Pharmacology/Pharmaceutical Industry
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.
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.
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
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.
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.
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: Vitamin K2 Reduces Nocturnal Leg Cramps in Older Adults
28 Oct, 2024 | 18:59h | UTCBackground Nocturnal leg cramps (NLCs) affect 50% to 60% of adults, causing significant discomfort, sleep disturbances, and reduced quality of life. Current treatments lack robust evidence for efficacy and safety, with quinine no longer recommended due to severe adverse effects. Vitamin K2 has shown promise in reducing muscle cramps in dialysis patients, suggesting potential benefits for managing NLCs.
Objective To evaluate whether vitamin K2 supplementation reduces the frequency, duration, and severity of nocturnal leg cramps in older adults compared with placebo.
Methods In this multicenter, double-blind, placebo-controlled randomized clinical trial conducted in China from September 2022 to December 2023, 199 community-dwelling individuals aged 65 years or older with at least two episodes of NLCs over a two-week screening period were enrolled. Participants were randomly assigned in a 1:1 ratio to receive daily oral vitamin K2 (menaquinone-7, 180 μg) or placebo for eight weeks. The primary outcome was the mean number of NLCs per week. Secondary outcomes included cramp duration and severity, measured on a 1 to 10 analog scale.
Results Of the 199 participants (mean age 72.3 ± 5.5 years; 54.3% female), 103 received vitamin K2 and 96 received placebo. Baseline weekly cramp frequency was similar between groups (vitamin K2: 2.60 ± 0.81; placebo: 2.71 ± 0.80). Over eight weeks, the vitamin K2 group experienced a significant reduction in mean weekly cramps to 0.96 ± 1.41, while the placebo group increased to 3.63 ± 2.20 (between-group difference: −2.67; 95% CI, −2.86 to −2.49; P < .001). The vitamin K2 group also showed greater reductions in cramp severity (mean decrease of 2.55 ± 2.12 points vs 1.24 ± 1.16 points in placebo) and duration (mean decrease of 0.90 ± 0.88 minutes vs 0.32 ± 0.78 minutes in placebo). No adverse events related to vitamin K2 were reported.
Conclusions Vitamin K2 supplementation significantly reduced the frequency, severity, and duration of nocturnal leg cramps in older adults, demonstrating both efficacy and safety.
Implications for Practice Vitamin K2 may offer an effective and safe therapeutic option for managing NLCs in older individuals, addressing a significant unmet clinical need in primary care.
Study Strengths and Limitations Strengths include the randomized, double-blind design and focus on an older population; limitations involve the relatively mild symptoms of participants and lack of assessment of quality of life or sleep improvements.
Future Research Further studies should assess the impact of vitamin K2 on sleep quality and quality of life in patients with more severe NLCs and explore the underlying mechanisms of its muscle-relaxing effects.
RCT: ICS-Formoterol and ICS-SABA Reduce Severe Asthma Exacerbations Compared With SABA Alone
28 Oct, 2024 | 18:12h | UTCBackground: Asthma affects millions worldwide and is managed using inhaled relievers to alleviate acute symptoms. While short-acting β agonists (SABA) are commonly used, combining inhaled corticosteroids (ICS) with SABA or formoterol may enhance outcomes. Recent guidelines recommend ICS-formoterol as the preferred reliever, but the optimal choice remains uncertain, especially following the recent FDA approval of ICS-SABA.
Objective: To compare the efficacy and safety of SABA alone, ICS-SABA, and ICS-formoterol as reliever therapies in asthma.
Methods: This systematic review and network meta-analysis included 27 randomized controlled trials involving 50,496 adult and pediatric asthma patients. Trials compared SABA alone, ICS-SABA, and ICS-formoterol as reliever therapies, ensuring similar maintenance treatments across groups. Outcomes assessed were severe asthma exacerbations, asthma symptom control (Asthma Control Questionnaire-5 [ACQ-5]), asthma-related quality of life (Asthma Quality of Life Questionnaire [AQLQ]), adverse events, and mortality.
Results: Compared with SABA alone, both ICS-containing relievers significantly reduced severe exacerbations:
- ICS-formoterol: Risk ratio (RR) 0.65 (95% CI, 0.60–0.72); risk difference (RD) –10.3% (95% CI, –11.8% to –8.3%).
- ICS-SABA: RR 0.84 (95% CI, 0.73–0.95); RD –4.7% (95% CI, –8.0% to –1.5%).
