.

• Reperfusion in STEMI

  • Primary percutaneous coronary intervention (PPCI) is the preferred strategy if it can be performed within 90 minutes (or 120 minutes for transfers).
  • In patients with anticipated long delays, fibrinolytic therapy is recommended if there are no contraindications and the patient presents within 12 hours of symptom onset.

• Routine Invasive vs. Selective Invasive Strategy in NSTE-ACS

  • Patients at intermediate or high ischemic risk benefit from an invasive strategy during hospitalization.
  • Low-risk patients may undergo a selective invasive approach, incorporating noninvasive testing to guide the need for angiography.

• Multivessel Coronary Artery Disease Management

  • For hemodynamically stable STEMI patients with nonculprit lesions, complete revascularization (either during the index procedure or staged) lowers future events.
  • In NSTE-ACS, complete revascularization decisions (PCI vs. CABG) depend on anatomical complexity and comorbidities.

• Antithrombotic Therapy

  • Initiate dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12 inhibitor (ticagrelor or prasugrel preferred over clopidogrel for most) for at least 12 months in patients without high bleeding risk.
  • To reduce bleeding risk in patients with ACS several strategies are available:
    a) in patients at risk for gastrointestinal bleeding, a proton pump inhibitor is recommended;
    b) in patients who have tolerated dual antiplatelet therapy with ticagrelor, transition to ticagrelor monotherapy is recommended ≥1 month after PCI;
    c) in patients who require long-term anticoagulation, aspirin discontinuation is recommended 1 to 4 weeks after PCI with continued use of a P2Y12 inhibitor (preferably clopidogrel).

• Parenteral Anticoagulation

  • All ACS patients should receive an anticoagulant (e.g., unfractionated heparin, low-molecular-weight heparin, bivalirudin) depending on the clinical scenario and planned strategy (PCI, CABG, or medical management).

• Lipid Management

  • High-intensity statin therapy is recommended in all ACS patients.
  • Add a nonstatin agent (e.g., ezetimibe, PCSK9 inhibitor) if LDL cholesterol remains ≥70 mg/dL on maximally tolerated statin.

• Heart Failure and Cardiogenic Shock

  • In acute MI with cardiogenic shock, immediate revascularization of the culprit lesion is indicated.
  • Selected patients with STEMI-related cardiogenic shock may benefit from a short-term microaxial flow pump if they fit specific criteria; close attention to vascular complications and renal failure is required.

• In-Hospital Care and Complications

  • Use telemetry for rhythm monitoring in unstable patients and evaluate left ventricular ejection fraction prior to discharge.
  • Mechanical complications (e.g., ventricular septal rupture) require rapid surgical consultation; short-term mechanical circulatory support devices may be a bridge to surgery.

• Secondary Prevention and Discharge

  • Refer all patients to a cardiac rehabilitation program to reduce rehospitalizations and improve functional status. A home-based program is acceptable when center-based options are not feasible.
  • Repeat lipid panel 4 to 8 weeks postdischarge to confirm adequate LDL-lowering.
  • Annual influenza vaccination is recommended to reduce cardiovascular events and mortality.
  • Consider low-dose colchicine in certain post-ACS patients to reduce the risk of recurrent ischemic events if there are no contraindications.
  • Based on one trial, red blood cell transfusion to maintain hemoglobin of 10 g/dL may be reasonable in patients with ACS and acute or chronic anemia who are not actively bleeding.

Conclusion:
Adherence to these recommendations can significantly improve in-hospital and postdischarge outcomes for patients with acute coronary syndromes. By focusing on rapid identification, prompt reperfusion, tailored antithrombotic therapies, aggressive risk factor modification, and ongoing follow-up (including cardiac rehabilitation), clinicians can lower morbidity, mortality, and readmissions. The guideline also underscores the need to balance bleeding and ischemic risks, use high-intensity lipid-lowering strategies, and provide a structured discharge plan for long-term secondary prevention.

Reference:
Rao SV, O’Donoghue ML, Ruel M, et al. 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Journal of the American College of Cardiology. In Press, Corrected Proof. Available online 27 February 2025. DOI: https://doi.org/10.1016/j.jacc.2024.11.009

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Systematic Review: Shorter Antibiotic Courses Often Prove Non-Inferior for Common Bacterial Infections

3 Feb, 2025 | 10:00h | UTC

Background: The overuse of antibiotics contributes significantly to the global rise in antimicrobial resistance (AMR). Shorter antibiotic treatment courses have gained traction as an important antimicrobial stewardship intervention. They can potentially reduce drug-related side effects, healthcare costs, and selection pressure favoring resistant pathogens. This review synthesizes findings from randomized controlled trials (RCTs) on antibiotic duration across various common bacterial infections—including respiratory tract, genitourinary, skin and soft tissue, bone/joint, and intra-abdominal infections—to inform practical, day-to-day clinical decision-making.

Objective:

1. To assess the comparative efficacy of short- versus long-course antibiotic therapy for frequent bacterial infections.
2. To highlight key evidence gaps, particularly for severe infections, critically ill populations, and low- to middle-income settings.
3. To propose practical treatment durations in light of current guidelines and study outcomes.

Methods:

• Comprehensive search of MEDLINE and Embase through July 2024 (PROSPERO 2021, CRD42021276209).
• Inclusion: RCTs that compared differing antibiotic durations for bacterial infections or perioperative prophylaxis, reporting clinical cure, relapse, or mortality.
• Exclusion: Non-bacterial infections (viral/fungal), pilot studies, non-randomized designs.
• Data extraction: Patient demographics, infection type, interventions, outcomes, adherence, and risk-of-bias assessment per the RoB 2 tool.
• Guideline review: Major international guidelines (e.g., IDSA, NICE, WHO) were examined to contextualize trial findings.

Results:

• A total of 315 RCTs were included; 85% concluded no difference, non-inferiority, or equivalence of shorter compared with longer antibiotic courses.
• Shorter therapy (often 5–7 days) is well-supported for uncomplicated bacterial sinusitis, community-acquired pneumonia (CAP), simple urinary tract infections (UTIs), cellulitis, and intra-abdominal infections with adequate surgical source control.
• Evidence for reducing duration in severe infections (e.g., bloodstream infections, ventilator-associated pneumonia caused by non-fermenting Gram-negative bacilli) or in critically ill populations remains limited.
• Only 7% of RCTs involved intensive care unit (ICU) patients, and 14% were conducted in low- or middle-income countries.
• Methodologically, 15% of trials posed a low risk of bias; however, non-adherence to assigned durations was common (median 11% per study). Very few trials tracked emergence of resistant organisms through follow-up cultures.

Key findings:

1. Acute GAS Pharyngotonsillitis:
   10 days of penicillin V or amoxicillin remains the conventional standard to ensure microbiological eradication and minimize rheumatic fever risk. While 5 days of azithromycin may be used in macrolide-responsive settings, it is not preferred as first-line therapy due to broader-spectrum activity and limited evidence for preventing complications, particularly in high-risk populations.
2. Community-Acquired Pneumonia (CAP):
   • Outpatient adults with mild to moderate CAP typically improve with 5 days of appropriate therapy (e.g., amoxicillin, doxycycline, or a macrolide), provided patients show clinical stability.
   • Severe CAP or complicated presentations (e.g., MRSA, Pseudomonas, multi-lobar involvement) may need 7–10 days or until clinical stability is achieved.
3. Acute Bacterial Sinusitis (Adults):
   • 5–7 days of amoxicillin/clavulanate or other first-line agents usually suffice if the diagnosis is certain.
4. Genitourinary Infections:
   • Uncomplicated Cystitis (Non-Pregnant Women):
     • 3–5 days of nitrofurantoin or trimethoprim/sulfamethoxazole is often adequate, reflecting strong RCT support.
   • Pyelonephritis or Complicated UTIs (e.g., in men, catheter-associated):
     • While some RCTs show 7 days can be as effective as 14 days in afebrile males with mild UTI, a trial in febrile males demonstrated inferior outcomes with shorter courses. Clinicians should exercise caution in febrile or higher-risk cases.
5. Skin and Soft Tissue Infections (e.g., Cellulitis):
   • 5–6 days of effective oral therapy is sufficient for uncomplicated cellulitis if there is marked clinical improvement by Day 5.
   • For recurrent abscesses or complicated scenarios, duration may need to be extended or individualized.
6. Bone and Joint Infections:
   • 6 weeks is often sufficient for vertebral osteomyelitis in stable patients.
   • For prosthetic joint infections with retained hardware, 6 weeks of therapy was inferior to 12 weeks in a key trial, necessitating individualized duration based on surgical management.
7. Intra-Abdominal Infections:
   • With adequate source control, 4–5 days of antibiotics commonly yields outcomes on par with extended courses.
   • Longer therapy (≥7 days) may be needed when abscesses are not fully drained or in immunocompromised patients.
8. Perioperative Prophylaxis:
   • A single preoperative dose (possibly repeated if surgery is prolonged or blood loss is excessive) is sufficient in most procedures.
   • Continuing prophylaxis beyond 24 hours rarely provides additional benefit and may increase adverse events.

Conclusions: Numerous well-conducted RCTs support shorter antibiotic courses for many common bacterial infections. Nonetheless, high-quality data are sparse for severe or complex infections, pediatric populations with significant comorbidities, and low-resource settings. Clinicians should tailor antibiotic duration to the infection type, disease severity, patient factors, and local resistance patterns—while remaining cognizant that shorter courses can safely balance efficacy, safety, and stewardship aims in many cases.

Study Strengths and Limitations:

• Strengths: Large volume of RCTs, broad infection scope, and inclusion of diverse study designs. Substantial evidence supports shortening antibiotic regimens for multiple common infections.
• Limitations: Underrepresentation of severe, ICU-level infections, children with serious comorbidities, and low-resource settings. High variation in diagnostic criteria, antibiotic choices, and adherence monitoring. Many trials reported low event rates, posing potential non-inferiority bias.

Future Research:

• Well-powered RCTs focusing on severe infections (e.g., MDR Gram-negative bloodstream infections, staphylococcal bacteremia, ventilator-associated pneumonia with resistant pathogens).
• Trials in low- and middle-income countries with robust microbiological and economic assessments.
• Studies using adaptive designs and validated biomarkers to refine duration–response relationships and detect shifts in AMR at the population level.

Reference: Mo Y, Tan WC, Cooper BS. Antibiotic duration for common bacterial infections—a systematic review. JAC-Antimicrobial Resistance. 2025;7(1):dlae215. DOI: https://doi.org/10.1093/jacamr/dlae215

 

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Introducing Our Free WhatsApp Channels for Daily Internal Medicine Articles!

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

 

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RCT: Dapagliflozin Plus Calorie Restriction Achieves Higher Remission Rate of Type 2 Diabetes

30 Jan, 2025 | 10:10h | UTC

Background: Type 2 diabetes (T2DM) is often regarded as a chronic, progressive disease. Nonetheless, trials such as DiRECT have challenged this view by demonstrating that remission may be achieved through substantial weight loss. SGLT2 inhibitors—among them dapagliflozin—induce urinary glucose excretion and moderate weight reduction, yet their ability to promote sustained remission of early T2DM is not fully understood. Recent editorials highlight the promise of combining pharmacological therapies with dietary interventions while stressing the need to address cost, sustainability, and patient selection for best outcomes.

