Archives
Test-Negative Study: RSV Vaccine May Reduce Hospitalizations and ED Visits in Adults Aged ≥60
16 Nov, 2024 | 14:18h | UTCBackground: Respiratory syncytial virus (RSV) is a significant cause of morbidity and mortality among older adults in the USA, with an estimated 100,000–160,000 RSV-associated hospitalizations annually in those aged 60 years and older. In 2023, RSV vaccines were recommended for this population, showing efficacy in clinical trials. However, real-world effectiveness data, particularly against severe outcomes like hospitalizations in high-risk groups, are limited.
Objective: To assess the real-world effectiveness of RSV vaccination against RSV-associated hospitalizations and emergency department (ED) encounters among adults aged 60 years and older during the 2023–24 RSV season in the USA.
Methods: A test-negative design analysis was conducted using data from the Virtual SARS-CoV-2, Influenza, and Other Respiratory Viruses Network (VISION), encompassing eight states. Adults aged ≥60 presenting with RSV-like illness and tested for RSV from Oct 1, 2023, to Mar 31, 2024, were included. Vaccination status was determined through electronic health records, immunization registries, and medical claims. Vaccine effectiveness (VE) was estimated by comparing the odds of vaccination among RSV-positive cases and RSV-negative controls, adjusting for age, sex, race and ethnicity, comorbidities, and geographic region.
Results: Among 28,271 hospitalizations for RSV-like illness in immunocompetent adults aged ≥60, VE against RSV-associated hospitalization was 80% (95% CI 71–85). VE against RSV-associated critical illness (ICU admission or death) was 81% (95% CI 52–92). In 8,435 hospitalizations among immunocompromised adults, VE was 73% (95% CI 48–85) against RSV-associated hospitalization. Among 36,521 ED encounters in immunocompetent adults, VE against RSV-associated ED visits was 77% (95% CI 70–83). VE estimates were consistent across age groups and vaccine products.
Conclusions: RSV vaccination effectively prevented RSV-associated hospitalizations and ED visits among adults aged ≥60 during the first season post-approval, including those at highest risk due to advanced age or immunocompromise.
Implications for Practice: These findings support recommending RSV vaccination for adults aged ≥60 to reduce severe RSV-related morbidity and mortality. Clinicians should consider advising eligible patients to receive the RSV vaccine to prevent hospitalizations and critical illness.
Study Strengths and Limitations: Strengths include a large, geographically diverse cohort and integrated medical, laboratory, and vaccination data, allowing robust VE estimates across subgroups. Limitations involve potential misclassification of vaccination status, residual confounding, and reliance on clinician-directed RSV testing, which may introduce bias.
Future Research: Further studies are needed to evaluate the duration of vaccine protection over multiple RSV seasons and to assess VE in other high-risk populations and settings.
Phase 3 RCT: Resmetirom Significantly Improves NASH Resolution and Liver Fibrosis
16 Nov, 2024 | 13:56h | UTCBackground: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatments. It significantly increases the risk of liver-related complications, especially in patients with type 2 diabetes. Resmetirom, a thyroid hormone receptor beta-selective agonist, is being investigated for its potential to treat NASH and liver fibrosis.
Objective: To evaluate the efficacy and safety of resmetirom in resolving NASH and improving fibrosis in adults with biopsy-confirmed NASH and fibrosis stages F1B to F3.
Methods: This double-blind, placebo-controlled phase 3 trial randomized 966 adults with NASH to receive once-daily resmetirom (80 mg or 100 mg) or placebo for 52 weeks. Primary endpoints included (1) NASH resolution with no fibrosis worsening and (2) fibrosis improvement by at least one stage without NAFLD activity score worsening. Secondary outcomes included changes in lipid profiles and liver biomarkers.
Results: At 52 weeks, NASH resolution occurred in 25.9% of patients receiving 80 mg and 29.9% receiving 100 mg of resmetirom, compared with 9.7% in the placebo group (P<0.001 for both doses vs. placebo). Fibrosis improved by at least one stage in 24.2% (80 mg) and 25.9% (100 mg) of resmetirom-treated patients versus 14.2% for placebo (P<0.001). LDL cholesterol reductions were −13.6% (80 mg) and −16.3% (100 mg) at 24 weeks versus 0.1% for placebo (P<0.001). Improvements were also noted in triglycerides, liver enzymes, and imaging biomarkers. Adverse events, primarily mild gastrointestinal symptoms, were more frequent with resmetirom. Serious adverse events were similar across groups (10.9%–12.7%).
Conclusions: Resmetirom significantly improved NASH resolution and fibrosis compared to placebo, demonstrating its potential as a treatment for NASH with liver fibrosis.
Implications for Practice: Resmetirom offers a promising treatment option for NASH, potentially altering the disease course and improving outcomes. Clinicians should monitor for regulatory approval and long-term safety data.
Study Strengths and Limitations: Strengths include robust biopsy-confirmed endpoints and a large sample size. Limitations include short follow-up and lack of clinical-outcome data.
Future Research: Long-term studies are needed to assess durability, safety, and effects on clinical outcomes like cirrhosis and liver-related mortality.
RCT: Once-Weekly Semaglutide Reduces Weight and Knee Osteoarthritis Pain in Obese Patients
16 Nov, 2024 | 13:41h | UTCBackground: Obesity is a major risk factor for the development and progression of knee osteoarthritis, leading to chronic pain and reduced mobility. Weight reduction has been shown to alleviate symptoms, but sustained, non-surgical interventions are limited. Glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide, have demonstrated efficacy in weight management; however, their impact on knee osteoarthritis pain is not well established.
Objective: To assess the efficacy of once-weekly subcutaneous semaglutide (2.4 mg) versus placebo, alongside lifestyle interventions, on body weight reduction and pain related to knee osteoarthritis in adults with obesity.
Methods: In this 68-week, double-blind, randomized, placebo-controlled trial conducted at 61 sites across 11 countries, 407 adults with obesity (BMI ≥30) and moderate knee osteoarthritis with at least moderate pain were enrolled. Participants were randomized in a 2:1 ratio to receive semaglutide or placebo, in addition to counseling on a reduced-calorie diet and increased physical activity. The primary endpoints were the percentage change in body weight and the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score from baseline to week 68.
Results: Semaglutide treatment resulted in a mean weight reduction of −13.7% compared to −3.2% with placebo (P<0.001). The mean change in WOMAC pain score was −41.7 points with semaglutide versus −27.5 points with placebo (P<0.001), indicating a significant reduction in pain. Additionally, semaglutide led to greater improvements in physical function scores and a decrease in the use of nonsteroidal anti-inflammatory drugs. Serious adverse events were similar between groups; however, gastrointestinal disorders led to more discontinuations in the semaglutide group (6.7% vs. 3.0%).
Conclusions: Once-weekly subcutaneous semaglutide significantly reduces body weight and alleviates pain related to knee osteoarthritis in obese adults, compared to placebo, when combined with lifestyle modifications. These findings support semaglutide as an effective non-surgical intervention for weight management and symptom relief in this population.
Implications for Practice: Semaglutide may be considered as part of a comprehensive treatment strategy for obese patients with knee osteoarthritis, potentially improving pain, physical function, and reducing reliance on analgesics. Clinicians should weigh the benefits against potential gastrointestinal side effects.
Study Strengths and Limitations: Strengths include the randomized, double-blind design and a sizable, diverse cohort. Limitations involve the absence of imaging follow-up, lack of metabolic and inflammatory marker assessments, and no post-treatment outcome data to evaluate the sustainability of benefits after discontinuation.
Future Research: Further studies are warranted to explore the long-term effects of semaglutide on knee osteoarthritis progression, its mechanisms of action on joint pathology, and its effectiveness in broader patient populations.
Review: Lung Transplantation
16 Nov, 2024 | 13:33h | UTCIntroduction: Lung transplantation has progressed from experimental to standard therapy for life-threatening lung diseases, offering improved survival and quality of life. Challenges include primary graft dysfunction, chronic lung allograft dysfunction (CLAD), infections, and long-term immunosuppression effects. This review highlights current practices, developments, and opportunities to enhance this transformative therapy.
Key Recommendations
- Candidate Selection: Selection criteria have shifted from strict contraindications to a holistic approach emphasizing physiologic age, frailty, and recoverability. Early referral and multidisciplinary assessment are recommended to address barriers and optimize outcomes.
- Donor-Lung Utilization: Extended-criteria donors, including older donors and those with smoking histories, are increasingly used. Ex vivo lung perfusion allows detailed lung assessment and reconditioning, while antiviral therapies enable transplantation of lungs from hepatitis C-positive donors.