Compared with ICS-SABA, ICS-formoterol further reduced severe exacerbations (RR 0.78; RD –5.5%). Both ICS-containing relievers modestly improved asthma symptom control compared with SABA alone. No increase in adverse events was observed with either ICS-containing therapy.
Conclusions: Both ICS-formoterol and ICS-SABA as reliever therapies reduce severe asthma exacerbations and improve symptom control compared with SABA alone, without increasing adverse events. ICS-formoterol may offer additional benefits over ICS-SABA in reducing exacerbations.
Implications for Practice: These findings support the use of ICS-containing reliever therapies over SABA alone in asthma management to reduce severe exacerbations and improve control. ICS-formoterol may be preferred when a greater reduction in exacerbations is desired.
Study Strengths and Limitations: High-certainty evidence strengthens these conclusions, but the lack of direct comparisons between ICS-formoterol and ICS-SABA and limited pediatric data are notable limitations.
Future Research: Direct head-to-head trials comparing ICS-formoterol and ICS-SABA, particularly in pediatric populations, are needed to confirm these findings.
RCT: Early DOACs Safe and Non-Inferior to Delayed Initiation Post-Stroke with Atrial Fibrillation
28 Oct, 2024 | 17:52h | UTCBackground: Atrial fibrillation increases ischaemic stroke risk, and patients are prone to recurrence. Prompt anticoagulation post-stroke is critical, but optimal timing is unclear due to bleeding concerns. Guidelines often delay DOAC initiation without strong evidence.
Objective: To determine if early DOAC initiation (≤4 days) is non-inferior to delayed initiation (7–14 days) in preventing recurrent ischaemic events without increasing intracranial haemorrhage risk in patients with acute ischaemic stroke and atrial fibrillation.
Methods: In this multicentre, open-label, blinded-endpoint, phase 4 randomised controlled trial at 100 UK hospitals, 3,621 adults with atrial fibrillation and acute ischaemic stroke were randomised to early or delayed DOAC initiation. Eligibility required physician uncertainty about timing. Participants and clinicians were unmasked; outcomes were adjudicated by a masked committee. The primary outcome was a composite of recurrent ischaemic stroke, symptomatic intracranial haemorrhage, unclassifiable stroke, or systemic embolism within 90 days.
Results: Among 3,621 patients (mean age 78.5; 45% female), the primary outcome occurred in 59 patients (3.3%) in both early and delayed groups (adjusted risk difference 0.0%, 95% CI –1.1 to 1.2%). Upper confidence limit below the 2% non-inferiority margin (p=0.0003) confirmed non-inferiority. Symptomatic intracranial haemorrhage rates were similar (0.6% early vs 0.7% delayed; p=0.78). No significant differences in mortality or heterogeneity across subgroups.
Conclusions: Early DOAC initiation within 4 days is non-inferior to delayed initiation in preventing recurrent events without increasing intracranial haemorrhage risk. Findings challenge guidelines advising delayed anticoagulation and support early initiation regardless of stroke severity.
Implications for Practice: Clinicians should consider starting DOACs within 4 days post-stroke in atrial fibrillation patients. Early initiation is safe and effective, potentially improving outcomes and suggesting guidelines may need revision.
Study Strengths and Limitations: Strengths include large sample size and masked outcome adjudication. Limitations include exclusion of patients with very severe strokes and low event rates, potentially limiting detection of rare adverse events.
Future Research: Further studies should explore optimal DOAC timing within 4 days and assess safety in patients with severe strokes or extensive haemorrhagic transformation.
Post-trial Follow-up: Empagliflozin Shows Sustained Benefits Post-Discontinuation in Chronic Kidney Disease
25 Oct, 2024 | 20:29h | UTCBackground: Chronic kidney disease (CKD) progression leads to end-stage kidney disease, affecting quality of life and increasing cardiovascular morbidity and mortality. Empagliflozin, an SGLT2 inhibitor, has shown renal and cardiovascular benefits during active treatment. The persistence of these effects post-discontinuation is uncertain.
Objective: To evaluate how the cardiorenal benefits of empagliflozin evolve after stopping the medication, by assessing the composite outcome of kidney disease progression or cardiovascular death during both the active trial and a subsequent post-trial follow-up.