Objective: This study aimed to determine whether adding dapagliflozin (10 mg/day) to a moderate calorie restriction diet (energy deficit of 500–750 kcal/day) could increase T2DM remission rates in overweight or obese adults with a notably short median diabetes duration of 0.2–0.3 years, relative to calorie restriction alone.

Methods: Researchers conducted a multicenter, double-blind, placebo-controlled, randomized trial at 16 centers in China, recruiting 328 adults (20–70 years old, body mass index >25) with early T2DM (duration <6 years). Patients who were currently using any antidiabetic medications other than metformin were excluded. Participants were allocated to receive dapagliflozin 10 mg/day or placebo for 12 months. Both groups received dietary counseling and were instructed to maintain a calorie deficit of 500–750 kcal/day. When individuals achieved normoglycemia (fasting plasma glucose <110 mg/dL and HbA1c <6.5%) for two consecutive months, all antidiabetic medications—including dapagliflozin—were discontinued. The primary outcome was diabetes remission (HbA1c <6.5% and fasting plasma glucose <126 mg/dL for ≥2 months off medications). Secondary endpoints included changes in weight, body composition, blood pressure, insulin resistance (HOMA-IR), and lipid profiles.

Results: Over 12 months, 44% of participants in the dapagliflozin-plus-diet arm achieved remission, compared with 28% in the diet-alone arm (risk ratio 1.56, 95% CI 1.17 to 2.09; P=0.002). Mean weight loss was −5.0 kg in the dapagliflozin group versus −3.2 kg in placebo, with additional improvements in body fat, systolic blood pressure, HDL cholesterol, and triglycerides. Mild and moderate adverse events occurred at similar rates in both groups, and two patients in the dapagliflozin arm experienced serious urinary tract infections requiring hospitalization. No deaths occurred during the trial.

Conclusions: Dapagliflozin combined with moderate calorie restriction resulted in a significantly higher remission rate of early T2DM (median duration 0.2–0.3 years) compared with calorie restriction alone. This combined intervention also led to greater reductions in body weight and improvements in cardiometabolic risk factors, with an acceptable safety profile over 12 months.

Implications for Practice: For clinicians managing adults with relatively short-duration T2DM, the addition of dapagliflozin to a structured dietary program may offer a promising route toward remission. Nevertheless, cost considerations—particularly for long-term SGLT2 inhibitor therapy—require thoughtful assessment in routine practice. While the required weight loss was more modest than in some very-low-calorie interventions, maintaining remission may still depend on ongoing lifestyle modification. Providers should also evaluate patient eligibility carefully, noting that the greatest benefits may be realized in those with early-stage disease and minimal comorbidity.

Study Strengths and Limitations: Strengths include a randomized, placebo-controlled design across multiple centers, a feasible dietary regimen, and robust participant adherence. Limitations include a relatively short follow-up after drug discontinuation, potentially overestimating durable remission, and use of a two-month remission definition that may not reflect sustained outcomes. Furthermore, the study population had very early-stage diabetes (median duration 0.2–0.3 years), limiting applicability to patients with longer-standing disease or different ethnic backgrounds.

Future Research: Longer-term trials are needed to assess whether extending the period of drug or lifestyle support can sustain remission and to identify subgroups most likely to benefit. Additional research should also evaluate how discontinuing SGLT2 inhibitors might impact cardiovascular and renal outcomes over time. Comparisons with newer agents that produce greater weight loss (e.g., GLP-1 receptor agonists) could further clarify optimal approaches.

Reference:

1. Liu Y, Chen Y, Ma J, et al. Dapagliflozin plus calorie restriction for remission of type 2 diabetes: multicentre, double blind, randomised, placebo controlled trial. The BMJ 2025; 388:e081820. DOI: https://doi.org/10.1136/bmj-2024-081820
2. Hope D, Valabhji J. SGLT2 inhibitors and dietary calorie restriction for type 2 diabetes remission (Editorial). The BMJ 2025; 388:r40. DOI: https://doi.org/10.1136/bmj.r40

 

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Review: Type 2 Myocardial Infarction

29 Jan, 2025 | 10:00h | UTC

Introduction: Type 2 myocardial infarction (MI) is defined by an imbalance in myocardial oxygen supply and demand without atherothrombosis, though it may involve non-atherothrombotic coronary pathologies (e.g., coronary embolism, vasospasm, spontaneous dissection). Challenges in diagnosis and treatment arise from its heterogeneous aetiologies (e.g., sepsis, hypoxia, arrhythmias, or coronary emboli) and frequent overlap with underlying coronary artery disease (CAD). No approaches to investigation or treatments have yet been shown to definitively improve outcomes, and most recommendations remain theoretical strategies in need of validation.

Key Recommendations:

1. Identify and Correct Underlying Triggers:
   • Recognize that Type 2 MI often occurs in the context of acute illness (e.g., sepsis, hypoxia, anemia, or tachyarrhythmias).
   • Address precipitating factors (e.g., treat infection, restore blood pressure, correct anemia) to reduce further myocardial ischemia.
2. Distinguish from Type 1 MI When Uncertain:
   • Use intracoronary imaging (OCT/IVUS) primarily to exclude plaque rupture or thrombosis if clinically indicated, especially when symptoms and ECG changes persist, recognizing that its utility in routine practice for Type 2 MI is not yet proven.
   • Carefully re-evaluate patients who remain unstable or have recurrent symptoms after correction of potential triggers, as up to 5% of cases may be reclassified as Type 1 MI.
3. Risk Stratification and Etiology-Specific Prognosis:
   • Evaluate the likelihood of obstructive coronary artery disease, which is present in ~68% of Type 2 MI cases (e.g., DEMAND-MI study), particularly in older patients or those with risk factors.
   • Perform echocardiography to identify left ventricular dysfunction or valvular abnormalities.
   • Recognize that patients with Type 2 MI due to hypoxia or anemia have approximately double the 1-year mortality risk compared to those with tachyarrhythmia-triggered events.
   • Note that cardiovascular event rates can be similar to those in Type 1 MI, suggesting that future risk is at least as high.
4. Consider Secondary Prevention in the Context of Limited Evidence:
   • If coronary atherosclerosis is confirmed, single antiplatelet therapy and high-intensity lipid-lowering therapy may be considered; however, there are no dedicated trials validating these approaches exclusively in Type 2 MI.
   • For patients with confirmed left ventricular dysfunction and signs of heart failure, adapt guideline-directed medical therapy carefully, paying close attention to hemodynamic stability.
5. Monitor Long-Term Outcomes and Address Comorbidities:
   • Recognize that patients with Type 2 MI have poor overall prognosis and high rates of non-cardiovascular mortality, yet they also face substantial cardiovascular risk.
   • Manage chronic comorbidities aggressively (e.g., hypertension, diabetes, dyslipidemia) to minimize recurrent ischemic events.
   • Follow up with echocardiographic or other imaging evaluations where indicated, particularly for patients whose clinical course suggests underlying structural disease.

Conclusion:
Type 2 MI presents significant challenges due to its heterogeneous subtypes (e.g., coronary embolism, spontaneous coronary artery dissection, systemic hypoxia) and frequent diagnostic reclassification. While evidence-based guidance remains limited and no proven interventions have definitively improved outcomes, thorough clinical assessment, targeted imaging to rule out Type 1 MI, and individualized management of comorbidities can potentially improve patient care in this complex condition.

Reference:
Chapman AR, Taggart C, Boeddinghaus J, Mills NL, Fox KAA. Type 2 myocardial infarction: challenges in diagnosis and treatment. European Heart Journal. Published 10 December 2024. DOI: https://doi.org/10.1093/eurheartj/ehae803

 

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RCT: Sodium Zirconium Cyclosilicate Improves Spironolactone Uptitration in HFrEF but Raises Concern for Increased HF Events

28 Jan, 2025 | 10:00h | UTC

Background: Hyperkalemia remains a major barrier to optimal use of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure and reduced ejection fraction (HFrEF). While MRAs significantly reduce morbidity and mortality, real-world data show that fears surrounding hyperkalemia often lead to MRA down-titration or discontinuation. Sodium zirconium cyclosilicate (SZC), a newer oral potassium binder, has shown promise in managing hyperkalemia. However, its impact on MRA optimization and clinical outcomes in HFrEF has not been fully established.

Objective: To determine whether SZC can enable optimal dosing of spironolactone (≥25 mg/day) by preventing hyperkalemia in patients with symptomatic HFrEF, and to assess potential effects on heart failure outcomes.

Methods: This prospective, double-blind, randomized-withdrawal trial (REALIZE-K) enrolled adult patients with left ventricular ejection fraction ≤40% (NYHA class II-IV), on guideline-directed medical therapy but not on a full-dose MRA due to either prevalent hyperkalemia (serum potassium [K⁺] 5.1-5.9 mEq/L) or high hyperkalemia risk. During an open-label run-in, spironolactone was up-titrated (target 50 mg/day), and participants with hyperkalemia received SZC. Only those who achieved normokalemia (3.5-5.0 mEq/L) on spironolactone ≥25 mg/day continued into a 6-month randomized-withdrawal phase (SZC vs placebo). The primary endpoint was maintenance of normokalemia while on ≥25 mg/day spironolactone without rescue therapy for hyperkalemia. Key secondary outcomes included the time to first hyperkalemia event, time to spironolactone dose reduction/discontinuation due to hyperkalemia, and changes in health-related quality of life (Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score).

Results: A total of 203 participants were randomized (SZC: n=102; placebo: n=101). SZC significantly increased the proportion of participants who maintained normokalemia on ≥25 mg/day spironolactone (71% vs 36%; OR: 4.45; 95% CI: 2.89-6.86; p<0.001). Rates of hyperkalemia were also lower with SZC (HR: 0.51; 95% CI: 0.37-0.71; p<0.001), and fewer patients required spironolactone down-titration or discontinuation (HR: 0.37; 95% CI: 0.17-0.73; p=0.006). There was no difference in KCCQ-Clinical Summary Score between groups (p=0.72). Notably, more participants in the SZC arm had adjudicated heart failure events (10 vs 2 in placebo) over the 6-month period, although the trial was not powered to detect differences in clinical outcomes.

Conclusions: In patients with symptomatic HFrEF and prevalent or incident hyperkalemia, sodium zirconium cyclosilicate (SZC) successfully enabled higher spironolactone doses by maintaining potassium levels in the normal range. However, the increased rate of heart failure (HF) events in the SZC group raises concern, particularly given the study’s limited power for clinical outcomes and baseline imbalances favoring higher HF risk in the SZC group (older age, lower eGFR, higher NT-proBNP). Although these findings do not establish a definitive causal relationship, they underscore a possible risk of fluid retention and the importance of cautious use in higher-risk populations. Larger, event-driven trials are crucial to confirm whether SZC-related sodium exchange may exacerbate HF decompensation despite the benefits of more effective MRA therapy.