- Lung Allocation: Urgency-weighted scores prioritize factors like medical urgency and post-transplant survival. Recent updates include biologic disadvantages, patient access, and logistical efficiency to improve fairness and outcomes.
- Surgical Techniques: Bilateral sequential lung transplantation is standard, with ECMO replacing cardiopulmonary bypass in many cases. Surgical approaches are tailored to individual needs, with options like volume reduction or lobectomy for size mismatches.
- Postoperative Management: Primary graft dysfunction affects up to 25% of recipients and is a major early complication. Preventive strategies, ECMO support, and infection management are critical. Attention to airway complications and acute kidney injury further improves recovery.
- Immunosuppression: Maintenance therapy typically includes a calcineurin inhibitor, glucocorticoid, and cell-cycle inhibitor. Induction therapy is individualized. Ongoing studies are exploring adjunct therapies like mTOR inhibitors and inhaled immunosuppressants to prevent CLAD.
- Management of ALAD and CLAD: Early detection and treatment of acute lung allograft dysfunction are essential. CLAD, affecting half of recipients within 5 years, remains a major challenge. Current therapies slow progression, but further research is needed for targeted prevention and treatment.
- Infections: Infections remain a leading cause of morbidity and mortality. Prophylaxis against cytomegalovirus, fungal pathogens, and community-acquired viruses is essential to minimize complications and reduce CLAD risk.
- Cancer Risk: Post-transplant cancer risk is elevated due to immunosuppression. Lung cancer and post-transplant lymphoproliferative disease are the most common malignancies, emphasizing the need for routine surveillance and early intervention.
- Long-Term Outcomes: Median survival remains limited at 6.7 years. Efforts focus on improving long-term outcomes by balancing graft function maintenance with minimizing adverse effects of immunosuppression. Collaborative research aims to refine diagnostics, personalize therapies, and address CLAD mechanisms.
Conclusion: Enhanced donor utilization, tailored candidate selection, refined perioperative care, and robust long-term monitoring are pivotal to advancing lung transplantation. Ongoing research and collaboration are critical to overcoming challenges like CLAD, improving survival, and enhancing patient quality of life.
Meta-analysis: Urea May be Effective for the Treatment of SIADH-Induced Hyponatremia
15 Nov, 2024 | 14:01h | UTCBackground: Hyponatremia, defined as a serum sodium level below 135 mEq/L, is the most common electrolyte disorder in clinical practice, associated with increased mortality and prolonged hospital stays. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a frequent cause of euvolemic hyponatremia, particularly among hospitalized patients. Traditional treatments like fluid restriction and hypertonic saline have limitations, and guidelines are inconsistent regarding their use. Urea, an osmotic diuretic, has been proposed as an alternative therapy but is underutilized due to concerns about efficacy, safety, and patient tolerability.
Objective: To evaluate the effectiveness and safety of urea in treating hyponatremia caused by SIADH.
Methods: A systematic review and meta-analysis were conducted following PRISMA guidelines. Searches of MEDLINE, EMBASE, Cochrane CENTRAL, and Google Scholar up to November 2023 identified studies involving patients with SIADH-related hyponatremia treated with oral or nasogastric urea. Inclusion criteria encompassed clinical trials and observational studies reporting outcomes on serum sodium levels, symptom resolution, or adverse effects.
Results: Sixteen observational studies involving 518 patients (430 treated with urea) met inclusion criteria. Urea treatment significantly increased serum sodium levels (mean difference [MD], 9.21 mEq/L [95% CI, 7.36-11.06]; P < 0.01) despite high heterogeneity (I² = 89%). Subgroup analyses showed significant sodium increases at 24 hours and at 2, 3, 5, 7, 14 days, and 1 year post-treatment. Patients with severe hyponatremia (<120 mEq/L) experienced greater sodium increases (MD, 18.04 mEq/L [95% CI, 13.68-22.39]) compared to those with moderate (120-129 mEq/L) or mild (130-135 mEq/L) hyponatremia. Urea’s efficacy was comparable to fluid restriction (MD, 0.81 mEq/L [95% CI, –0.93 to 2.55]; P = 0.4) and vaptans (MD, –2.43 mEq/L [95% CI, –6.31 to 1.45]; P = 0.2), and superior to no treatment (MD, 7.99 mEq/L [95% CI, 6.25-9.72]; P < 0.01). Adverse events were minor; poor palatability was the most common complaint.
Conclusions: Urea is an effective and safe treatment for SIADH-induced hyponatremia, significantly increasing serum sodium levels, particularly in severe cases. It offers a viable alternative to fluid restriction and vaptans with minimal adverse effects.
Implications for Practice: Urea should be considered a valuable treatment option for SIADH-induced hyponatremia, especially in resource-limited settings or when other therapies are contraindicated or poorly tolerated. Its cost-effectiveness and ease of administration may improve patient outcomes and reduce healthcare costs.
Study Strengths and Limitations: Strengths include a comprehensive search strategy and inclusion of diverse studies across multiple settings. Limitations are the reliance on observational studies due to the absence of randomized controlled trials, significant heterogeneity among studies, and the potential for publication bias.
Future Research: Randomized controlled trials are necessary to confirm urea’s efficacy and safety, establish standardized dosing regimens, and develop strategies to enhance palatability and patient adherence.
Meta-Analysis: Spinal Cord Stimulation May Be Effective for Chronic Back and Leg Pain
15 Nov, 2024 | 13:43h | UTCBackground: Chronic back and leg pain causes significant disability worldwide. Spinal cord stimulation (SCS) offers treatment for patients unresponsive to conventional medical management (CMM). The comparative efficacy of conventional and novel SCS forms versus CMM is debated, requiring thorough evaluation.
Objective: To evaluate the efficacy of conventional and novel SCS therapies compared with CMM in adults with chronic back or leg pain who had not previously used SCS.
Methods: A systematic review and Bayesian network meta-analysis per PRISMA guidelines were performed. MEDLINE, Embase, and Cochrane Library were searched up to September 2, 2022. Thirteen RCTs with 1,561 patients were included. Interventions were conventional SCS, novel SCS modalities (e.g., high-frequency, burst stimulation), and CMM. Primary outcomes were pain intensity (visual analog scale) and responder rates (≥50% pain relief) in back or leg. Secondary outcomes were quality of life (EQ-5D index) and functional disability (Oswestry Disability Index).
Results: At 6 months, both conventional and novel SCS were superior to CMM in five of six outcomes. For back pain responder rates, conventional SCS had an OR of 3.00 (95% CrI, 1.49–6.72) and novel SCS had an OR of 8.76 (95% CrI, 3.84–22.31) versus CMM. Pain intensity in the back decreased significantly with conventional SCS (MD, –1.17; 95% CrI, –1.64 to –0.70) and novel SCS (MD, –2.34; 95% CrI, –2.96 to –1.73). Leg pain intensity also decreased significantly with conventional SCS (MD, –2.89; 95% CrI, –4.03 to –1.81) and novel SCS (MD, –4.01; 95% CrI, –5.31 to –2.75) compared to CMM. Quality of life improved with both SCS therapies (conventional SCS MD, 0.15; 95% CrI, 0.09–0.21; novel SCS MD, 0.17; 95% CrI, 0.13–0.21). Functional disability improved significantly with conventional SCS (MD, –7.10; 95% CrI, –10.91 to –3.36).
Conclusions: Both conventional and novel SCS therapies are associated with significant improvements in pain relief, quality of life, and functional ability compared with CMM in patients with chronic back and leg pain at 6 months.
Implications for Practice: The results support integrating SCS therapies into clinical practice for patients with chronic back and leg pain unresponsive to CMM.
Study Strengths and Limitations: Strengths include inclusion of recent RCTs and use of Bayesian network meta-analysis, allowing comprehensive evidence synthesis with both direct and indirect comparisons, enhancing reliability. Limitations involve potential biases due to challenges in blinding participants and assessors, as patients can perceive whether a device is active. Heterogeneity among studies in patient populations and interventions may affect generalizability. Inability to include long-term efficacy data due to crossover in many trials limits understanding of sustained outcomes.
Future Research: Long-term RCTs are needed to assess sustained efficacy and safety of SCS therapies. Future studies should compare different SCS modalities directly and identify patient subgroups most likely to benefit.
RCT: Tirzepatide Significantly Reduces Weight and Diabetes Risk in Obese Adults with Prediabetes
15 Nov, 2024 | 13:29h | UTCBackground: Obesity is a chronic disease that significantly increases the risk of type 2 diabetes, particularly in individuals with prediabetes. Weight reduction has been shown to improve insulin sensitivity and beta-cell function, potentially delaying or preventing the onset of type 2 diabetes. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated significant weight loss and glycemic control in short-term studies.