Methods: In the EMPA-KIDNEY trial, 6609 patients with CKD were randomized to receive empagliflozin 10 mg daily or placebo and were followed for a median of 2 years during the active trial. Eligible patients had an eGFR of 20–45 ml/min/1.73 m² or an eGFR of 45–90 ml/min/1.73 m² with a urinary albumin-to-creatinine ratio ≥200 mg/g. After the active trial, 4891 surviving patients (74%) consented to a 2-year post-trial follow-up without the trial medication, although open-label SGLT2 inhibitors could be prescribed by local practitioners. The primary outcome was a composite of kidney disease progression or cardiovascular death assessed 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 sustained benefits after discontinuation. The risk of kidney disease progression was 23.5% with empagliflozin versus 27.1% with placebo. Cardiovascular death occurred in 3.8% of the empagliflozin group and 4.9% of the placebo group (HR, 0.75; 95% CI, 0.59–0.95). There was no significant difference in noncardiovascular mortality.
Conclusions: Empagliflozin continued to confer cardiorenal benefits for up to 12 months after discontinuation in patients with CKD at risk for progression. The sustained reduction in kidney disease progression and cardiovascular death suggests long-term advantages of empagliflozin beyond active treatment, supporting its role in CKD management.
Implications for Practice: These findings support the early initiation and continued use of empagliflozin in patients with CKD to maximize long-term cardiorenal benefits. Clinicians should consider empagliflozin as part of standard care for a broad range of CKD patients, regardless of diabetes status, to slow disease progression and reduce cardiovascular risk.
Study Strengths and Limitations: While the study’s large, diverse CKD population and extended follow-up enhance its generalizability, reliance on local creatinine measurements and lack of hospitalization data during post-trial follow-up are limitations.
Future Research: Further studies should explore the mechanisms underlying the sustained benefits of empagliflozin after discontinuation and assess long-term effects on hospitalization and quality of life in CKD patients.
Cohort Study: GIP/GLP-1 Receptor Agonist Prescriptions Linked to Reduced Opioid Overdose and Alcohol Intoxication
20 Oct, 2024 | 18:36h | UTCBackground: Opioid use disorder (OUD) and alcohol use disorder (AUD) are prevalent conditions leading to significant morbidity and mortality, including overdose and intoxication. Current pharmacotherapies for OUD and AUD are underutilized due to barriers like access and stigma. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), used for type 2 diabetes and obesity, have shown potential in modulating reward pathways associated with substance use, suggesting a possible role in reducing substance-related harms.
Objective: To estimate the association between prescriptions of glucose-dependent insulinotropic polypeptide (GIP) and/or GLP-1 receptor agonists and the incidence of opioid overdose and alcohol intoxication in patients with OUD and AUD, respectively, and to assess this association among patients with comorbid type 2 diabetes and obesity.
Methods: This retrospective cohort study analyzed de-identified electronic health record data from 136 U.S. health systems in the Oracle Cerner Real-World Data, covering over 100 million patients from January 2014 to September 2022. Adults aged 18 years or older with a history of OUD (n = 503,747) or AUD (n = 817,309) were included. The exposure was defined as having one or more prescriptions of GIP/GLP-1 RAs after the first OUD or AUD diagnosis. The primary outcomes were the incidence rates of opioid overdose in the OUD cohort and alcohol intoxication in the AUD cohort.
Results: Patients with GIP/GLP-1 RA prescriptions had significantly lower rates of opioid overdose (aIRR in OUD patients: 0.60; 95% CI, 0.43–0.83) and alcohol intoxication (aIRR in AUD patients: 0.50; 95% CI, 0.40–0.63) compared to those without such prescriptions. The protective association remained significant among patients with comorbid type 2 diabetes and obesity.
Conclusions: Prescriptions of GIP and/or GLP-1 receptor agonists are associated with lower rates of opioid overdose and alcohol intoxication in patients with OUD and AUD. These protective effects persist across various subgroups, including those with comorbid type 2 diabetes and obesity.
Implications for Practice: GLP-1 RAs show promise for reducing substance-related harms in patients with OUD and AUD. Clinicians may consider the potential benefits of GIP/GLP-1 RA prescriptions in this population, while recognizing the need for further research to establish causality and understand underlying mechanisms.
Study Strengths and Limitations: Strengths include a large, diverse patient population and adjustment for multiple confounders. Limitations involve the retrospective observational design limiting causal inference and reliance on data from Cerner-affiliated health systems, which may affect generalizability.