Implications for Practice: SZC offers clinicians a means to sustain or escalate spironolactone dosing in hyperkalemia-prone HFrEF patients who would otherwise face MRA discontinuation. Still, the unexpected signal of increased HF events highlights the need for vigilant patient selection, fluid status monitoring, and regular follow-up. Clinicians should balance the advantages of maintaining guideline-recommended MRA doses against potential costs, the patient’s baseline HF severity, and possible sodium retention. Individualized care, particularly in older patients or those with high NT-proBNP levels, remains critical until more robust outcome data are available.

Study Strengths and Limitations: Strengths include strict definitions of hyperkalemia, a rigorous protocol for titrating spironolactone and SZC, and high rates of concurrent guideline-directed therapies. Limitations encompass the modest sample size, short follow-up period, and imbalance in baseline risk factors favoring the placebo group. Also, the study was not powered for major clinical events, limiting interpretability of the heart failure outcome signals.

Future Research: Further large-scale, long-term investigations are needed to clarify whether the higher incidence of HF events seen with SZC reflects underlying population differences or a genuine treatment-related risk. Such studies should prioritize hard clinical endpoints (eg, HF hospitalization, cardiovascular mortality), capture real-world tolerability data, and incorporate cost-effectiveness analyses. Research into the mechanisms of sodium exchange in compromised HF patients may also help identify subgroups that stand to gain the most from potassium-binding strategies or, conversely, experience undue risk.

Reference: Kosiborod MN, Cherney DZI, Desai AS, et al. “Sodium Zirconium Cyclosilicate for Management of Hyperkalemia During Spironolactone Optimization in Patients With Heart Failure.” Journal of the American College of Cardiology. 2025; DOI: https://doi.org/10.1016/j.jacc.2024.11.014

 

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Phase 2b RCT: Abelacimab Significantly Reduces Bleeding Events Compared with Rivaroxaban in Patients with Atrial Fibrillation

27 Jan, 2025 | 11:00h | UTC

Background: Atrial fibrillation (AF) elevates stroke risk roughly fivefold, necessitating anticoagulation therapy to reduce embolic events. Direct oral anticoagulants (DOACs) have replaced vitamin K antagonists as the preferred agents, given their comparable efficacy and lower risk of intracranial hemorrhage. However, significant bleeding—especially gastrointestinal bleeding—still occurs with DOACs, prompting ongoing efforts to develop safer anticoagulants. Abelacimab, a fully human monoclonal antibody targeting factor XI (and its active form, XIa), is hypothesized to “uncouple” thrombosis from hemostasis, potentially lowering bleeding risk. Early data in knee arthroplasty prevention suggested reduced venous thromboembolism (VTE) without increased bleeding. This trial (AZALEA–TIMI 71) aimed to compare the bleeding rates of monthly subcutaneous abelacimab with once-daily rivaroxaban in patients with AF and moderate-to-high stroke risk.

Objective: To evaluate whether subcutaneous abelacimab at two doses (150 mg or 90 mg monthly) leads to fewer major or clinically relevant nonmajor bleeding events than rivaroxaban (20 mg or 15 mg daily) in patients with AF.

Methods: In this phase 2b, parallel-group, partially blind, randomized trial, 1287 adults with AF (CHA2_22​DS2_22​-VASc ≥3–4 and moderate/high stroke risk) were assigned 1:1:1 to abelacimab 150 mg, abelacimab 90 mg, or open-label rivaroxaban. Treatment continued for a median of 2.1 years. The primary endpoint was major or clinically relevant nonmajor bleeding, adjudicated by a blinded events committee. Levels of free factor XI were measured to gauge abelacimab’s pharmacodynamics. The trial was halted early based on a recommendation from the independent data monitoring committee due to unexpectedly large reductions in bleeding with abelacimab.

Results: Median age was 74 years, and 44% of participants were female. In the final analysis of the complete dataset, major or clinically relevant nonmajor bleeding occurred at rates of 3.2 and 2.6 events per 100 person-years for abelacimab 150 mg and 90 mg, respectively, versus 8.4 per 100 person-years for rivaroxaban. Corresponding hazard ratios were 0.38 (95% CI, 0.24–0.60) for the 150-mg dose and 0.31 (95% CI, 0.19–0.51) for the 90-mg dose (P<0.001 for both comparisons). The incidence of major gastrointestinal bleeding was notably lower with abelacimab (0.5% in both arms) compared with rivaroxaban (4.2%). Although not powered for stroke prevention, ischemic stroke rates were numerically higher with abelacimab, underscoring the need for larger efficacy trials.

Conclusions: Monthly abelacimab led to substantial and sustained reduction of free factor XI and demonstrated significantly lower bleeding rates than rivaroxaban in patients with AF. While these findings suggest a potentially safer profile for abelacimab, definitive conclusions about stroke prevention require phase 3 studies.

Implications for Practice: Should abelacimab maintain efficacy in preventing thromboembolism in forthcoming trials, it may offer an alternative to existing DOACs, particularly for patients at elevated bleeding risk (e.g., gastrointestinal). However, clinicians must consider real-world factors such as possible high drug cost, insurance coverage, and the logistics of monthly subcutaneous injections. Abelacimab is investigational and not yet approved; its role will depend on phase 3 efficacy and cost-effectiveness outcomes.

Study Strengths and Limitations: Strengths include randomized design, relatively long follow-up (median 2.1 years), and direct comparison to an established DOAC. The major limitation is that the trial was not sufficiently powered to evaluate stroke or systemic embolism. Moreover, the open-label design between abelacimab and rivaroxaban could introduce bias, partly mitigated by blinded dose assignments for abelacimab and blinded endpoint adjudication. The predominantly White population may limit generalizability.

Future Research: Ongoing phase 3 studies (e.g., LILAC–TIMI 76) will clarify abelacimab’s efficacy and safety in larger cohorts, particularly regarding stroke prevention. Comparative cost analyses, real-world adherence, and exploration of subcutaneous administration logistics will be crucial in determining abelacimab’s long-term clinical value. Additional investigations into factor XIa inhibitors (e.g., small molecules, antisense oligonucleotides) may further expand this therapeutic class.

Reference:

1. Ruff CT, Patel SM, Giugliano RP, Morrow DA, Hug B, Kuder JF, et al. “Abelacimab versus Rivaroxaban in Patients with Atrial Fibrillation.” New England Journal of Medicine. 2025;392:361–371. DOI: https://doi.org/10.1056/NEJMoa2406674
2. Angiolillo DJ, Capodanno D. “Uncoupling Thrombosis and Hemostasis by Inhibiting Factor XI.” New England Journal of Medicine. 2025;392:400–403. DOI: https://doi.org/10.1056/NEJMe2414209
3. Mandrola JM. “Factor XI Inhibitors May Not Be Dead.” This Week in Cardiology Podcast. January 24, 2025. https://www.medscape.com/viewarticle/1002184#vp_3

 

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2024 VA/DOD Clinical Practice Guideline for Stroke Rehabilitation

26 Jan, 2025 | 17:07h | UTC

Introduction:
This document summarizes the updated 2024 clinical practice guideline (CPG) jointly developed by the U.S. Department of Veterans Affairs (VA) and the U.S. Department of Defense (DOD). It addresses stroke rehabilitation across inpatient, outpatient, and community settings, emphasizing an interdisciplinary approach. The main objective is to provide evidence-based recommendations to guide clinical decision-making and improve functional outcomes and quality of life for adult stroke survivors.

Key Recommendations:

1. Transition to Community
   • Case Management: Suggest using case management services at discharge to enhance activities of daily living (ADLs) and functional independence (“weak for”).
   • Behavioral/Psychosocial Interventions: Recommend psychosocial supports, such as stress management and motivational interviewing, to improve patient and caregiver depression, family function, and overall quality of life (“weak for”).
   • Psychoeducation: Encourage structured education on stroke care and self-management for patients and their caregivers to boost functional independence and social support.
2. Motor Therapy
   • Task-Specific Practice: Strongly recommend repetitive or task-oriented practice to improve motor function, gait, posture, and ADLs (“strong for”).
   • Mirror Therapy: Suggest mirror therapy to improve motor outcomes, ADLs, and unilateral spatial neglect (“weak for”).
   • Rhythmic Auditory Stimulation: Suggest adding external auditory cues (e.g., music or metronome) to assist in gait training (“weak for”).
   • Neuromuscular Electrical Stimulation: Suggest neuromuscular electrical stimulation for enhancing upper- or lower-extremity motor recovery (“weak for”).
   • Botulinum Toxin for Spasticity: Suggest botulinum toxin for focal spasticity, considering patient-specific characteristics and preferences, though evidence shows comparable efficacy to oral baclofen except in ankle spasticity (“weak for”).
3. Dysphagia, Aphasia, and Cognition
   • Dysphagia Rehabilitation:
     • Chin tuck against resistance for swallowing impairment (“weak for”).
     • Respiratory muscle strength training (for those without tracheostomy) to reduce aspiration risk (“weak for”).
   • Aphasia Rehabilitation:
     • No specific intensity level of language therapy is proven superior; tailor therapy duration and frequency to individual needs (“neither for nor against”).
   • Cognitive Outcomes:
     • Current evidence does not support or refute SSRIs for cognitive recovery; consider other individualized cognitive rehabilitation strategies (“neither for nor against”).
   • Unilateral Spatial Neglect:
     • Mirror therapy may help address neglect and improve ADLs (“weak for”).
4. Mental Health
   • Depression Treatment:
     • Suggest SSRIs or SNRIs for patients with established poststroke depression (“weak for”).
     • Recommend psychotherapy (e.g., cognitive behavioral therapy) and consider mindfulness-based therapies for depression following stroke (“weak for”).
   • Prevention of Depression:
     • Suggest against prophylactic antidepressants for preventing poststroke depression due to risk of adverse effects, such as fractures (“weak against”).
5. Telehealth
   • Consider telerehabilitation as an alternative or adjunct to in-person therapy if it aligns with patient preferences and clinical feasibility (“weak for”).
   • Evidence is inconclusive regarding telerehabilitation for dysphagia, aphasia, or caregiver support; use individualized judgment (“neither for nor against”).
6. Noninvasive Brain Stimulation
   • Insufficient evidence to recommend for or against repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), or continuous theta burst stimulation to enhance motor recovery (“neither for nor against”).

Conclusion:
These updated 2024 VA/DOD stroke rehabilitation guidelines underscore the importance of an interdisciplinary and patient-centered approach that integrates medical, psychological, and rehabilitative strategies. Adopting these recommendations—particularly around early case management, targeted motor therapies (task-specific practice, mirror therapy, neuromuscular electrical stimulation), dysphagia interventions, and tailored mental health treatments—can improve functional outcomes, optimize quality of life, and reduce poststroke morbidity.