Objective: To evaluate the long-term efficacy and safety of tirzepatide in reducing body weight and delaying progression to type 2 diabetes in obese adults with prediabetes over a period of three years.
Methods: In this phase 3, double-blind, randomized, controlled trial (SURMOUNT-1), 1032 obese adults with prediabetes were randomized 1:1:1:1 to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo, alongside lifestyle intervention, for 176 weeks, followed by a 17-week off-treatment period. The primary endpoints included percent change in body weight and onset of type 2 diabetes during the treatment and follow-up periods.
Results: At week 176, participants receiving tirzepatide achieved significant mean weight reductions of –12.3% (5 mg), –18.7% (10 mg), and –19.7% (15 mg), compared to –1.3% with placebo (P<0.001 for all comparisons). Progression to type 2 diabetes was significantly lower in the tirzepatide groups (1.3%) compared to placebo (13.3%), with a hazard ratio of 0.07 (95% CI, 0.0 to 0.1; P<0.001). After the 17-week off-treatment period, 2.4% of tirzepatide-treated participants and 13.7% of placebo-treated participants had developed type 2 diabetes (hazard ratio, 0.12; 95% CI, 0.1 to 0.2; P<0.001). Common adverse events were gastrointestinal and generally mild to moderate.
Conclusions: Three years of tirzepatide treatment in obese adults with prediabetes resulted in substantial and sustained weight loss and significantly reduced the risk of progression to type 2 diabetes compared to placebo, with an acceptable safety profile.
Implications for Practice: Tirzepatide may be an effective long-term therapeutic option for weight management and diabetes prevention in obese patients with prediabetes, potentially altering clinical approaches to obesity and metabolic disease management.
Study Strengths and Limitations: Strengths include the long duration of the trial and large sample size, providing robust data on long-term efficacy and safety. Limitations involve participant attrition and higher withdrawal rates, especially in the placebo group, which may affect the generalizability of the findings.
Future Research: Further studies are needed to explore the mechanisms of tirzepatide’s effects on beta-cell function and insulin sensitivity, as well as its impact on cardiovascular outcomes and quality of life in diverse populations.
Target Trial Emulation: SGLT-2 Inhibitors May Reduce Recurrent Nephrolithiasis in Patients with Type 2 Diabetes and Pre-existing Nephrolithiasis
10 Nov, 2024 | 18:17h | UTCBackground: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors, initially approved for glycemic control in type 2 diabetes, have demonstrated multiple cardiometabolic and renal benefits, including reducing serum urate levels and lowering gout flare-ups. However, data on the effectiveness of SGLT-2 inhibitors in preventing recurrent nephrolithiasis, especially among patients with concomitant gout, are limited.
Objective: To evaluate the comparative effectiveness of SGLT-2 inhibitors versus glucagon-like peptide-1 (GLP-1) receptor agonists in reducing the recurrence of nephrolithiasis among patients with type 2 diabetes and pre-existing nephrolithiasis, including those with concomitant gout.
Methods: A target trial emulation study was conducted using a population-based cohort from British Columbia, Canada, between January 2014 and June 2022. Adults with type 2 diabetes and pre-existing nephrolithiasis who initiated an SGLT-2 inhibitor or a GLP-1 receptor agonist were included. The primary outcome was recurrent nephrolithiasis events identified from emergency department visits, hospital admissions, or outpatient diagnoses. Inverse probability of treatment weighting was applied to adjust for baseline differences.
Results: After weighting, 14,456 patients initiating SGLT-2 inhibitors and 5,877 initiating GLP-1 receptor agonists were analyzed. The incidence of recurrent nephrolithiasis was significantly lower among SGLT-2 inhibitor users (105.3 per 1000 person-years) compared to GLP-1 receptor agonist users (156.4 per 1000 person-years), with an adjusted rate ratio of 0.67 (95% CI 0.57 to 0.79) and a rate difference of –51 per 1000 person-years (number needed to treat [NNT] = 20).
Conclusions: SGLT-2 inhibitor use is associated with a significant reduction in recurrent nephrolithiasis among patients with type 2 diabetes and pre-existing nephrolithiasis, including those with concomitant gout. These findings suggest that SGLT-2 inhibitors may offer dual benefits in managing nephrolithiasis recurrence and gout comorbidities.
Implications for Practice: In patients with type 2 diabetes and a history of nephrolithiasis, particularly those with concomitant gout, SGLT-2 inhibitors may be a valuable addition to current treatment strategies to reduce the recurrence of kidney stones and manage comorbid conditions.
Study Strengths and Limitations: Strengths include the use of a large, population-based cohort and rigorous statistical methods to emulate a target trial, enhancing causal inference. Limitations involve potential residual confounding due to unmeasured factors such as body mass index and laboratory measures, and the inability to capture nephrolithiasis events not requiring medical attention.
Future Research: Further studies are warranted to explore the mechanisms underlying the nephrolithiasis protective effects of SGLT-2 inhibitors, assess their impact in patients without diabetes, and investigate the effects on different types of kidney stones.
Review: Frailty in Older Adults
10 Nov, 2024 | 18:03h | UTCIntroduction: Frailty is a state of decreased physiological reserve and increased vulnerability to adverse health outcomes, becoming more prevalent with age. This review by Kim and Rockwood outlines definitions, biological mechanisms, measurement, and management of frailty in older adults, aiming to guide clinical practice.
Key Recommendations:
- Definitions of Frailty: Clinicians should recognize two predominant concepts: the Fried frailty phenotype, defining frailty as a clinical syndrome with features like exhaustion, weakness, slowness, inactivity, and weight loss; and the deficit-accumulation model, quantifying frailty based on accumulated health deficits.
- Biology of Frailty: Understanding biological mechanisms—such as chronic inflammation, cellular senescence, mitochondrial dysfunction, deregulated nutrient sensing, and hormonal changes—is essential for identifying modifiable risk factors and developing targeted interventions.
- Measurement of Frailty: Utilize validated assessment tools appropriate to the clinical context. The Fried frailty phenotype and the deficit-accumulation frailty index are widely used; brief screening tools and performance measures like gait speed can be practical, especially in acute care settings.
- Management and Interventions for Frailty: Management should focus on increasing physiological reserve through multicomponent interventions. Exercise (aerobic and resistance training), combined with nutritional support, comprehensive geriatric assessment, and medication optimization, has been shown to ameliorate frailty and improve mobility, strength, and daily functioning.
- Frailty Screening Before Stressful Treatments: In high-risk clinical contexts such as oncology and surgery, pre-treatment frailty assessment can guide decision-making, personalize care plans, and improve outcomes by reducing treatment-related adverse effects.
- Evidence Gaps and Future Directions: More research is needed on effective strategies for frailty identification, interventions to prevent or reverse frailty, and the cost-effectiveness of frailty-guided care models, particularly in primary care settings.
Conclusion: Incorporating frailty assessment into clinical practice enables personalized, holistic care that aligns with older patients’ health goals and needs. Interventions targeting frailty can enhance physiological reserve, reduce vulnerability to stressors, and improve clinical outcomes. Further research is essential to optimize frailty management strategies and fully realize the benefits of frailty-guided care in our aging society.
News Release: Seven-Day Antibiotic Regimen Effective for Bloodstream Infections
10 Nov, 2024 | 17:54h | UTCIntroduction: A recent large-scale, multicenter randomized clinical trial has shown that a seven-day course of antibiotics is as effective as the traditional 14-day regimen for treating hospitalized patients with bloodstream infections (BSIs). This finding addresses a critical need in medical practice to optimize antibiotic use amid rising concerns about antimicrobial resistance and healthcare costs.
Highlights: The Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) trial evaluated 3,608 patients with BSIs across 74 hospitals in seven countries, including the United States, Canada, and Australia. Patients were randomized to receive either a seven-day or a 14-day antibiotic course, with the choice of antibiotic, dosage, and administration route determined by their healthcare team.
- Efficacy Results: The 90-day mortality rates were similar between the two groups—14.5% in the seven-day group versus 16.1% in the 14-day group—demonstrating the non-inferiority of the shorter regimen.
- Secondary Outcomes: Rates of relapse, ICU mortality, hospital mortality, and other clinical markers showed no significant differences between the two groups.
- Patient Demographics: The study included a diverse patient population, with 55% in intensive care units at enrollment. Infections originated from various sources, most commonly the urinary tract (42.2%), abdomen (18.8%), and lungs (13.0%).
- Applicability: Exclusion criteria were minimal, enhancing the generalizability of the findings to everyday clinical practice. Patients with extreme immunosuppression or undrained abscesses were excluded, but those with conditions like renal failure were included.