Future Research: Prospective clinical trials are needed to validate these findings, elucidate underlying mechanisms, and assess the efficacy and safety of GIP/GLP-1 RAs as treatments for substance use disorders.
Cohort Study: Levonorgestrel IUD Use Linked to Increased Breast Cancer Risk in Premenopausal Women
20 Oct, 2024 | 18:13h | UTCBackground: Levonorgestrel-releasing intrauterine systems (LNG-IUSs) are increasingly used, especially among Danish premenopausal women over 30 years old, as a preferred method of hormonal contraception. Previous studies have suggested an increased risk of breast cancer with LNG-IUS use but did not adequately address the duration of continuous use or account for other hormonal contraceptive exposures.
Objective: To assess the risk of breast cancer associated with continuous use of LNG-IUSs, accounting for other hormonal exposures.
Methods: In this nationwide Danish cohort study, 78,595 first-time LNG-IUS users aged 15–49 years from 2000 to 2019 were identified and matched 1:1 by birth year to nonusers of hormonal contraceptives. Exclusion criteria included prior hormonal contraceptive use within 5 years, previous cancer, postmenopausal hormone therapy, and pregnancy at baseline. Participants were followed from initiation until breast cancer diagnosis, other cancer, pregnancy, hormone therapy initiation, emigration, death, or December 31, 2022. Cox proportional hazards models adjusted for confounders estimated hazard ratios (HRs) for breast cancer associated with continuous LNG-IUS use.
Results: During a mean follow-up of 6.8 years, 1,617 breast cancer cases occurred: 720 among LNG-IUS users and 897 among nonusers. The mean age was 38 years. Continuous LNG-IUS use was associated with a higher breast cancer risk compared to nonuse (HR, 1.4; 95% CI, 1.2–1.5). HRs by duration were 1.3 (95% CI, 1.1–1.5) for 0–5 years, 1.4 (95% CI, 1.1–1.7) for >5–10 years, and 1.8 (95% CI, 1.2–2.6) for >10–15 years. Excess breast cancer cases per 10,000 users were 14 (95% CI, 6–23), 29 (95% CI, 9–50), and 71 (95% CI, 15–127), respectively. The trend test for duration was not statistically significant (P = .15).
Conclusions: Continuous use of LNG-IUSs was associated with an increased risk of breast cancer among women aged 15–49 years compared to nonuse of hormonal contraceptives. The absolute increase in risk was low.
Implications for Practice: Healthcare providers should inform women about the potential increased breast cancer risk associated with LNG-IUS use, especially considering its widespread and long-term use among premenopausal women. While the absolute risk increase is small, this information is essential for making informed contraceptive choices.
Study Strengths and Limitations: Strengths include the large, nationwide cohort and adjustment for multiple confounders. Limitations include potential underestimation of risk due to unrecorded LNG-IUS removals before the recommended duration, lack of a statistically significant trend with duration suggesting possible low statistical precision or non-causal association, and the possibility of unmeasured confounding.
Future Research: Further studies are needed to confirm these findings, clarify the causal relationship, and understand the mechanisms underlying the potential increased breast cancer risk with LNG-IUS use.
Psychedelic-Assisted Therapy May Reduce Anxiety and Depression in Patients with Life-Threatening Diseases
20 Oct, 2024 | 18:02h | UTCBackground: Anxiety, depression, and existential distress are prevalent among individuals facing life-threatening illnesses, significantly impacting their quality of life. Traditional treatments often have limited efficacy in this population. Psychedelic-assisted therapy, involving substances like psilocybin and LSD under professional supervision, has been proposed as a potential intervention. However, these substances are illegal in most countries and pose potential risks.
Objective: To assess the benefits and harms of psychedelic-assisted therapy compared to placebo or active comparators in treating anxiety, depression, and existential distress in people with life-threatening diseases.
Methods: This Cochrane systematic review included six randomized controlled trials conducted in the USA and Switzerland between 2011 and 2022. A total of 149 participants (140 analyzed), aged 36 to 64 years with life-threatening illnesses (e.g., cancer), were randomized to receive psychedelic-assisted therapy using classical psychedelics (psilocybin or LSD) or MDMA. Interventions included preparatory sessions, the psychedelic experience, and integration sessions. Comparators were active placebos (e.g., low-dose psychedelic or niacin) or placebo. Primary outcomes were anxiety, depression, and existential distress measured 1 to 12 weeks post-intervention.