Reference:

• Eapen BC, Tran J, Ballard-Hernandez J, et al. Stroke Rehabilitation: Synopsis of the 2024 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guidelines. Annals of Internal Medicine. 2025. DOI: https://doi.org/10.7326/ANNALS-24-02205
• Cramer SC. Moving Stroke Rehabilitation Forward and Into the Future. Annals of Internal Medicine. 2025. DOI: https://doi.org/10.7326/ANNALS-24-03568

 

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Multidrug-resistant Gram-negative bacterial infections: Key Updates and Practical Strategies

25 Jan, 2025 | 22:53h | UTC

Introduction: This summary highlights essential points from a recent review in The Lancet addressing multidrug-resistant Gram-negative bacterial (MDR-GNB) infections. It discusses the global epidemiology, diagnostic advances, and therapeutic approaches, aiming to guide clinicians in managing these difficult-to-treat pathogens, which include resistant Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii.

Key Recommendations:

1. Use Rapid Diagnostics to Guide Therapy
   • Employ molecular tests (e.g., multiplex PCR) to detect resistance genes quickly and facilitate targeted treatment.
   • Consider phenotypic assays (e.g., CarbaNP, carbapenemase inactivation method) and MALDI-TOF for rapid organism identification and mechanism-specific information.
2. Optimize Antibiotic Selection Based on Resistance Mechanisms
   • AmpC-Producing Enterobacterales (e.g., Enterobacter spp.): Use cefepime if in vitro susceptibility is confirmed.
   • ESBL-Producing Enterobacterales: Carbapenems (e.g., meropenem) remain the mainstay for serious infections.
   • Carbapenem-Resistant Enterobacterales (CRE): Use novel β-lactam/β-lactamase inhibitor agents (e.g., ceftazidime–avibactam, meropenem–vaborbactam, imipenem–relebactam) based on specific carbapenemase mechanisms. For metallo-β-lactamase producers, consider aztreonam plus ceftazidime–avibactam or future co-formulations (e.g., aztreonam–avibactam).
   • DTR-Pseudomonas aeruginosa: Ceftolozane–tazobactam is preferred if active in vitro. Ceftazidime–avibactam or imipenem–relebactam may also be options depending on local susceptibility data.
   • Carbapenem-Resistant Acinetobacter baumannii (CRAB): High-dose sulbactam combinations (e.g., sulbactam–durlobactam) were studied in combination with imipenem–cilastatin during trials; further data are needed to clarify optimal clinical use.
3. Consider Non-Antibiotic Modalities for Refractory Cases
   • Investigational therapies—such as bacteriophages and antivirulence agents—are under clinical evaluation.
   • Fecal microbiota transplantation has shown variable decolonization efficacy in small studies, and randomized trials have yielded limited or inconclusive results.
4. Emphasize Antimicrobial Stewardship and Infection Control
   • Restrict newer agents to cases where standard treatments have failed or resistance patterns require them.
   • Maintain rigorous infection control practices (e.g., contact precautions, hand hygiene, isolation measures) to reduce nosocomial spread of MDR-GNB.
   • Observational data suggest shorter antibiotic courses (7–10 days) might be adequate in select cases, but robust clinical trial evidence is still pending.

Conclusion:
By combining rapid diagnostics, judicious use of existing and novel antibiotics, and robust infection prevention measures, clinicians can significantly improve outcomes for patients with MDR-GNB infections. However, access to advanced diagnostics and new therapies remains limited in many regions, and further clinical trials are needed to determine optimal treatment and duration strategies. Early mechanism-focused detection and targeted therapy enhance clinical success, reduce toxicity, and help preserve the efficacy of newly approved agents.

Reference:
Macesic N, Uhlemann A-C, Peleg AY. Multidrug-resistant Gram-negative bacterial infections. The Lancet. 2025;405(10474):257-272. DOI: https://doi.org/10.1016/S0140-6736(24)02081-6

 

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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

 

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2024 ACC/AHA Guideline for the Management of Lower Extremity Peripheral Artery Disease

21 Jan, 2025 | 12:44h | UTC

Introduction:
This summary highlights key points from the 2024 ACC/AHA guideline on managing patients with lower extremity peripheral artery disease (PAD). It addresses diagnosis, risk stratification, and treatment strategies to reduce major adverse cardiovascular events (MACE) and major adverse limb events (MALE), focusing on four clinical subsets of PAD—asymptomatic PAD, chronic symptomatic PAD, chronic limb-threatening ischemia (CLTI), and acute limb ischemia (ALI). Its overarching goal is to optimize cardiovascular risk reduction, preserve limb function, and improve quality of life (QOL).

Key Recommendations:

1. Clinical Assessment and Diagnosis
   • Perform a thorough history and physical examination in patients at risk of PAD (e.g., older adults, those with diabetes, hypertension, dyslipidemia, smokers, or known atherosclerosis).
   • Measure the ankle-brachial index (ABI) to establish the diagnosis of PAD; use toe-brachial index (TBI) for patients with noncompressible arteries.
   • Obtain imaging (e.g., duplex ultrasound, CT angiography, MR angiography) when planning revascularization or in cases with inconclusive ABI.
2. Risk Factor Management (Guideline-Directed Medical Therapy)
   • Antiplatelet and Antithrombotic Therapy:
     • Recommend single antiplatelet therapy (e.g., aspirin or clopidogrel) for symptomatic PAD to reduce MACE.
     • Consider low-dose rivaroxaban (2.5 mg twice daily) plus low-dose aspirin in patients at low bleeding risk to reduce MALE.
   • Lipid-Lowering Therapy:
     • Initiate high-intensity statin therapy in all patients with PAD to reduce cardiovascular and limb events.
     • Add ezetimibe or a PCSK9 inhibitor if LDL-C levels remain above target (≥70 mg/dL).
   • Blood Pressure Control:
     • Target a systolic blood pressure <130 mm Hg in patients with PAD; ACE inhibitors or angiotensin-receptor blockers can further reduce cardiovascular risk.
   • Diabetes Management:
     • Optimize glycemic control, especially in CLTI; newer agents (e.g., SGLT2 inhibitors, GLP-1 receptor agonists) can reduce cardiovascular risk in PAD with type 2 diabetes.
   • Smoking Cessation:
     • Strongly advise cessation of all forms of tobacco and nicotine; offer pharmacotherapy (e.g., varenicline, bupropion, nicotine replacement) and behavioral counseling.
3. Exercise Therapy
   • Supervised Exercise Therapy (SET):
     • A cornerstone of care for patients with claudication to improve walking performance and quality of life.
     • Generally performed 3 times per week for at least 12 weeks in a supervised setting (e.g., cardiac rehab facility).
   • Structured Community-Based (Home-Based) Programs:
     • Include regularly prescribed walking regimens, with periodic clinical follow-up and coaching to promote adherence.
4. Revascularization for Chronic Symptomatic PAD
   • Initial Approach:
     • Offer revascularization (endovascular, surgical, or hybrid) if patients have functionally limiting claudication that fails to improve with medical therapy and structured exercise.
   • Endovascular vs. Surgical:
     • Select a strategy based on lesion characteristics, availability of adequate vein conduit, and patient comorbidities.
     • Combining revascularization with supervised exercise generally yields better functional outcomes.
   • Common Femoral Disease:
     • Surgical endarterectomy remains a highly durable option.
     • Endovascular approaches can be considered for select cases, particularly where surgical risk is high or anatomy is favorable.
5. Management of Chronic Limb-Threatening Ischemia (CLTI)
   • Team-Based Care:
     • Collaborate with vascular specialists, podiatrists, wound-care experts, and other clinicians for optimal outcomes.
   • Revascularization Goals:
     • Prevent amputation, heal wounds, and reduce rest pain.
     • Both endovascular and surgical methods can be effective; selection depends on anatomy, available vein conduit, and patient risk profile (e.g., the BEST-CLI and BASIL-2 trials guide decisions).
   • Adjunctive Wound Care:
     • Use local wound management (e.g., debridement, negative pressure therapy, offloading) to facilitate healing.
     • Treat infection aggressively; urgent revascularization plus antibiotics is essential.
   • Pressure Offloading:
     • Custom footwear and casts/shoes reduce plantar pressure and help prevent or heal foot ulcers.
6. Acute Limb Ischemia (ALI)
   • Immediate Recognition:
     • Suspect ALI in patients with sudden onset of pain, pallor, pulselessness, paresthesia, and paralysis.
     • Determine limb viability (categories I–III) rapidly.
   • Treatment:
     • Begin anticoagulation (e.g., IV unfractionated heparin) unless contraindicated.
     • Urgent revascularization (surgical embolectomy, catheter-directed thrombolysis, or mechanical thrombectomy) for salvageable limbs.
     • Monitor for compartment syndrome and consider fasciotomy if needed.
7. Preventive Foot Care
   • Educate patients on self-inspection, daily hygiene, and protective footwear.
   • Screen regularly for high-risk conditions (neuropathy, calluses, deformities, infection).
   • Promptly address any foot lesions to avoid progression to ulceration, infection, or gangrene.
8. Longitudinal Follow-Up
   • Schedule regular visits to monitor:
     • Cardiovascular risk factor control (lipids, blood pressure, glycemic targets, smoking).
     • Lower extremity symptoms, functional status, and foot health.
     • Need for repeat ABI, duplex ultrasound, or imaging after revascularization to detect restenosis.
   • Reinforce adherence to structured exercise, medication regimens, and foot care strategies.

Conclusion:
These recommendations underscore the importance of personalized, multidisciplinary care that addresses both cardiovascular and limb-related outcomes in patients with lower extremity PAD. A combination of comprehensive risk-factor modification, supervised or structured exercise programs, and strategic use of revascularization can significantly reduce the risk of major limb loss, improve symptoms, and enhance QOL. Ongoing follow-up is critical to detect disease progression, optimize therapy, and maintain patient engagement in preventative care.

Reference:
2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2024; DOI: https://doi.org/10.1161/CIR.0000000000001251

 

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Management of Cervical Artery Dissection: Key Points From the AHA Scientific Statement

21 Jan, 2025 | 11:05h | UTC

Introduction:
This document summarizes the American Heart Association (AHA) scientific statement on cervical artery dissection (CAD), an important cause of ischemic stroke, especially in younger and middle-aged adults. Cervical artery dissection often presents with nonspecific symptoms—such as headache, neck pain, or partial Horner syndrome—but can lead to serious neurological deficits. Early recognition, targeted imaging, appropriate acute treatment, and well-informed decisions on antithrombotic therapy are essential to optimize patient outcomes.