Lead investigator Dr. Nick Daneman emphasized, “These findings underscore the effectiveness of a shorter antibiotic regimen in patients with bloodstream infections, which is welcomed as we look to identify evidence-based prescribing guidelines for serious bacterial infections.”
Conclusion: The BALANCE trial provides robust evidence that a seven-day antibiotic course is sufficient for treating BSIs, potentially transforming current clinical practice. Adopting shorter antibiotic regimens can reduce healthcare costs, minimize adverse effects, and combat antimicrobial resistance without compromising patient outcomes. This aligns with antimicrobial stewardship goals and promotes more efficient use of healthcare resources.
Source: This study was presented at IDWeek 2024, the joint annual meeting of the Infectious Diseases Society of America and other related organizations. The research was conducted by a team from Sunnybrook Health Sciences Centre and the University of Toronto, led by Dr. Nick Daneman and Dr. Robert Fowler. More information can be found at: http://www.idsociety.org/news–publications-new/articles/2024/antibiotic-treatment-regimen-for-bloodstream-infections-can-safely-be-cut-by-half
RCT: Preemptive TAVR Does Not Improve Composite Outcomes but May Improve Quality of Life in HFrEF Patients with Moderate Aortic Stenosis
10 Nov, 2024 | 14:18h | UTCBackground: Heart failure with reduced ejection fraction (HFrEF) management emphasizes neurohormonal modulation and afterload reduction. Moderate aortic stenosis (AS) increases afterload, potentially worsening outcomes in HFrEF patients. While transcatheter aortic valve replacement (TAVR) is established for severe AS, its benefit in moderate AS remains uncertain.
Objective: To determine whether TAVR provides clinical benefits over guideline-directed medical therapy (GDMT) in patients with HFrEF and moderate AS.
Methods: In the TAVR UNLOAD randomized controlled trial, 178 symptomatic HFrEF patients (left ventricular ejection fraction 20%-50%) on GDMT with moderate AS were randomized 1:1 to receive TAVR with a balloon-expandable valve or clinical AS surveillance (CASS) with aortic valve replacement upon progression to severe AS. The primary endpoint was the hierarchical occurrence of: (1) all-cause death; (2) disabling stroke; (3) disease-related hospitalizations and heart failure equivalents; and (4) change from baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS).
Results: The mean age was 77 years, 20.8% were female, and 55.6% were in NYHA class III or IV. Median follow-up was 23 months. In the CASS group, 43% underwent TAVR due to progression to severe AS at a median of 12 months. TAVR was not superior to CASS for the primary endpoint (win ratio 1.31; 95% CI: 0.91-1.88; P = 0.14). However, at 1 year, TAVR resulted in a greater improvement in KCCQ-OSS compared with CASS (12.8 ± 21.9 vs 3.2 ± 22.8 points; P = 0.018). There were no significant differences in all-cause mortality or major adverse events between groups.
Conclusions: In HFrEF patients with moderate AS on GDMT, TAVR was not superior to clinical surveillance for the primary composite endpoint but was associated with improved quality of life at 1 year.
Implications for Practice: Preemptive TAVR may offer quality-of-life benefits in select symptomatic HFrEF patients with moderate AS but does not reduce mortality or major cardiovascular events compared to surveillance. Clinicians should weigh patient-specific factors when considering TAVR for moderate AS.
Study Strengths and Limitations: Strengths include being the first randomized trial assessing TAVR in moderate AS with HFrEF. Limitations involve being underpowered due to slow enrollment and protocol changes, and a high crossover rate (43% in the CASS group underwent TAVR), potentially attenuating differences between groups.
Future Research: Larger, adequately powered trials are needed to confirm these findings and identify patients who may benefit most from preemptive TAVR in moderate AS.
Cochrane: Galantamine Improves Cognitive Function in Alzheimer’s Disease but Not in Mild Cognitive Impairment
10 Nov, 2024 | 13:40h | UTCBackground: Alzheimer’s disease is the leading cause of dementia. While incurable, symptomatic treatments like galantamine, a cholinesterase inhibitor, are approved for Alzheimer’s disease.
Objective: To assess the clinical effects and adverse events of galantamine in people with Alzheimer’s disease or mild cognitive impairment.
Methods: A systematic review of double-blind, parallel-group, randomized controlled trials comparing oral galantamine with placebo in people with Alzheimer’s disease or mild cognitive impairment. Outcomes included cognitive function, global function, activities of daily living, functional disability, behavioral function, and adverse events.
Results: Twenty-one studies with 10,990 participants were included. Treatment durations ranged from eight weeks to two years. In Alzheimer’s disease, galantamine at 16 mg to 24 mg/day for six months significantly improved cognitive function compared to placebo (MD –2.86 on ADAS-cog, 95% CI –3.29 to –2.43; six studies, 3049 participants; high-certainty evidence). Functional disability improved (MD 2.12 on DAD, 95% CI 0.75 to 3.49; three studies, 1275 participants), as did behavioral function (MD –1.63 on NPI, 95% CI –3.07 to –0.20; two studies, 1043 participants). Participants receiving galantamine had higher rates of premature discontinuation (OR 1.41, 95% CI 1.19 to 1.68; six studies, 3336 participants) and nausea (OR 2.89, 95% CI 2.40 to 3.49; seven studies, 3616 participants). Death rates were reduced in the galantamine groups (OR 0.56, 95% CI 0.33 to 0.96; six studies, 3493 participants).
In mild cognitive impairment, galantamine did not improve cognitive function (MD –0.21 on ADAS-cog/MCI, 95% CI –0.78 to 0.37; two studies, 1901 participants; low-certainty evidence) or activities of daily living (MD 0.30 on ADCS-ADL-MCI, 95% CI –0.26 to 0.86). Adverse events and discontinuation rates were higher with galantamine.
Conclusions: Galantamine at 16 mg to 24 mg/day improves cognitive function, functional ability, and behavior over six months in Alzheimer’s disease, with clinically meaningful changes. Gastrointestinal adverse events are common and may limit tolerability. Galantamine is not effective in mild cognitive impairment.
Implications for Practice: Galantamine may be considered for symptomatic treatment in mild to moderate Alzheimer’s disease to improve cognition, daily functioning, and behavior, weighing the benefits against the increased risk of gastrointestinal adverse events. It is not recommended for people with mild cognitive impairment.
Study Strengths and Limitations: Strengths include a large sample size and high-certainty evidence for key outcomes in Alzheimer’s disease. Limitations involve high attrition rates and potential bias due to higher discontinuation in galantamine groups. The evidence for mild cognitive impairment is of low certainty due to risk of bias and imprecision.
Future Research: Further trials are needed in more diverse clinical populations, including those with severe Alzheimer’s disease and over longer durations. Research should focus on quality of life outcomes, cost-effectiveness, and subgroup analyses based on individual-level factors.
RCT: QFR Not Non-Inferior to FFR in Guiding Revascularization of Intermediate Coronary Stenoses
10 Nov, 2024 | 13:23h | UTCBackground: Fractional flow reserve (FFR) is the gold standard for assessing the functional significance of intermediate coronary stenoses and guiding revascularization decisions. Quantitative flow ratio (QFR) is a novel, noninvasive computational method for estimating FFR from angiography without the need for pressure wires. Despite promising diagnostic accuracy, the efficacy of QFR compared to FFR in clinical outcomes remains uncertain.
Objective: To determine whether a QFR-guided strategy is non-inferior to an FFR-guided strategy regarding 12-month clinical outcomes in patients with intermediate coronary stenosis.
Methods: In this multicentre, randomized, open-label, non-inferiority trial (FAVOR III Europe), 2,000 patients from 34 European centers with intermediate coronary stenosis (40–90% diameter stenosis) were randomized 1:1 to QFR-guided or FFR-guided revascularization strategies. The primary endpoint was a composite of death, myocardial infarction, and unplanned revascularisation at 12 months.
Results: At 12 months, the primary endpoint occurred in 6.7% of patients in the QFR group and 4.2% in the FFR group (hazard ratio [HR] 1.63; 95% CI 1.11–2.41). The upper limit of the 90% CI exceeded the predefined non-inferiority margin, indicating that QFR did not meet non-inferiority to FFR. Additionally, more patients underwent revascularisation in the QFR group (67.5%) compared to the FFR group (59.9%).
Conclusions: A QFR-guided strategy did not demonstrate non-inferiority to an FFR-guided strategy for guiding coronary revascularization in patients with intermediate stenoses. The use of QFR led to more revascularizations without an improvement in clinical outcomes.
Implications for Practice: While QFR offers a non-invasive alternative to FFR, these findings suggest that QFR should not replace FFR when available for guiding revascularization decisions in intermediate coronary stenosis.