Results: Psychedelic-assisted therapy with classical psychedelics may reduce anxiety and depression compared to active placebo:
- Anxiety: Mean difference (MD) of −8.41 points on the STAI-Trait scale (20–80 range; 95% CI, −12.92 to −3.89; 5 studies, 122 participants; low-certainty evidence).
- Depression: MD of −4.92 points on the Beck Depression Inventory (0–63 range; 95% CI, −8.97 to −0.87; 4 studies, 112 participants; low-certainty evidence).
The effect on existential distress was mixed and very uncertain. No treatment-related serious adverse events or grade 3/4 adverse events were reported. Common mild to moderate adverse events included elevated blood pressure, nausea, anxiety, and transient psychotic-like symptoms, which resolved shortly after the sessions.
Conclusions: Psychedelic-assisted therapy with classical psychedelics may reduce symptoms of anxiety and depression in patients with life-threatening diseases, but the evidence is of low certainty due to methodological limitations and small sample sizes. The effects of MDMA-assisted therapy are very uncertain.
Implications for Practice: While findings are promising, clinicians should exercise caution due to the low certainty of evidence and legal restrictions surrounding psychedelic substances.
Study Strengths and Limitations: Strengths include randomized designs and standardized therapeutic protocols involving preparation and integration sessions. Limitations are high risk of bias due to unblinding, small sample sizes, potential expectation bias, and cross-over designs with carry-over effects.
Future Research: Larger, well-designed RCTs with rigorous blinding are needed to confirm these findings. Future studies should explore long-term outcomes, diverse patient populations, and strategies to mitigate bias, such as using active placebos and measuring expectancy effects.
RCT: Granulocyte Colony-Stimulating Factor (GCSF) Enhances 90-Day Survival and Reduces Complications in Severe Alcohol-Associated Hepatitis
20 Oct, 2024 | 17:23h | UTCStudy Design and Population: This randomized trial evaluated 126 patients with severe alcohol-associated hepatitis (SAH) eligible for steroid treatment, with discriminant function scores between 32 and 90. Patients were randomized into three groups: prednisolone alone, GCSF alone, and combined GCSF plus prednisolone (GPred). Prednisolone was administered at 40 mg/day, while GCSF was given at 150-300 mcg/d for 7 days, then every third day for up to 12 doses over a month.
Main Findings: The GPred group showed significantly higher 90-day survival (88.1%) compared to prednisolone alone (64.3%, P = 0.03) and GCSF alone (78.6%). The 28-day survival was similar across groups. The GPred group also had more steroid responders by day 7 and showed greater improvements in discriminant function and MELDNa scores. Additionally, patients in the GPred group had significantly lower rates of infections, acute kidney injury, hepatic encephalopathy, and rehospitalizations.
Implications for Practice: Adding GCSF to prednisolone improves survival and reduces the risk of infections and complications in patients with severe alcohol-associated hepatitis. This combination therapy could be considered for improving outcomes in steroid-eligible patients with SAH.
RCT: Low-Dose Amitriptyline Effective as Second-Line Treatment for Irritable Bowel Syndrome
20 Oct, 2024 | 15:56h | UTCBackground: Most patients with irritable bowel syndrome (IBS) are managed in primary care. When first-line therapies—such as dietary changes and antispasmodic drugs—are ineffective, the UK National Institute for Health and Care Excellence (NICE) recommends considering low-dose tricyclic antidepressants as second-line treatment. However, their effectiveness in primary care is uncertain, and they are infrequently prescribed in this setting.
Objective: To determine whether titrated low-dose amitriptyline is effective as a second-line treatment for IBS in primary care.
Methods: In a randomized, double-blind, placebo-controlled, phase 3 trial (ATLANTIS) conducted at 55 general practices in England, 463 adults aged 18 years or older with Rome IV IBS and ongoing symptoms despite first-line therapies were randomized 1:1 to receive low-dose oral amitriptyline (10 mg once daily) or placebo for 6 months. Dose titration over 3 weeks up to 30 mg once daily was allowed according to symptoms and tolerability. The primary outcome was the IBS Severity Scoring System (IBS-SSS) score at 6 months. Secondary outcomes included subjective global assessment (SGA) of relief of IBS symptoms, adequate relief for at least 50% of weeks, and adverse events.