Key Recommendations:

• Epidemiology and Risk Factors
  • CAD accounts for up to 25% of ischemic strokes in adults under 50 years of age, with a slightly higher incidence in men but lower peak age in women.
  • Risk factors include genetic predispositions (eg, connective tissue disorders), anatomic variants (elongated styloid process, vascular tortuosity), minor cervical trauma, and comorbidities such as hypertension or fibromuscular dysplasia.
• Diagnosis and Imaging
  1. Clinical Suspicion
     • Suspect CAD in younger adults with new or worsening neck pain, headache, pulsatile tinnitus, partial Horner syndrome, or cranial nerve involvement, especially if there is a history of recent minor neck trauma or manipulation.
     • Up to 8%–12% of patients may have isolated neck or head pain with no initial ischemic signs.
  2. Imaging Modalities
     • Magnetic Resonance Imaging (MRI)/Magnetic Resonance Angiography (MRA): High-resolution, fat-suppressed T1-weighted sequences are useful for detecting intramural hematoma.
     • Computed Tomography Angiography (CTA): Good sensitivity and specificity for luminal abnormalities and can detect intraluminal thrombus. Avoid false positives by distinguishing imaging artifacts from true double lumens or intimal flaps.
     • Conventional Digital Subtraction Angiography (DSA): Historically the gold standard but reserved for equivocal cases because of procedure-related risks (eg, iatrogenic dissection).
     • Ultrasound with Color Doppler: Operator-dependent but helpful for serial follow-up of vessel remodeling.
  3. Additional Diagnostic Testing
     • Connective Tissue Disorders: Consider genetic counseling if physical exam, family history, or recurrent dissections suggest a monogenic disorder (eg, vascular Ehlers-Danlos).
     • Screening for Fibromuscular Dysplasia (FMD): Patients with CAD, especially those with hypertension or evidence of FMD in other vascular beds, may warrant renal artery imaging.
     • Aortic and Intracranial Imaging: Aortic root dilation and cerebral aneurysms may be more prevalent in CAD; consider advanced imaging (eg, MRA) based on clinical judgment.
• Hyperacute and Acute Stroke Management
  1. Intravenous Thrombolysis (IVT):
     • IVT (alteplase or tenecteplase) remains reasonable for otherwise eligible acute ischemic stroke patients, with no specific evidence of higher hemorrhagic risk in CAD. Caution is advised if there is intracranial extension of the dissection or other significant bleeding risk factors.
  2. Mechanical Thrombectomy:
     • Recommended for large-vessel occlusion in CAD patients who meet standard thrombectomy criteria. Tandem lesions (extracranial dissection and intracranial occlusion) can be addressed via retrograde (intracranial first) or antegrade (extracranial first) approach, with similar overall outcomes reported.
  3. Acute or Subacute Stenting:
     • May be considered in selected cases of severe flow-limiting stenosis leading to distal hypoperfusion or in persistent ischemia despite optimal medical therapy. Stenting in tandem occlusions can improve reperfusion but carries added risks (in-stent restenosis, stent thrombosis, or need for dual antiplatelet therapy).
• Antithrombotic Therapy for Secondary Stroke Prevention
  1. Rationale for Early Treatment:
     • Artery-to-artery embolization underpins most CAD-related ischemic events. Early initiation of antithrombotics (ideally within the first 24–72 hours) reduces further embolic risk.
  2. Choice of Agent: Antiplatelet vs Anticoagulant
     • When to Prefer Anticoagulation:
       • Patients with high-risk imaging features: severe stenosis (>50%–70%), intraluminal thrombus, occlusion, multiple or early recurrent dissections.
       • Traditional option is heparin bridging to Vitamin K antagonist (target INR ≈2–3), but direct oral anticoagulants (DOACs) can be considered based on patient profile and preference.
     • When to Prefer Antiplatelet Therapy:
       • Patients with lower stroke risk (no significant stenosis, no intraluminal thrombus) or higher bleeding risk (large infarct, hemorrhagic transformation, intradural extension).
       • Aspirin monotherapy is typical; a short course of dual antiplatelet therapy (aspirin + clopidogrel) for 21–90 days can be considered if minor stroke/TIA criteria apply and bleeding risk is acceptable.
  3. Practical Start-Up and Monitoring:
     • Begin therapy as soon as deemed safe, ideally after hemorrhagic complications are excluded.
     • For VKA: bridge with heparin (IV unfractionated or low–molecular-weight) for at least 5 days until INR is therapeutic for ≥24 hours.
     • Regularly monitor clinical response and, if relevant, INR in anticoagulated patients.
  4. Duration of Therapy:
     • Minimum 3–6 months of antithrombotics, with vessel imaging at follow-up (eg, 3 or 6 months) to assess for healing or persistent dissection.
     • Decisions to extend antithrombotic therapy past the 6-month mark may be considered in the context of an individual’s overall vascular risk factor profile and in the context of neuroimaging features as remodeling occurs.
     • Consider extended or indefinite therapy (often antiplatelet) if persistent stenosis, high-risk anatomic factors, or recurrent dissections occur.
• Risk of Recurrent Dissection and Lifestyle Precautions
  • Recurrence rates range from 1% to 2% per year but are higher in the first few months post-dissection. Fibromuscular dysplasia and younger age are associated with increased recurrence risk.
  • It is reasonable to advise patients to avoid high-risk neck activities (eg, contact sports, extreme neck manipulation) for 1–6 months or until imaging confirms vessel healing. In those with a known connective tissue disorder or recurrent dissection, lifelong caution is appropriate.
• Follow-Up Imaging and Management of Dissecting Aneurysms
  • Recanalization most often occurs by 6–12 months; persistent occlusions or stenoses beyond 12 months rarely recanalize further.
  • Dissecting aneurysms form or enlarge in some cases but seldom rupture. Antithrombotic choice does not appear to affect aneurysm resolution rates.
  • Endovascular or surgical interventions are reserved for enlarging or symptomatic aneurysms causing compression or other complications.

Conclusion: Cervical artery dissection warrants vigilant clinical recognition, prompt imaging, and individualized treatment strategies. Early antithrombotic therapy—whether anticoagulation or antiplatelet—plays a critical role in preventing stroke. Decisions should reflect both the patient’s hemorrhagic risk and the presence of imaging features predictive of stroke. Mechanical thrombectomy and, in selected cases, stenting are viable acute interventions for high-risk presentations. Although recurrences are uncommon, thoughtful follow-up imaging, patient education, and avoidance of high-risk neck activities are central to minimizing future dissections and optimizing outcomes.

Reference: Yaghi S, Engelter S, Del Brutto VJ, Field TS, Jadhav AP, Kicielinski K, Madsen TE, Mistry EA, Salehi Omran S, Pandey A, Raz E, on behalf of the American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; and Council on Peripheral Vascular Disease. Treatment and Outcomes of Cervical Artery Dissection in Adults: A Scientific Statement From the American Heart Association. Stroke. 2024;55(3). DOI: https://doi.org/10.1161/STR.0000000000000457

 

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Pseudo-Endocrine Disorders: Clinical Realities and Responsible Management

20 Jan, 2025 | 11:42h | UTC

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Network Meta-analysis: Oseltamivir Fails to Improve Key Outcomes in Nonsevere Influenza

20 Jan, 2025 | 11:17h | UTC

Background: Influenza causes significant respiratory morbidity and can lead to severe complications, especially in high-risk individuals. Current guidelines endorse antiviral therapy, yet the evidence for reducing mortality, hospital admission, and symptom duration in nonsevere cases remains controversial. Recent recommendations have often focused on neuraminidase inhibitors (e.g., oseltamivir), despite uncertainties regarding clinical impact and adverse effects. An editorial accompanying this study underscores the need to reexamine routine antiviral use, especially oseltamivir, given minimal benefit observed in outpatient populations.

Objective: To assess and compare the efficacy and safety of direct-acting antiviral medications (baloxavir, oseltamivir, laninamivir, zanamivir, peramivir, umifenovir, favipiravir, and amantadine) in treating patients with nonsevere influenza.

Methods: This systematic review and network meta-analysis included 73 randomized clinical trials (N=34,332) that evaluated antivirals vs placebo, standard care, or another antiviral. Eligible studies enrolled nonhospitalized patients with confirmed or suspected influenza. Outcomes included mortality, hospital admission, time to symptom alleviation, adverse events, and emergence of antiviral resistance. Risk of bias was assessed with a modified Cochrane tool, and the certainty of evidence was rated using the GRADE approach. Pooled estimates were generated with a frequentist random-effects model, focusing on both absolute risk differences and relative measures.

Results:

• Mortality: Across all antiviral agents, there was high-certainty evidence of little or no effect on mortality in both low-risk and high-risk patients compared with standard care or placebo.
• Hospital Admission: In low-risk patients, none of the antivirals significantly altered admission rates (high certainty). In high-risk patients, oseltamivir had little or no effect on hospitalization (high certainty), whereas baloxavir may reduce admissions (low certainty).
• Time to Alleviation of Symptoms: Baloxavir shortened symptom duration by approximately one day (moderate certainty) without increasing adverse events. Oseltamivir and zanamivir likely produced smaller decreases (<1 day; moderate certainty). Umifenovir may also shorten symptoms (low certainty).
• Adverse Events: Baloxavir did not increase treatment-related adverse events (high certainty) but may lead to viral resistance in around 10% of cases (low certainty). Oseltamivir probably increases adverse events such as nausea and vomiting (moderate certainty).
• Serious Outcomes (ICU Admission, Duration of Hospitalization): Data were limited, with uncertainty regarding meaningful reductions in these measures.

Conclusions: Baloxavir may reduce hospital admissions for high-risk patients and significantly shorten symptom duration without notable treatment-related adverse events. Oseltamivir shows little effect on mortality or hospitalization for nonsevere influenza, with only modest (likely not clinically important) reductions in symptom duration and a higher rate of adverse events. Other antivirals either demonstrate uncertain clinical benefits or likely provide no major advantages in this patient population.

Implications for Practice: These findings suggest that routine use of oseltamivir for outpatients with nonsevere influenza should be reconsidered, especially in low-risk groups. Baloxavir appears favorable for high-risk patients, though clinicians should monitor potential drug resistance. Given the minimal impact on major outcomes and the cost considerations, prescribers should weigh the benefits and harms of these antivirals, aligning treatment decisions with patient risk profiles and clinical judgment.

Study Strengths and Limitations: Strengths include a comprehensive search, large pooled population, and rigorous GRADE-based analysis of certainty. Limitations involve low event rates for hospital admissions and mortality, limiting power for certain outcomes, and sparse data on some antivirals (e.g., amantadine). Additionally, few trials reported ICU admissions or mechanical ventilation needs, restricting conclusions about severe complications.

Future Research: Further high-quality studies should evaluate patient-important outcomes such as mechanical ventilation and severe complications in diverse populations. Investigations into combination strategies, alternative dosing, and resistance patterns would help clarify the long-term viability of baloxavir and other antivirals, particularly in high-risk cohorts.

Reference:

1. Gao Y, Zhao Y, Liu M, et al. Antiviral Medications for Treatment of Nonsevere Influenza: A Systematic Review and Network Meta-Analysis. JAMA Internal Medicine. Published online January 13, 2025. DOI: http://doi.org/10.1001/jamainternmed.2024.7193
2. Baghdadi JD, Grady D, Morgan DJ. The Limited Role for Antiviral Therapy in Influenza. JAMA Internal Medicine. Published online January 13, 2025. DOI: http://doi.org/10.1001/jamainternmed.2024.7258

 

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Network Meta-Analysis: Distinct Benefit–Risk Profiles of GLP-1 Receptor Agonists, DPP-4 Inhibitors, and SGLT2 Inhibitors

19 Jan, 2025 | 12:27h | UTC

Background: Type 2 diabetes (T2D) is a global health challenge due to its high prevalence and associated risks for cardiovascular (CV) and renal complications. Newer glucose-lowering drug (GLD) classes—dipeptidyl peptidase 4 inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium-glucose cotransporter 2 inhibitors (SGLT2i)—offer unique benefits and safety profiles. Although many large randomized outcome trials have demonstrated their efficacy, the benefit–risk balance among these agents remains incompletely understood, especially regarding non-traditional outcomes such as psychiatric disorders and neurodegenerative diseases. Given their generally higher costs and frequent industry sponsorship of the trials, it is critical to evaluate these classes in a systematic and impartial manner.