Study Strengths and Limitations: Strengths include a large sample size and a multicentre design enhancing generalisability. Limitations encompass the lack of blinding, potential operator learning curves with QFR, and a lower-than-expected event rate in the FFR group, which may have affected the non-inferiority assessment.
Future Research: Further studies are warranted to refine QFR technology and evaluate its role in different patient populations and clinical settings where FFR is not readily available.
Meta-analysis: Hemodiafiltration Reduces Mortality in Kidney Failure Patients Compared to Hemodialysis
7 Nov, 2024 | 12:19h | UTCBackground: Kidney failure patients undergoing hemodialysis face high mortality rates, with approximately 50% dying within five years of initiating treatment. Hemodiafiltration, a convection-based therapy that removes a broader spectrum of uraemic toxins, has been proposed to improve survival outcomes. Previous studies have shown mixed results regarding its efficacy, and uncertainties remain about its effects on specific patient subgroups, dose-response relationships with convection volume, and cause-specific mortality.
Objective: To compare the effects of online hemodiafiltration versus standard hemodialysis on all-cause and cause-specific mortality in patients with kidney failure.
Methods: An individual patient data meta-analysis of five randomized controlled trials was conducted, encompassing 4,153 patients (2,083 on hemodiafiltration and 2,070 on hemodialysis). Databases including MEDLINE, Embase, and the Cochrane Central Register were searched up to July 17, 2024. The primary outcome was all-cause mortality. Subgroup analyses based on patient characteristics and dose–response analyses using convection volume were performed.
Results: Over a median follow-up of 30 months, all-cause mortality occurred in 477 patients (23.3%) receiving hemodiafiltration and 559 patients (27.0%) receiving hemodialysis. Hemodiafiltration significantly reduced all-cause mortality (hazard ratio [HR] 0.84, 95% CI 0.74–0.95) compared to hemodialysis. Cardiovascular mortality was also lower in the hemodiafiltration group (HR 0.78, 95% CI 0.64–0.96), particularly deaths due to cardiac causes (HR 0.67, 95% CI 0.50–0.89). No differential effects were observed across predefined patient subgroups. A dose-dependent relationship was found between higher convection volumes and reduced mortality risk.
Conclusions: Hemodiafiltration significantly reduces all-cause and cardiovascular mortality in patients with kidney failure compared to standard hemodialysis. The mortality benefit is dose-dependent, with higher convection volumes associated with greater risk reductions.
Implications for Practice: These findings support the adoption of online hemodiafiltration as a superior alternative to conventional hemodialysis. Clinicians should consider implementing high-dose hemodiafiltration to improve survival outcomes in patients with kidney failure.
Study Strengths and Limitations: Strengths include the large sample size and use of individual patient data, allowing for comprehensive subgroup and dose–response analyses. Limitations involve heterogeneity among the included studies and potential biases due to open-label designs. The lack of blinding may have influenced outcome reporting.
Future Research: Further studies are needed to evaluate the long-term benefits of hemodiafiltration on patient-reported outcomes, cost-effectiveness, and environmental impacts. Investigations into the optimal convection volumes and the mechanisms underlying the observed mortality reductions are also warranted.
News Release: CLEAR SYNERGY Trial Finds No Cardiovascular Benefit of Colchicine Post-Myocardial Infarction
7 Nov, 2024 | 11:55h | UTCIntroduction: The international CLEAR SYNERGY (OASIS 9) trial investigated the long-term cardiovascular effects of colchicine in patients undergoing percutaneous coronary intervention (PCI) following acute myocardial infarction (MI). Colchicine, an anti-inflammatory agent, had previously shown promise in reducing cardiovascular events in patients with coronary artery disease. This study aimed to evaluate whether colchicine could improve outcomes in a high-risk post-MI population.
Highlights:
- Study Design: Over 7,000 patients with acute MI (95% with STEMI) were enrolled and randomized to receive either colchicine 0.5 mg daily or placebo, in addition to standard care. The trial featured a 2×2 factorial design, also assessing spironolactone versus placebo.
- Primary Outcome: After a median follow-up of 3.5 years, the primary endpoint—a composite of cardiovascular death, MI, stroke, or ischemia-driven revascularization—occurred in 9.1% of the colchicine group and 9.3% of the placebo group (Hazard Ratio [HR] 0.99; 95% Confidence Interval [CI] 0.85-1.16; p=0.93), indicating no significant difference.
- Secondary Outcomes: There were no significant differences in individual components of the primary endpoint, including cardiovascular death (3.3% vs. 3.2%), MI (2.9% vs. 3.1%), or ischemia-driven revascularization (4.6% vs. 4.7%). All-cause mortality was slightly lower in the colchicine group but not statistically significant.
- Safety Profile: Colchicine was associated with a higher incidence of diarrhea (10.2% vs. 6.6%; p<0.001). Serious infections were similar between groups.
- Comparison with Previous Studies: The findings contrast with earlier trials like COLCOT and LoDoCo2, which reported cardiovascular benefits with colchicine in similar patient populations. Possible reasons for the discrepancy include differences in patient characteristics, study design, and the impact of external factors such as the COVID-19 pandemic.
Conclusion: The CLEAR SYNERGY trial concludes that routine use of colchicine following PCI for acute MI does not reduce the risk of major adverse cardiovascular events. These results suggest reevaluating the role of colchicine in post-MI management and may influence future guideline recommendations. Clinicians should consider these findings when prescribing colchicine, balancing the lack of cardiovascular benefit against the potential for gastrointestinal side effects.
Source: This research was conducted by the Population Health Research Institute and presented at the Transcatheter Cardiovascular Therapeutics (TCT) conference on October 29, 2024. Detailed results are available through the American College of Cardiology (https://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2024/10/25/04/34/clear-synergy) and TCTMD (https://www.tctmd.com/news/colchicine-surprise-no-help-post-mi-large-clear-synergy-trial-shows).
Guideline: Management of Urinary Tract Infections in Pediatrics and Adults
5 Nov, 2024 | 18:59h | UTCIntroduction: Urinary tract infections (UTIs) are among the most common infections worldwide, significantly impacting patient quality of life and imposing substantial clinical and economic burdens. Despite advancements in diagnosis and treatment, UTIs continue to cause high morbidity and mortality, ranging from simple cystitis to life-threatening sepsis. Addressing the discrepancy between evidence quality and recommendation strength in existing guidelines, the WikiGuidelines Group has developed a consensus statement. This guideline aims to provide evidence-based recommendations for the prevention, diagnosis, and management of UTIs across diverse clinical settings.
Key Recommendations:
- Cranberry Products:
- Recommendation: Cranberry juice or supplements are recommended for preventing symptomatic, culture-verified UTIs in women with recurrent UTIs, children, and individuals susceptible after interventions.
- Quality of Evidence: Moderate
- Recommendation Strength: Strong
- Methenamine Hippurate:
- Recommendation: Methenamine hippurate is recommended as an alternative to prophylactic antibiotics for preventing recurrent UTIs in patients with intact bladder anatomy.
- Quality of Evidence: Moderate
- Recommendation Strength: Strong
- Topical Estrogen:
- Recommendation: Vaginal estrogen therapy is recommended for postmenopausal women to reduce recurrent UTIs by restoring the vaginal microbiome.
- Quality of Evidence: High
- Recommendation Strength: Strong
- Empirical Treatment Regimens:
- Recommendation: For uncomplicated cystitis, nitrofurantoin is recommended as a first-line agent. For pyelonephritis, trimethoprim/sulfamethoxazole or a first-generation cephalosporin are reasonable first-line agents, depending on local resistance rates.
- Quality of Evidence: Moderate
- Recommendation Strength: Strong
- Treatment Duration for Acute Cystitis in Adults:
- Recommendation:
- Nitrofurantoin: 5 days
- Trimethoprim/sulfamethoxazole: 3 days
- Oral fosfomycin: Single dose
- Quality of Evidence: High
- Recommendation Strength: Strong
- Recommendation:
- Treatment Duration for Acute Pyelonephritis in Adults:
- Recommendation:
- Fluoroquinolones: 5–7 days
- Dose-optimized β-lactams: 7 days
- Quality of Evidence: High
- Recommendation Strength: Strong
- Recommendation:
- Antimicrobial Stewardship:
- Recommendation: De-escalation of antibiotics and the use of mostly or all oral treatment regimens are recommended to optimize antimicrobial use and reduce adverse effects.
- Quality of Evidence: High
- Recommendation Strength: Strong
Conclusion: The consensus highlights a significant lack of high-quality prospective data in many areas related to UTIs, limiting the ability to provide clear recommendations. Implementing these evidence-based guidelines can enhance patient care by promoting effective prevention strategies, accurate diagnosis based on clinical symptoms, appropriate treatment durations, and robust antimicrobial stewardship. This approach is expected to improve clinical outcomes, reduce antimicrobial resistance, and preserve the effectiveness of current treatments.
RCT: Lipoprotein(a) and LDL-C as Independent Cardiovascular Risk Factors in Statin Trials
5 Nov, 2024 | 17:50h | UTCBackground: Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) [Lp(a)] are both known risk factors for atherosclerotic cardiovascular disease (ASCVD). However, the interaction between Lp(a) and LDL-C levels in relation to ASCVD risk, especially in the context of LDL-C-lowering treatments like statins, remains unclear. This study aimed to clarify if LDL-C reduction impacts Lp(a)-associated ASCVD risk.
Objective: This meta-analysis examined whether LDL-C reduction with statins affects ASCVD risk mediated by elevated Lp(a) levels.
Methods: Data from 27,658 participants across six statin trials were analyzed, including both placebo and statin groups. ASCVD risk was assessed using multivariable Cox proportional hazards models with adjustments for various cardiovascular risk factors. The study evaluated continuous associations between Lp(a) levels, LDL-C levels, and ASCVD risk.
Results: Elevated Lp(a) levels were associated with higher ASCVD risk across all LDL-C levels, even among patients with the lowest LDL-C achieved through statin therapy. Statin-treated patients with Lp(a) >50 mg/dL exhibited a significantly higher ASCVD risk, even in the lowest quartile of achieved LDL-C (HR 1.38, 95% CI 1.06–1.79). The highest risk was observed in individuals with both elevated Lp(a) and LDL-C levels (HR 1.90, 95% CI 1.46–2.48).
Conclusions: Lp(a) and LDL-C are independent risk factors for ASCVD, with LDL-C lowering alone insufficient to mitigate the risk associated with elevated Lp(a).
Implications for Practice: These findings underscore the need for distinct strategies to manage patients with elevated Lp(a), particularly as LDL-C reduction alone does not fully address the associated ASCVD risk.
Study Strengths and Limitations: This study’s strength lies in its large participant pool and robust statistical analysis; however, variability in Lp(a) measurement methods across trials may limit precision.
Future Research: Investigations into therapies specifically targeting Lp(a) may offer additional ASCVD risk reduction beyond LDL-C lowering alone.
Cohort Study: Late Ventricular Arrhythmias After Primary PCI for STEMI Are Rare but Increase Mortality
5 Nov, 2024 | 15:24h | UTCBackground: Ventricular tachycardia (VT) and ventricular fibrillation (VF) are critical complications following ST-segment elevation myocardial infarction (STEMI). While early VT/VF typically occurs before or shortly after reperfusion, contemporary data on the incidence of late VT/VF post-primary percutaneous coronary intervention (PCI) are limited. Understanding the risk of late VT/VF is essential for optimizing in-hospital monitoring and discharge timing.
Objective: To assess the risk of late VT and VF after primary PCI in patients with STEMI, identify associated factors, and evaluate their impact on in-hospital mortality.
Methods: This cohort study analyzed data from 174,126 adults with STEMI treated with primary PCI between January 1, 2015, and December 31, 2018, using the National Cardiovascular Data Registry Chest Pain–MI Registry. Late VT/VF was defined as events occurring one or more days after PCI. Multivariable logistic regression was employed to identify factors associated with late VT/VF and its association with in-hospital mortality.
Results: Among the patients, 8.9% experienced VT or VF after primary PCI. Late VT/VF occurred in 2.4% of patients overall and 1.7% of those with uncomplicated STEMI. Late VT/VF associated with cardiac arrest was rare, occurring in 0.4% of all patients and 0.1% of patients with uncomplicated STEMI. Decreased left ventricular ejection fraction (LVEF) was the most significant factor associated with late VT/VF with cardiac arrest (adjusted odds ratio [AOR] for every 5-unit decrease ≤40%: 1.67; 95% CI, 1.54–1.85). Late VT/VF was linked to increased odds of in-hospital mortality (AOR, 6.40; 95% CI, 5.63–7.29).
Conclusions: Late VT/VF after primary PCI for STEMI is infrequent, particularly in patients with uncomplicated presentations. However, when late VT/VF occurs, it is associated with a significantly higher risk of in-hospital mortality.
Implications for Practice: While vigilant monitoring remains crucial, patients with uncomplicated STEMI may be candidates for earlier discharge through shared decision-making. Identifying high-risk patients for late VT/VF can enable tailored monitoring strategies to improve outcomes.
Study Strengths and Limitations: Strengths include a large, contemporary cohort and detailed data on in-hospital VT/VF events. Limitations involve the observational design, potential unmeasured confounders, and the inability to differentiate between VT and VF due to registry definitions.
Future Research: Further studies are warranted to develop precise risk prediction models for late VT/VF and to explore effective out-of-hospital monitoring strategies post-STEMI.
2023 VA/DoD Clinical Practice Guidelines for the Management of Headache
3 Nov, 2024 | 18:45h | UTCIntroduction: Headache disorders, notably migraine and tension-type headache (TTH), are among the most prevalent and disabling neurological conditions globally, significantly impacting individuals’ quality of life and imposing substantial societal costs. This 2023 guideline provides primary care clinicians with evidence-based recommendations for the evaluation, treatment, and prevention of migraine and TTH, aiming to enhance patient care and outcomes.
Key Recommendations:
- Acute Migraine Treatment:
- Triptans (eletriptan, frovatriptan, rizatriptan, sumatriptan, zolmitriptan) are strongly recommended for short-term migraine relief. (Strength: Strong for)
- Aspirin–Acetaminophen–Caffeine combination is strongly recommended for acute migraine treatment. (Strength: Strong for)
- Gepants (ubrogepant, rimegepant) are suggested as options for acute migraine management. (Strength: Weak for)
- NSAIDs (aspirin, ibuprofen, naproxen) and acetaminophen are suggested for acute migraine relief. (Strength: Weak for)
- Preventive Migraine Therapy:
- CGRP Monoclonal Antibodies (erenumab, fremanezumab, galcanezumab) are strongly recommended for preventing episodic or chronic migraine. (Strength: Strong for)
- Angiotensin Receptor Blockers (candesartan, telmisartan) are recommended for episodic migraine prevention. (Strength: Strong for)
- Topiramate and valproate are suggested for migraine prevention. (Strength: Weak for)
- Lisinopril, magnesium, memantine, and atogepant are suggested for preventing episodic migraine. (Strength: Weak for)
- OnabotulinumtoxinA injections are suggested for preventing chronic migraine but not episodic migraine. (Strength: Weak for chronic migraine; Weak against for episodic migraine)
- Gabapentin is not recommended for preventing episodic migraine. (Strength: Weak against)
- Tension-Type Headache Management:
- For acute TTH, ibuprofen (400 mg) or acetaminophen (1000 mg) are suggested. (Strength: Weak for)
- Amitriptyline is suggested for preventing chronic TTH. (Strength: Weak for)
- Nonpharmacologic Interventions:
- Physical Therapy is suggested for managing TTH and migraine. (Strength: Weak for)
- Aerobic Exercise or progressive strength training is suggested for preventing TTH and migraine. (Strength: Weak for)
- Injections and Procedures:
- Greater Occipital Nerve Block is suggested for short-term migraine treatment. (Strength: Weak for)
Conclusion: The 2023 VA/DoD Clinical Practice Guideline provides updated, evidence-based recommendations for managing migraine and TTH, incorporating new pharmacologic agents and nonpharmacologic interventions. The inclusion of newer medications, such as CGRP inhibitors, offers additional options for patients who may not respond to traditional therapies.
RCT: Atrasentan Reduces Proteinuria in Patients with IgA Nephropathy
3 Nov, 2024 | 18:29h | UTCBackground: IgA nephropathy is the most common primary glomerular disease worldwide, leading to a substantial risk of kidney failure. Despite treatment with renin–angiotensin system (RAS) inhibitors, many patients experience persistent proteinuria and progressive kidney function decline. Endothelin-1, acting via the endothelin type A receptor, contributes to the disease’s pathophysiology. Atrasentan, a selective endothelin type A receptor antagonist, has shown potential in reducing proteinuria in prior studies.
Objective: To evaluate the efficacy and safety of atrasentan in reducing proteinuria among patients with IgA nephropathy.
Methods: In this phase 3, multinational, double-blind, randomized controlled trial, adults with biopsy-proven IgA nephropathy, urinary protein excretion of at least 1 g/day, and an estimated glomerular filtration rate (eGFR) of at least 30 ml/min/1.73 m² were enrolled. Patients on maximum tolerated doses of ACE inhibitors or ARBs were randomized 1:1 to receive atrasentan (0.75 mg/day) or placebo for 132 weeks. The primary outcome was the change in the 24-hour urinary protein-to-creatinine ratio from baseline to week 36, assessed in a prespecified interim analysis of the first 270 patients.