Objective: To systematically compare the benefits and risks of DPP4i, GLP-1RAs, and SGLT2i in adults with T2D, heart failure, or chronic kidney disease, focusing on 21 outcomes spanning macrovascular and microvascular events, infections, psychiatric outcomes, and cancer risk.

Methods: Researchers searched PubMed, Embase, and CENTRAL through November 2023 for randomized placebo-controlled cardiovascular and kidney outcome trials of DPP4i, GLP-1RAs, or SGLT2i in adults with T2D, heart failure, or chronic kidney disease. Twenty-six trials (N=198,177 participants) met inclusion criteria. A novel PAtient-centered treatment ranking via Large-scale Multivariate network meta-analysis (PALM) approach was used to synthesize population-averaged odds ratios (ORs) with 95% confidence intervals (CIs). This approach allowed for the simultaneous evaluation of multiple outcomes and the generation of weighted origami plots to visualize treatment rankings across different disease categories. Heterogeneity (I²) and publication bias (Egger’s test) were also assessed.

Results:

• Macrovascular: GLP-1RAs reduced major adverse cardiovascular events (MACE) versus placebo (OR 0.85, 95% CI 0.79–0.92) and DPP4i. GLP-1RAs also lowered stroke risk (OR range 0.82–0.85 vs comparators). SGLT2i yielded the largest reduction in hospitalization for heart failure (OR 0.68, 95% CI 0.64–0.73 vs placebo). DPP4i had a lower amputation risk relative to SGLT2i (OR 0.85, 95% CI 0.75–0.95).
• Microvascular: SGLT2i most effectively reduced renal composite outcomes versus DPP4i and placebo (OR ~0.67). However, DPP4i was linked to higher neuropathy risk (OR 1.10, 95% CI 1.02–1.18 vs placebo).
• Psychiatric and Neurodegenerative: DPP4i was associated with a reduced risk of depression, suicide, and alcohol use disorder compared to placebo. A lower Parkinson’s disease risk (OR 0.54, 95% CI 0.32–0.92) was also noted. GLP-1RAs showed a possible increased risk of suicidal ideation vs DPP4i, though evidence remains inconclusive.
• Infections/Inflammation: SGLT2i substantially increased genital infections (OR 3.11, 95% CI 2.15–4.50 vs placebo). DPP4i had higher pancreatitis risk vs all comparators.
• Cancer: GLP-1RAs were linked to increased thyroid cancer risk (OR range 1.58–2.70), though overall cancer risk and pancreatic cancer did not differ significantly across treatments.

Conclusions: Each newer GLD class offers specific advantages along with distinct safety considerations. GLP-1RAs appear particularly effective for macrovascular endpoints but carry a signal for thyroid malignancy. SGLT2i provide notable cardioprotective and renoprotective effects, offset by risk of genital infections and an increased risk of amputation compared to DPP4i. DPP4i tend to have neutral CV/renal outcomes yet may protect against certain psychiatric issues and neurodegenerative conditions, balanced by increased pancreatitis risk. Personalized treatment strategies, with attention to comorbidities and adverse event profiles, remain essential—particularly given the generally elevated costs of these newer agents. It is important to note that these findings are largely based on indirect comparisons in the absence of head-to-head trials, which is a limitation.

Implications for Practice: Clinicians should weigh cardiovascular risk, kidney function, mental health status, and potential malignancy when prescribing GLDs. SGLT2i may be favored in patients with heart failure or chronic kidney disease, while GLP-1RAs may be ideal for those with high atherosclerotic CV risk. DPP4i could be considered in patients with psychiatric or neurologic comorbidities but require caution regarding pancreatitis. Cost considerations and access may also influence real-world use.

Study Strengths and Limitations: Strengths include a large number of participants, broad outcome coverage, and a multivariate network meta-analysis that accommodates indirect comparisons. Limitations arise from underreported outcomes (e.g., psychiatric, neurodegenerative), heterogeneous trial populations, potential publication bias for some outcomes, and possible off-target influences not fully captured. Furthermore, sponsor involvement in all included trials warrants cautious interpretation of benefit–risk claims.

Future Research: Head-to-head trials comparing newer GLDs for psychiatric and neurologic endpoints, along with detailed reporting of rare adverse events (e.g., pancreatitis, cancer subtypes), are needed. Studies on real-world cost-effectiveness and access issues could clarify how to optimize therapy in routine practice. Additional investigations into long-term safety signals (including suicidality and thyroid malignancies) would further guide clinical decision-making.

Reference: Tang H, Zhang B, Lu Y, Donahoo WT, Singh Ospina N, Kotecha P, Lu Y, Tong J, Smith SM, et al. “Assessing the benefit–risk profile of newer glucose-lowering drugs: A systematic review and network meta-analysis of randomized outcome trials.” Diabetes, Obesity and Metabolism. First published: 26 December 2024. DOI: http://doi.org/10.1111/dom.16147

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Review: Identification and Treatment of Alcohol Use Disorder

19 Jan, 2025 | 11:41h | UTC

Introduction: This summary provides key insights from a comprehensive review published in the New England Journal of Medicine about the clinical identification and management of alcohol use disorder (AUD). The document highlights AUD’s chronic, relapsing course, its underdiagnosis in general practice, and its wide-ranging health and social impacts. Emphasis is placed on early recognition, the importance of nonjudgmental communication, and the potential for effective treatment across various medical settings.

Key Recommendations:

• Routine Screening and Assessment: Clinicians should routinely ask about alcohol use, employing validated tools (e.g., AUDIT, AUDIT-C, or CAGE) to gauge risk. When self-reporting is unreliable, biologic markers (e.g., γ-glutamyl transpeptidase or phosphatidylethanol) can help detect recent or chronic use.
• Nonjudgmental, Patient-Centered Approach: Engagement improves when patients feel supported rather than stigmatized. Collaboration in care planning can enhance adherence, especially for individuals who are ambivalent about changing their alcohol consumption patterns.
• Brief Interventions: Time-limited counseling, guided by motivational interviewing principles, is effective in reducing alcohol use. These interventions can be delivered by primary care professionals and may motivate further treatment or pharmacotherapy.
• Psychosocial Therapies: Multiple methods—including cognitive behavioral therapy, motivational enhancement, acceptance and commitment therapy, and peer-supported programs (e.g., Alcoholics Anonymous, SMART Recovery)—offer benefit. Clinicians are encouraged to adapt and integrate these treatments based on availability, patient preference, and severity of dependence.
• Pharmacologic Treatment: Medications such as naltrexone (once daily), acamprosate (three times daily), and supervised disulfiram are approved and effective for AUD. Naltrexone helps reduce craving and heavy drinking; acamprosate supports abstinence; and disulfiram, though aversive if alcohol is consumed, can reinforce abstinence in motivated patients. Other agents (e.g., topiramate, gabapentin) show promise but are not universally approved.
• Management of Withdrawal: Outpatient or inpatient treatment of withdrawal depends on clinical stability and coexisting conditions. Benzodiazepines remain first-line for symptom control, with close monitoring to prevent complications like seizures and delirium tremens. Nutritional support, particularly thiamine replacement, is essential to avert Wernicke–Korsakoff syndrome.
• Addressing Coexisting Conditions: AUD commonly co-occurs with mental health disorders (e.g., depression, anxiety) and other substance use (especially tobacco). Screening for suicidality and referring for specialized care can improve overall outcomes. Medical complications (e.g., alcoholic liver disease, hypertension) may also improve with sustained alcohol reduction or abstinence.
• Ongoing Support and Follow-up: AUD has a relapsing course, so long-term care, repeated assessments, and revisiting treatment goals are crucial. Follow-up visits can reinforce progress, manage relapses, and promote sustained recovery efforts.

Conclusion: Recognizing and treating alcohol use disorder significantly improves patient outcomes in both physical and mental domains. Generalist clinicians play a pivotal role in screening, initiating brief interventions, and coordinating care. Timely, evidence-based interventions and a supportive, empathetic stance can reduce the immense burden of AUD, enhance treatment retention, and improve quality of life for affected individuals.

Reference: Haber PS. Identification and Treatment of Alcohol Use Disorder. New England Journal of Medicine. 2025;392:258-266. DOI: http://doi.org/10.1056/NEJMra2306511

 

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RCT: Infrequent Zoledronate Infusions Reduce Vertebral Fractures in Early Postmenopausal Women Without Osteoporosis

18 Jan, 2025 | 16:48h | UTC

Background: Osteoporosis prevention typically targets older, higher-risk populations with significantly reduced bone mineral density (BMD). However, many fragility fractures occur in women who do not meet the traditional diagnostic threshold for osteoporosis (T score ≤ –2.5). This study investigated whether infrequent administration of zoledronate could prevent vertebral fractures in early postmenopausal women (50 to 60 years of age) who have BMD values between normal and osteoporotic ranges.

Objective: To determine if administering intravenous zoledronate once at baseline—and again 5 years later—could reduce the incidence of morphometric vertebral fractures and other fracture types over a 10-year period in early postmenopausal women without osteoporosis.

Methods:

• Design: A 10-year, prospective, double-blind, randomized, placebo-controlled trial.
• Population: 1054 women (mean age 56.0) within 10 years post-menopause, with lumbar spine or hip T scores <0 but >–2.5, recruited from the electoral roll in Auckland, New Zealand.
• Interventions: Participants were randomly assigned (1:1:1) to receive:
  1. Zoledronate 5 mg at baseline and again at Year 5 (zoledronate–zoledronate)
  2. Zoledronate 5 mg at baseline and placebo at Year 5 (zoledronate–placebo)
  3. Placebo infusions at baseline and Year 5 (placebo–placebo)
• Follow-up: 10 years, with repeated BMD and spine X-ray assessments at baseline, Year 5, and Year 10.
• Primary Endpoint: Incidence of new morphometric vertebral fractures, defined by semiquantitative radiographic methods.
• Secondary Endpoints: Fragility fracture, any fracture, major osteoporotic fracture, changes in BMD, and bone-turnover markers.