Results: Among these patients (135 per group), the geometric mean percentage reduction in the urinary protein-to-creatinine ratio at week 36 was significantly greater with atrasentan (−38.1%) compared to placebo (−3.1%), yielding a between-group difference of −36.1 percentage points (95% CI, −44.6 to −26.4; P<0.001). Adverse events were similar between groups. Fluid retention was reported in 11.2% of the atrasentan group and 8.2% of the placebo group but did not lead to discontinuation. No cases of cardiac failure or severe edema occurred.
Conclusions: Atrasentan significantly reduced proteinuria compared to placebo in patients with IgA nephropathy without significant safety concerns.
Implications for Practice: Atrasentan may serve as an effective additional therapy for patients with IgA nephropathy who remain at high risk of progression despite standard care, potentially influencing clinical decision-making toward more aggressive proteinuria reduction strategies.
Study Strengths and Limitations: Strengths include the randomized controlled design and a representative high-risk population. Limitations involve the interim analysis nature of the data and underrepresentation of Black patients, which may limit generalizability.
Future Research: Long-term effects on eGFR decline and the potential benefits of combining atrasentan with other therapies, such as SGLT2 inhibitors, warrant further investigation.
Multisociety Guidelines for Perioperative Management of GLP-1 Receptor Agonists
3 Nov, 2024 | 14:27h | UTCIntroduction: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed the management of metabolic diseases such as type 2 diabetes, obesity, and heart failure by enhancing glycemic control and promoting satiety. However, their effect of delaying gastric emptying has raised perioperative safety concerns due to the risk of residual gastric contents leading to pulmonary aspiration during anesthesia. Reports of aspiration incidents and gastrointestinal side effects like nausea and vomiting have prompted the need for unified clinical guidance. This multisociety clinical practice guideline aims to provide recommendations for safely managing patients on GLP-1RAs during the perioperative period, balancing metabolic benefits with procedural risks.
Key Recommendations:
- Shared Decision-Making:
- Collaborative Approach: The continuation or discontinuation of GLP-1RAs should involve shared decision-making among the patient, surgical team, anesthesia providers, and prescribing clinicians.
- Risk Assessment: Evaluate factors that elevate the risk of delayed gastric emptying and aspiration, including:
- Dose Escalation Phase: Higher risk during dose escalation compared to maintenance.
- Higher Dosage: Increased gastrointestinal side effects with higher doses.
- Weekly Formulations: Greater side effects with weekly dosing compared to daily formulations.
- Gastrointestinal Symptoms: Presence of nausea, vomiting, abdominal pain, dyspepsia, or constipation.
- Comorbid Conditions: Conditions like gastroparesis, bowel dysmotility, or neurological disorders affecting gastric motility.
- Timing: Conduct risk assessments well in advance of surgery to allow for appropriate preoperative planning.
- Management of GLP-1RA Therapy:
- Continuation in Low-Risk Patients: GLP-1RAs may be continued preoperatively in patients without elevated risk factors.
- Balancing Risks in High-Risk Patients:
- Metabolic vs. Procedural Risks: Weigh the risks of aspiration against potential metabolic complications like hyperglycemia if GLP-1RAs are withheld.
- Avoiding Bias: Decisions should not be based solely on obesity status to prevent bias.
- Discontinuation Guidelines:
- Daily Formulations: Hold on the day of surgery.
- Weekly Formulations: Discontinue one week prior to surgery.
- Day-of-Surgery Assessment: All patients should be evaluated for symptoms of delayed gastric emptying on the day of the procedure, regardless of GLP-1RA usage.
- Minimizing Aspiration Risk:
- Preoperative Dietary Modifications:
- Liquid Diet: Implement a liquid diet for at least 24 hours before surgery, similar to protocols for colonoscopy and bariatric procedures.
- Gastric Content Assessment:
- Point-of-Care Ultrasound: Use gastric ultrasound to assess residual gastric contents when there is concern for delayed emptying, acknowledging potential limitations in resources and expertise.
- Anesthesia Plan Adjustments:
- Rapid Sequence Induction: Consider rapid sequence induction with tracheal intubation to minimize aspiration risk in patients with confirmed or suspected delayed gastric emptying.
- Procedure Continuation vs. Cancellation: Engage in shared decision-making to weigh the benefits of proceeding with the procedure against the risks, aiming to avoid unnecessary cancellations.
- Preoperative Dietary Modifications:
Conclusion: By adopting these recommendations, healthcare providers can enhance patient safety during the perioperative period for those receiving GLP-1RA therapy. The guidelines emphasize individualized care through shared decision-making, considering both metabolic benefits and procedural risks. Implementing these practices is expected to reduce aspiration incidents, optimize surgical outcomes, and ensure equitable care without bias against patients with obesity or metabolic disorders. As new evidence and medications emerge, these guidelines may be updated to reflect best practices.
Reference: Kindel TL, Wang AY, Wadhwa A, et al. Multisociety clinical practice guidance for the safe use of glucagon-like peptide-1 receptor agonists in the perioperative period. Surgery for Obesity and Related Diseases. 2024; In Press. https://doi.org/10.1016/j.soard.2024.08.033
Clinical Trial Follow-up: Empagliflozin Continues to Reduce Cardiorenal Risks Post-Discontinuation in CKD Patients
3 Nov, 2024 | 13:08h | UTCBackground: Chronic kidney disease (CKD) progression leads to end-stage kidney disease, adversely affecting quality of life, increasing cardiovascular morbidity and mortality, and imposing high economic costs. Previous trials, including the EMPA-KIDNEY trial, demonstrated that empagliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, provides cardiorenal benefits in CKD patients at risk of progression. The persistence of these benefits after discontinuation of the drug remains uncertain.
Objective: To assess how the effects of empagliflozin on kidney disease progression and cardiovascular outcomes evolve after discontinuation in patients with CKD.
Methods: In this randomized, double-blind, placebo-controlled trial, 6,609 patients with CKD were assigned to receive empagliflozin 10 mg daily or placebo and followed for a median of 2 years during the active trial period. Eligible patients had an estimated glomerular filtration rate (eGFR) between 20 and less than 45 ml/min/1.73 m², or between 45 and less than 90 ml/min/1.73 m² with a urinary albumin-to-creatinine ratio of at least 200 mg/g. After the active trial, 4,891 surviving patients consented to a 2-year post-trial follow-up without the trial drug, during which local practitioners could prescribe open-label SGLT2 inhibitors. The primary composite outcome was kidney disease progression or cardiovascular death from the start of the active trial to the end of the post-trial period.
Results: During the combined active and post-trial periods, a primary outcome event occurred in 26.2% of patients in the empagliflozin group and 30.3% in the placebo group (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.72–0.87). During the post-trial period alone, the HR was 0.87 (95% CI, 0.76–0.99), indicating continued benefit after drug discontinuation. The risk of kidney disease progression was 23.5% in the empagliflozin group versus 27.1% in the placebo group (HR, 0.79; 95% CI, 0.72–0.87). Cardiovascular death occurred in 3.8% and 4.9% of patients, respectively (HR, 0.75; 95% CI, 0.59–0.95). No significant effect was observed on death from noncardiovascular causes (5.3% in both groups).
Conclusions: In patients with CKD at risk for progression, empagliflozin continued to confer cardiorenal benefits for up to 12 months after discontinuation. These findings suggest that short-term treatment with empagliflozin has lasting effects on kidney and cardiovascular outcomes.
Implications for Practice: Empagliflozin should be considered for a broad range of CKD patients to slow disease progression and reduce cardiovascular risk, with benefits extending beyond active treatment. Clinicians should initiate empagliflozin therapy in eligible CKD patients to maximize long-term cardiorenal protection.
Study Strengths and Limitations: Strengths include the large sample size, broad eligibility criteria, and high follow-up rates. Limitations involve the exclusion of certain regions during post-trial follow-up and reliance on local eGFR measurements during this period.
Future Research: Further studies are needed to understand the mechanisms behind the sustained benefits of empagliflozin after discontinuation and to explore the long-term effects of extended treatment durations.
RCT: No Significant Difference Between Intraosseous and Intravenous Vascular Access in Out-of-Hospital Cardiac Arrest Outcomes
3 Nov, 2024 | 12:58h | UTCBackground: Out-of-hospital cardiac arrest (OHCA) is a major global health concern, resulting in high mortality rates despite advancements in emergency care. In Denmark alone, approximately 5,000 cases occur annually, with a 30-day survival rate of only about 14%. Rapid vascular access during cardiopulmonary resuscitation (CPR) is crucial for administering medications like epinephrine, as recommended by international guidelines. Both intraosseous (IO) and intravenous (IV) routes are routinely used, but their comparative effectiveness remains unclear. Current guidelines favor IV access for initial attempts, yet this recommendation is based on very low-certainty evidence, highlighting the need for well-designed clinical trials.
Objective: To compare the effectiveness of initial intraosseous versus intravenous vascular access on sustained return of spontaneous circulation (ROSC) in adults experiencing nontraumatic OHCA.
Methods: This randomized, parallel-group superiority trial was conducted across all five regions of Denmark, covering 5.9 million inhabitants. Adults aged 18 years or older with nontraumatic OHCA requiring vascular access during CPR were randomized to receive either initial IO or IV access. The IO group was further randomized to humeral or tibial access for a secondary comparison. The primary outcome was sustained ROSC, defined as no need for chest compressions for at least 20 minutes. Key secondary outcomes included 30-day survival and survival with favorable neurologic outcome (modified Rankin scale score of 0–3). Procedural outcomes such as success rates of vascular access within two attempts, time to successful access, and time to first epinephrine administration were also assessed.
Results: Among 1,479 patients included in the primary analysis (731 in the IO group and 748 in the IV group), successful vascular access within two attempts was achieved in 92% of the IO group versus 80% of the IV group. Despite the higher success rate with IO access, the time to first successful access and time to first epinephrine dose were similar between groups. Sustained ROSC occurred in 30% of patients in the IO group and 29% in the IV group (risk ratio [RR], 1.06; 95% confidence interval [CI], 0.90–1.24; P=0.49). At 30 days, survival rates were 12% in the IO group and 10% in the IV group (RR, 1.16; 95% CI, 0.87–1.56), with favorable neurologic outcomes observed in 9% and 8% of patients, respectively (RR, 1.16; 95% CI, 0.83–1.62). No significant differences were found in procedural times, adverse events, or quality-of-life measures among survivors.
Conclusions: In adults with nontraumatic OHCA, initial intraosseous vascular access did not result in a significant difference in sustained ROSC compared to intravenous access. Both methods yielded comparable survival rates and neurologic outcomes at 30 days, suggesting that the choice of vascular access route may not critically impact immediate resuscitation success.
Implications for Practice: These findings indicate that emergency medical services can opt for either intraosseous or intravenous vascular access during resuscitation based on provider expertise, patient anatomy, and situational considerations without adversely affecting patient outcomes. Emphasizing flexibility in vascular access approach may facilitate quicker access and streamline resuscitation efforts in the prehospital setting.
Study Strengths and Limitations: Strengths include the randomized design, large sample size, and nationwide implementation, enhancing generalizability. Limitations involve potential crossover between groups, lack of blinding among clinicians, and the study being underpowered to detect small differences in long-term outcomes.
Future Research: Further studies are needed to assess long-term survival and neurologic outcomes, and to explore whether specific patient subgroups may benefit more from one vascular access method over the other during cardiac arrest resuscitation.
Reference: Vallentin MF, Granfeldt A, Klitgaard TL, et al. Intraosseous or Intravenous Vascular Access for Out-of-Hospital Cardiac Arrest. New England Journal of Medicine. 2024 Oct 31; DOI: http://doi.org/10.1056/NEJMoa2407616
RCT: Intraosseous vs. Intravenous Drug Administration in Out-of-Hospital Cardiac Arrest Shows No Difference in 30-Day Survival
3 Nov, 2024 | 12:48h | UTCBackground: Out-of-hospital cardiac arrest requires rapid drug administration, with medications like epinephrine being highly time-dependent. Intravenous access can be challenging prehospital due to environmental and patient factors, potentially delaying treatment. Intraosseous access may offer faster drug delivery, but its impact on clinical outcomes is unclear.
Objective: To compare the effectiveness of an intraosseous-first versus intravenous-first vascular access strategy on 30-day survival in adults experiencing out-of-hospital cardiac arrest requiring drug therapy.
Methods: In this multicenter, open-label, randomized trial across 11 UK emergency medical systems, 6,082 adults were assigned to receive either intraosseous-first or intravenous-first vascular access during resuscitation. The primary outcome was survival at 30 days. Secondary outcomes included return of spontaneous circulation and favorable neurologic function at hospital discharge (modified Rankin scale score ≤3).
Results: At 30 days, survival was 4.5% in the intraosseous group and 5.1% in the intravenous group (adjusted odds ratio [OR], 0.94; 95% confidence interval [CI], 0.68–1.32; P=0.74). Favorable neurologic outcome at discharge was similar between groups (2.7% vs. 2.8%; adjusted OR, 0.91; 95% CI, 0.57–1.47). Return of spontaneous circulation was lower in the intraosseous group (36.0% vs. 39.1%; adjusted OR, 0.86; 95% CI, 0.76–0.97).
Conclusions: An intraosseous-first vascular access strategy did not improve 30-day survival compared to an intravenous-first strategy in adults with out-of-hospital cardiac arrest. The intraosseous route was associated with a lower rate of return of spontaneous circulation.
Implications for Practice: Paramedics should consider that intraosseous access may not offer a survival advantage over intravenous access and may be linked to a reduced return of spontaneous circulation. This finding may influence decisions on vascular access during resuscitation efforts.
Study Strengths and Limitations: Strengths include a large, multicenter randomized design; limitations involve early termination reducing statistical power and inability to blind prehospital providers.
Future Research: Further studies should investigate why intraosseous access is associated with lower return of spontaneous circulation and assess if specific intraosseous techniques or sites affect outcomes.
RCT: Transcatheter Tricuspid-Valve Replacement Improves Symptoms and Quality of Life in Severe Tricuspid Regurgitation
3 Nov, 2024 | 12:37h | UTCBackground: Severe tricuspid regurgitation is associated with debilitating symptoms and increased mortality. Surgical intervention is infrequently performed due to high operative risks and late patient presentation, leading to poor outcomes. Transcatheter tricuspid-valve replacement offers a less invasive alternative versus surgical intervention, but data on its efficacy are limited.
Objective: To compare the safety and effectiveness of transcatheter tricuspid-valve replacement plus medical therapy versus medical therapy alone in patients with severe symptomatic tricuspid regurgitation.
Methods: In this international, multicenter randomized controlled trial, 400 patients with severe symptomatic tricuspid regurgitation despite optimal medical therapy were randomized in a 2:1 ratio to receive transcatheter tricuspid-valve replacement plus medical therapy (valve-replacement group, n=267) or medical therapy alone (control group, n=133). The primary outcome was a hierarchical composite of death from any cause, implantation of a right ventricular assist device or heart transplantation, postindex tricuspid-valve intervention, hospitalization for heart failure, and improvements in the KCCQ-OS score by at least 10 points, NYHA functional class by at least one class, and 6-minute walk distance by at least 30 meters.
Results: At one year, the win ratio favoring valve replacement was 2.02 (95% confidence interval [CI], 1.56 to 2.62; P<0.001), indicating superiority over medical therapy alone. Patients in the valve-replacement group had significant improvements in quality of life, with 66.4% achieving an increase of at least 10 points in the KCCQ-OS score compared to 36.5% in the control group. Improvement of at least one NYHA class was observed in 78.9% of the valve-replacement group versus 24.0% of the control group. Reduction of tricuspid regurgitation to mild or less was achieved in 95.2% of patients in the valve-replacement group, compared to 2.3% in the control group. Severe bleeding occurred more frequently in the valve-replacement group (15.4% vs. 5.3%; P=0.003), as did new permanent pacemaker implantation (17.8% vs. 2.3%; P<0.001).
Conclusions: Transcatheter tricuspid-valve replacement significantly improved clinical outcomes, symptoms, functional capacity, and quality of life in patients with severe tricuspid regurgitation compared to medical therapy alone, despite higher risks of severe bleeding and pacemaker implantation.
Implications for Practice: Transcatheter tricuspid-valve replacement offers a promising therapeutic option for patients with severe symptomatic tricuspid regurgitation who are at high surgical risk. Clinicians should consider this intervention to improve patient symptoms and quality of life, while carefully weighing the procedural risks, particularly bleeding and arrhythmias requiring pacemaker implantation.
Study Strengths and Limitations: Strengths of the study include its randomized controlled design and comprehensive evaluation of both clinical and patient-reported outcomes. Limitations involve the smaller control group due to the 2:1 randomization and a one-year follow-up period that may not capture long-term benefits or risks.
Future Research: Further studies with longer follow-up are needed to assess the durability of transcatheter tricuspid-valve replacement, its long-term impact on survival and hospitalization rates, and strategies to minimize procedural complications.