Results:

• Vertebral Fractures: Over 10 years, 6.3% of participants in the zoledronate–zoledronate group and 6.6% in the zoledronate–placebo group experienced a new morphometric vertebral fracture, versus 11.1% in placebo–placebo. After imputation, the relative risks versus placebo–placebo were 0.56 (95% CI, 0.34–0.92; p=0.04) and 0.59 (95% CI, 0.36–0.97; p=0.08), respectively.
• Other Fractures: The zoledronate–zoledronate group had a 30% reduced risk of any fracture (RR, 0.70; 95% CI, 0.56–0.88), and zoledronate–placebo showed a 23% reduction (RR, 0.77; 95% CI, 0.62–0.97), both compared with placebo–placebo.
• Bone Mineral Density: At Year 10, the zoledronate–zoledronate group had sustained BMD gains (~7–9 percentage points above placebo), whereas the zoledronate–placebo group retained a moderate advantage (~5–6 percentage points above placebo).
• Bone-Turnover Markers: Markers remained suppressed in the zoledronate–zoledronate group through Year 10, while in the zoledronate–placebo group, they gradually rose after Year 5 but stayed below baseline levels.
• Safety: Few adverse events were reported. Uveitis or episcleritis after the first infusion occurred in 1.1% of zoledronate recipients. No cases of osteonecrosis of the jaw or atypical femoral fractures were observed.

Conclusions: A single 5-mg dose of zoledronate, with an optional additional dose at five years, reduced the incidence of morphometric vertebral fractures and helped preserve BMD in younger postmenopausal women without osteoporosis. Both zoledronate regimens showed notable fracture-risk reductions and sustained effects on bone turnover.

Implications for Practice: These findings extend the potential role of zoledronate in fracture prevention to younger, early postmenopausal women without osteoporosis. Infrequent infusions are attractive because of their prolonged pharmacologic action and generally favorable safety profile. However, caution is warranted before broadly implementing this strategy for all postmenopausal women, as the data come from a relatively homogenous population and do not address other risk factors or comorbidities. Real-world adherence, healthcare resource allocation, and patient preferences must all be considered. Moreover, further evaluation of cost-effectiveness is essential, especially if expanding use to large populations. Longer follow-up in broader and more diverse groups may reveal less common adverse events that were not detected in this trial. Clinicians should therefore weigh individual risk–benefit profiles and await additional data before making universal recommendations.

Study Strengths and Limitations:

• Strengths: The trial’s 10-year duration, double-blind design, and high retention rate enhance its internal validity. Using radiographic assessments for vertebral fractures adds objectivity and robustness.
• Limitations: The trial predominantly involved healthy, early postmenopausal women of European descent, limiting the applicability of the findings to other ethnicities, older populations, or those with complex comorbidities. Only two zoledronate infusions at a five-year interval were evaluated, leaving the optimal dosing frequency unresolved. Further, while adverse events appeared uncommon here, the sample size and population profile may not adequately capture rare or long-latency adverse outcomes.

Future Research: Larger trials in more diverse demographic and clinical settings are necessary to determine whether infrequent zoledronate can safely and effectively reduce fracture risk across broader patient groups. Studies comparing different dosing schedules, as well as investigations into cost-effectiveness and logistics of administration, would be highly valuable. Longer-term surveillance in real-world cohorts should help clarify the incidence of uncommon adverse events. Ultimately, such additional evidence will guide whether infrequent zoledronate infusions might be integrated into routine practice for fracture prevention in postmenopausal women without osteoporosis.

Reference:

1. Bolland MJ, Nisa Z, Mellar A, et al. Fracture Prevention with Infrequent Zoledronate in Women 50 to 60 Years of Age. New England Journal of Medicine. 2025;392:239-248. DOI: http://doi.org/10.1056/NEJMoa2407031
2. Chapurlat R. Infrequent Zoledronate — Small Individual Gain, Larger Population Gain. New England Journal of Medicine. 2025;392:281-283. DOI: http://doi.org/10.1056/NEJMe2415376

 

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Screening for Osteoporosis to Prevent Fractures: Updated USPSTF Guidelines

18 Jan, 2025 | 15:19h | UTC

Introduction: This document summarizes the 2025 US Preventive Services Task Force (USPSTF) guideline on screening for osteoporosis to prevent fragility fractures. Osteoporosis, characterized by low bone mass and decreased bone quality, can lead to fractures that impair independence, increase morbidity, and raise mortality. The revised guidance builds on evidence that screening in select populations reduces fracture risk. Although the Task Force finds moderate net benefit for screening certain groups, it concludes that evidence remains insufficient to assess benefits and harms in other segments.

Key Recommendations:

1. Population and Rationale:
   • Women 65 years or older: The USPSTF concludes with moderate certainty that screening for osteoporosis in this age group leads to moderate net benefit for preventing osteoporotic fractures.
   • Postmenopausal women younger than 65 years at increased risk: Screening is recommended if a formal risk assessment or clinical risk factors indicate elevated risk, as moderate certainty suggests moderate benefit.
   • Men: The current evidence is insufficient to establish the balance of benefits and harms of screening men without known osteoporosis or prior fragility fractures.
2. Screening Methods:
   • The USPSTF identifies central dual-energy x-ray absorptiometry (DXA) of the hip or lumbar spine as the key screening test.
   • In younger postmenopausal women, a two-step approach is suggested: (1) assess risk factors (e.g., low body weight, smoking, parental history of hip fracture); (2) apply a validated tool (e.g., Osteoporosis Risk Assessment Instrument [ORAI] or Osteoporosis Self-assessment Tool [OST]) to determine who should proceed to DXA.
   • Tools such as FRAX may be used with or without BMD input to estimate 10-year fracture probability, but clinicians should be aware that tool accuracy and calibration vary by age, race/ethnicity, and underlying data sources.
3. Screening Intervals:
   • Current data do not clearly define an optimal interval for repeated screening.
   • Some evidence suggests little added value in repeating BMD tests within four to eight years if initial results are normal or only mildly low.
4. Management Following a Positive Screening Result:
   • After osteoporosis is confirmed, patients should be counseled on modifiable risk factors (e.g., smoking cessation, fall prevention) and assessed for pharmacotherapy.
   • Approved treatments (e.g., bisphosphonates, denosumab) have demonstrated benefit in reducing vertebral, hip, and other major fractures.
5. Harms of Screening and Treatment:
   • Screening anxiety and overdiagnosis are minimal concerns, though data are limited.
   • Bisphosphonate use has not been associated with significant excess serious adverse events in short- to medium-term trials, but rare events (e.g., atypical femur fractures, osteonecrosis of the jaw) remain possible with long-term use.
   • Denosumab reduces multiple fracture outcomes, though discontinuation can lead to rebound bone loss and increased risk of vertebral fractures without follow-up management.
   • The USPSTF underscores that treatment decisions should be individualized, especially in diverse populations and those with complex comorbidities.

Conclusion: These updated recommendations highlight the importance of osteoporosis screening in women 65 years or older and in younger postmenopausal women at higher fracture risk. Early detection with central DXA, informed by clinical risk tools, can reduce fracture incidence and related burdens. Further research is needed to clarify optimal screening intervals, the role of screening in men, and long-term treatment strategies. In the meantime, clinicians should collaborate with patients to personalize screening and treatment plans, considering both clinical risks and patient preferences.

Reference:

• US Preventive Services Task Force. Screening for Osteoporosis to Prevent Fractures: US Preventive Services Task Force Recommendation Statement. JAMA. Published online January 14, 2025. DOI: http://doi.org/10.1001/jama.2024.27154
• Editorials:
  • Ensrud KE, Crandall CJ. Fracture Risk Assessment as a Component of Osteoporosis Screening—Easier Said Than Done. JAMA. Published online January 14, 2025. DOI: http://doi.org/10.1001/jama.2024.27416
  • Ott SM. Research That Could Broaden the Scope of Bone Density Screening. JAMA Netw Open. 2025;8(1):e2460746. DOI: http://doi.org/10.1001/jamanetworkopen.2024.60746
• Evidence Report:
  • Kahwati LC, Kistler CE, Booth G, et al. Screening for Osteoporosis to Prevent Fractures: A Systematic Evidence Review for the US Preventive Services Task Force. JAMA. Published online January 14, 2025. DOI: http://doi.org/10.1001/jama.2024.21653

 

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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:

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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

 

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RCT: High-Flow Nasal Oxygen Noninferior to Noninvasive Ventilation for Most Acute Respiratory Failure Causes

13 Jan, 2025 | 13:11h | UTC

Background: Acute respiratory failure (ARF) arises from diverse etiologies and can manifest as hypoxemic or hypercapnic events. High-flow nasal oxygen (HFNO) and noninvasive ventilation (NIV) are common noninvasive respiratory support modalities, but robust comparative data in various ARF subgroups have been limited. Prior research suggests NIV may benefit chronic obstructive pulmonary disease (COPD) exacerbations and acute cardiogenic pulmonary edema (ACPE), yet for hypoxemic failure (including COVID-19 and immunocompromised populations), HFNO is often favored for its comfort and physiological advantages. The RENOVATE trial was designed to assess whether HFNO is noninferior to NIV for preventing intubation or death among five distinct groups of patients with ARF.

Objective: To determine if HFNO is noninferior to NIV in terms of the composite outcome of endotracheal intubation or death within seven days in patients with ARF, categorized into five subgroups: (1) nonimmunocompromised with hypoxemic ARF, (2) immunocompromised with hypoxemic ARF, (3) COPD exacerbation with respiratory acidosis, (4) ACPE, and (5) hypoxemic COVID-19.

Methods: This multicenter, adaptive, noninferiority randomized clinical trial enrolled 1800 hospitalized adults across 33 Brazilian centers. Patients were stratified by ARF etiology and randomized 1:1 to receive either HFNO or NIV. Treatment protocols allowed HFNO escalation to NIV (particularly for COPD or ACPE) if needed. The primary outcome was defined using a Bayesian hierarchical model with dynamic borrowing across subgroups; noninferiority was met if the posterior probability for an odds ratio (OR) below 1.55 reached ≥0.992. Predefined futility and superiority thresholds guided interim analyses, with a maximum sample size of 2000.

Results: Of 1800 randomized patients, 1766 completed the study (mean age 64 years; 40% women). The primary outcome (intubation or death by day 7) occurred in 39.0% (HFNO) vs 38.1% (NIV). HFNO was noninferior in four subgroups:

• Nonimmunocompromised with hypoxemia: 32.5% vs 33.1% (OR 1.02; posterior probability of noninferiority 0.999).
• COPD exacerbation with respiratory acidosis: 28.6% vs 26.2% (OR 1.05; probability 0.992).
• ACPE: 10.3% vs 21.3% (OR 0.97; probability 0.997).
• Hypoxemic COVID-19: 51.3% vs 47.0% (OR 1.13; probability 0.997).

The immunocompromised subgroup stopped enrollment early for futility; final results there did not confirm noninferiority (57.1% vs 36.4%; OR 1.07; probability 0.989). No significant differences in 28- or 90-day mortality emerged, although mortality rates were generally higher than in some previous trials. Comfort scores favored HFNO, and rates of serious adverse events were similar between groups.

Conclusions: In four of five ARF subgroups, HFNO met predefined noninferiority criteria compared with NIV regarding endotracheal intubation or death at seven days. However, immunocompromised patients with hypoxemic ARF remain an area of uncertainty, as do smaller subgroups (e.g., COPD) under non-borrowing analyses. Clinicians may consider HFNO as an alternative initial approach, recognizing that rescue NIV may still be necessary, particularly in COPD exacerbations.

Implications for Practice: These findings support using HFNO for a broad range of ARF etiologies as a first-line therapy. HFNO’s ease of use, patient comfort, and comparable safety profile may make it especially appealing. Nevertheless, clinicians should remain vigilant in immunocompromised patients and in COPD exacerbations when hypercapnia is pronounced. Potential cost variations between HFNO and NIV may influence real-world adoption, and local resources, staff expertise, and patient tolerance should guide final decisions.

Study Strengths and Limitations: Strengths include a large, diverse sample and a robust Bayesian adaptive design that allowed dynamic borrowing across subgroups. This approach increased precision but also introduced heterogeneity concerns. Some patient groups (particularly immunocompromised and COPD) were relatively small, limiting definitive conclusions in those strata. Additionally, early stopping for futility in immunocompromised patients curtailed full enrollment, and the trial compared HFNO only with face-mask NIV (rather than alternatives such as helmet CPAP).

Future Research: Further large-scale studies should refine whether HFNO can supplant NIV in COPD exacerbations and immunocompromised populations. Investigations on cost-effectiveness, patient-centered outcomes (comfort, quality of life), and comparative models (e.g., helmet NIV) are also warranted.

Reference:
• RENOVATE Investigators and the BRICNet Authors. High-Flow Nasal Oxygen vs Noninvasive Ventilation in Patients With Acute Respiratory Failure: The RENOVATE Randomized Clinical Trial. JAMA. Published online December 10, 2024. DOI: http://doi.org/10.1001/jama.2024.26244
• Frat JP, Le Pape S, Thille AW. Editorial: Is High-Flow Oxygen the Standard for All Patients With Acute Respiratory Failure? JAMA. Published online December 10, 2024. DOI: http://doi.org/10.1001/jama.2024.25906
• Freund Y, Vromant A. Editorial: Reevaluating Respiratory Support in Acute Respiratory Failure—Insights From the RENOVATE Trial and Implications for Practice. JAMA. Published online December 10, 2024. DOI: http://doi.org/10.1001/jama.2024.25869

 

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Network Meta-Analysis: TMP-SMX May Need Reassessment as First-Line Therapy for PCP in People With HIV

13 Jan, 2025 | 10:25h | UTC

Background: Pneumocystis jirovecii pneumonia (PCP) remains a severe opportunistic infection in people living with HIV (PWH), especially those with low CD4 counts. Trimethoprim–sulfamethoxazole (TMP-SMX) is widely recommended as first-line therapy; however, its toxicity profile can limit use. Alternative regimens such as dapsone–trimethoprim, clindamycin–primaquine, atovaquone, and pentamidine have been explored, but comprehensive comparative data are scarce.

Objective: This systematic review and network meta-analysis aimed to compare the efficacy (treatment failure, mortality) and tolerability (treatment change due to toxicity) of PCP treatment regimens in PWH. The goal was to determine whether TMP-SMX maintains superiority across these outcomes or if alternative regimens offer similar efficacy with improved safety profiles.

Methods: Researchers systematically searched Embase, Medline, and CENTRAL (inception through 3 February 2024) for randomized controlled trials (RCTs) comparing at least two PCP treatment regimens in PWH. Independent reviewers screened titles/abstracts and performed full-text reviews. Data extraction included population demographics, treatment arms, outcomes (treatment failure, all-cause mortality, treatment change), and risk-of-bias assessments using the Cochrane Risk-of-Bias 2 tool. A network meta-analysis using a frequentist random-effects model was performed to integrate direct and indirect comparisons, estimating relative treatment effects (risk ratios with 95% confidence intervals) and generating rankings via the surface under the cumulative ranking curve (SUCRA).

Results: Fourteen RCTs (1983–1996) with 1,788 participants across 27 treatment arms were included. No regimen demonstrated significant superiority over TMP-SMX in direct comparisons, although TMP-SMX outperformed atovaquone and trimetrexate plus folinic acid in reducing treatment failure. In the network analysis, clindamycin–primaquine, intravenous pentamidine, and TMP-SMX all had favorable SUCRA values for preventing treatment failure. For all-cause mortality, dapsone–trimethoprim and intravenous pentamidine ranked highest, while TMP-SMX was better than atovaquone in direct comparison. Notably, for tolerability, all alternative regimens tended to be safer than TMP-SMX, which ranked worst for toxicity. Inhaled pentamidine, trimetrexate plus folinic acid, and atovaquone were the best-tolerated therapies.

Conclusions: These findings suggest that TMP-SMX, although commonly used, might not be universally superior to all other regimens when balancing efficacy and safety in PWH with PCP. When the risk of renal or hematologic complications is high, considering clindamycin–primaquine or intravenous pentamidine may provide comparable efficacy with a more favorable safety profile. Inhaled pentamidine or atovaquone may offer good tolerability but should be carefully assessed for efficacy in moderate-to-severe disease.

Implications for Practice: When managing PCP in PWH, TMP-SMX may not always be the ideal standalone first-line choice, especially in patients at high risk for renal or hematologic complications. Clindamycin–primaquine and intravenous pentamidine could represent viable alternatives for clinicians seeking to balance efficacy with improved safety. Inhaled pentamidine or atovaquone may offer strong tolerability but should be carefully evaluated for their effectiveness in moderate-to-severe disease.

Study Strengths and Limitations: Strengths include a robust search strategy, strict inclusion criteria of RCTs, and the use of a network meta-analysis to integrate direct and indirect comparisons. Limitations involve the older timeframe of the included trials (most conducted before the modern ART era) and heterogeneous definitions of treatment failure, which may limit generalizability to broader contemporary clinical settings. Women and other high-risk populations were underrepresented, presenting another limitation.

Future Research: Contemporary RCTs should address the optimal dose and duration of TMP-SMX and alternative agents, include underrepresented groups (women, older adults, patients with renal impairment), and consider modern management of HIV and critical care practices. Ongoing investigations of novel agents like rezafungin may further refine first-line PCP treatment strategies.

Reference: Hatzl S, Posch F, Scholz L, … Bassetti M, Hoenigl M, Krause R. Comparative efficacy and safety of treatment regimens for Pneumocystis jirovecii pneumonia in people living with HIV: a systematic review and network meta-analysis of randomized controlled trials. Clinical Microbiology and Infection, Published online December 26, 2024. DOI: http://doi.org/10.1016/j.cmi.2024.12.024

 

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SR: Lower BP Targets Reduce Stroke Risk and Cardiovascular Events in Older Adults

16 Jan, 2025 | 12:42h | UTC

Background: Hypertension is a prevalent condition in older adults and a major risk factor for cardiovascular morbidity and mortality. Despite widely accepted benefits of treating blood pressure (BP) above 160 mmHg in this population, the optimal BP target remains uncertain. Many guidelines recommend a systolic BP (SBP) goal of < 140 mmHg in all adults, including those aged ≥ 65 years. However, evidence suggests older, possibly frail individuals might experience different benefit–risk ratios with more relaxed BP targets. This Cochrane review updates the previous 2017 analysis to determine whether aiming for higher BP targets in older adults (e.g., < 150–160 mmHg systolic) confers comparable or better outcomes than standard or more aggressive targets (< 140 mmHg).

Objective: To assess the effects of a higher BP target (SBP < 150–160 mmHg or diastolic BP < 95–105 mmHg) versus a lower (conventional or more aggressive) BP target (< 140/90 mmHg or lower) on mortality, stroke, and serious cardiovascular events in hypertensive adults aged ≥ 65 years.

Methods:

• Design and Searches: This is an updated Cochrane systematic review of randomized controlled trials (RCTs) comparing higher vs lower BP targets in older adults with hypertension. Databases searched through June 2024 included MEDLINE, Embase, CENTRAL, the Cochrane Hypertension Specialised Register, and ClinicalTrials.gov.
• Inclusion Criteria: RCTs of ≥ 1 year’s duration enrolling participants aged ≥ 65 years with baseline systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg. Trials had to compare a higher BP target range (SBP < 150–160/DBP < 95–105 mmHg) to a lower BP target (< 140/90 mmHg).
• Outcomes: Primary outcomes were all-cause mortality, stroke, institutionalization, and serious cardiovascular adverse events (including myocardial infarction, heart failure, and renal failure). Secondary outcomes included cardiovascular mortality, non-cardiovascular mortality, total serious adverse events, and withdrawals due to adverse effects.

Results:

• Included Studies: Four open-label RCTs (N = 16,732) from Japan and China, with mean ages around 70 years (range 65–77). Mean follow-up ranged from 2 to 4 years.
• Mortality: Lower BP targets may result in little to no difference in all-cause mortality (RR 1.14, 95% CI 0.95–1.37; low-certainty).
• Stroke Prevention: A lower BP target clearly reduced the risk of stroke (RR 1.33, 95% CI 1.06–1.67; high-certainty), with an absolute reduction of approximately 6 stroke events per 1000 individuals treated over ~3 years.
• Serious Cardiovascular Events: A lower BP target likely reduced total serious cardiovascular adverse events (RR 1.25, 95% CI 1.09–1.45; moderate-certainty), equating to roughly 10 fewer cardiovascular events per 1000 people treated.
• Adverse Effects: Lower BP targets likely did not increase withdrawals due to adverse effects (RR 0.99, 95% CI 0.74–1.33; moderate-certainty). Data on other adverse events (e.g., hypotension) were limited but showed small absolute differences.

Conclusions: Treating older adults’ systolic BP to < 140 mmHg (vs < 150–160 mmHg) reduces stroke and likely reduces overall serious cardiovascular events without clearly affecting all-cause mortality or increasing dropouts due to adverse effects. While these findings support standard BP targets (< 140 mmHg) for many older patients, the absolute reduction in events is modest. Caution may be warranted in individuals aged ≥ 80 years or those who are frail, as the included studies had fewer such participants.

Implications for Practice: For most older adults, targeting SBP < 140 mmHg can prevent a modest but meaningful number of cardiovascular events, particularly stroke. Clinicians should balance these benefits against patient-specific concerns, such as frailty, multiple comorbidities, and polypharmacy. Monitoring for hypotension, renal function changes, and other adverse effects remains important.

Study Strengths and Limitations:

• Strengths: Inclusion of four RCTs with low attrition rates; assessment of major vascular endpoints relevant to older adults.
• Limitations: All trials were open-label, increasing risk of bias in subjective outcomes. Adverse event reporting was incomplete, and very elderly or frail individuals were often underrepresented. Most data originated from Asian populations, limiting generalizability to other regions.

Future Research: Further RCTs in populations aged ≥ 80 years, those with significant frailty, or living in nursing homes are essential to clarify optimal BP targets. Studies should capture quality-of-life measures and long-term safety outcomes, especially regarding adverse drug–drug interactions in complex older patients.

Reference: Falk JM, Froentjes L, Kirkwood JE, Heran BS, Kolber MR, Allan GM, Korownyk CS, Garrison SR. Higher blood pressure targets for hypertension in older adults. Cochrane Database of Systematic Reviews. 2024; Issue 12. DOI: http://doi.org/10.1002/14651858.CD011575.pub3

 

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