Results: Among 463 participants (mean age 48.5 years; 68% female), low-dose amitriptyline was superior to placebo at 6 months, with a significant mean difference in IBS-SSS score between groups (–27.0; 95% CI, –46.9 to –7.1; P = .0079). More participants reported relief of IBS symptoms with amitriptyline compared to placebo (61% vs 45%; odds ratio [OR] 1.78; 95% CI, 1.19–2.66; P = .0050). Adequate relief of IBS symptoms for at least 50% of weeks was higher with amitriptyline (41% vs 30%; OR 1.56; 95% CI, 1.20–2.03; P = .0008). Adverse events were more frequent with amitriptyline, mainly related to anticholinergic effects such as dry mouth (54%) and drowsiness (53%), but most were mild. Withdrawals due to adverse events were slightly higher with amitriptyline (13% vs 9%).
Conclusions: Low-dose amitriptyline was superior to placebo as a second-line treatment for IBS in primary care and was safe and well tolerated.
Implications for Practice: General practitioners should consider prescribing low-dose amitriptyline to patients with IBS whose symptoms do not improve with first-line therapies, providing appropriate support for patient-led dose titration.
Study Strengths and Limitations: Strengths include the large sample size, primary care setting, and extended treatment duration. Limitations involve underrepresentation of patients with IBS with constipation, potential unblinding due to side effects, and a predominantly White participant population.
Future Research: Further trials assessing amitriptyline as a first-line therapy for IBS in primary care and studies on long-term outcomes are recommended.
Reference: Ford AC, Wright-Hughes A, Alderson SL, et al. Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment in Primary Care (ATLANTIS): a Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial. Lancet. 2023; DOI: http://doi.org/10.1016/S0140-6736(23)01523-4
Systematic Review: Anifrolumab and Belimumab Improve Disease Control in Systemic Lupus Erythematosus; Voclosporin and Belimumab Effective in Lupus Nephritis
20 Oct, 2024 | 14:26h | UTCBackground: Systemic lupus erythematosus (SLE) management remains challenging due to disease heterogeneity and varying severity. New studies since the 2019 EULAR recommendations necessitate an update to inform clinical practice.
Objective: To analyze new evidence (2018–2022) for SLE management to inform the 2023 update of the European League Against Rheumatism (EULAR) recommendations.
Methods: Systematic literature reviews (SLRs) were conducted in Medline and Cochrane Library databases, covering publications from January 2018 to December 2022. Research focused on five domains: (1) efficacy and safety of SLE treatments, (2) benefits of remission/low disease activity, (3) risks of treatment tapering/withdrawal, (4) management of SLE with antiphospholipid syndrome, and (5) safety of varicella zoster virus (VZV) and SARS-CoV2 immunizations.
Results: A total of 439 relevant articles were identified, predominantly observational studies of low or moderate quality. High-quality randomized controlled trials (RCTs) documented the efficacy of anifrolumab, a type 1 interferon receptor inhibitor, in non-renal SLE, and belimumab and voclosporin, a novel calcineurin inhibitor, in lupus nephritis (LN) when compared with standard care. For specific organ manifestations outside LN, high-quality data were lacking. Multiple observational studies confirmed the benefits of attaining clinical remission or low disease activity, reducing the risk of adverse outcomes. Two RCTs with some concerns found higher relapse rates in patients who discontinued glucocorticoids or immunosuppressants in SLE and LN, respectively; however, observational studies suggest that treatment withdrawal may be feasible in a subset of patients.
Conclusions: Anifrolumab and belimumab achieve better disease control than standard care in extrarenal SLE, while combination therapies with belimumab and voclosporin showed higher response rates in high-quality RCTs in LN. Remission and low disease activity are associated with favorable long-term outcomes. In patients achieving these targets, glucocorticoids and immunosuppressive therapy may be gradually tapered.
Implications for Practice: Clinicians should consider anifrolumab and belimumab for extrarenal SLE, and belimumab and voclosporin for LN. Monitoring and aiming for remission or low disease activity can reduce adverse outcomes. Gradual tapering of glucocorticoids and immunosuppressants may be considered in patients achieving these targets, with careful monitoring for relapse.
Study Strengths and Limitations: Strengths include comprehensive SLRs and inclusion of recent high-quality RCTs. Limitations involve the predominance of low-quality observational studies, lack of high-quality data for specific organ manifestations, and potential bias in treatment withdrawal studies.
Future Research: Further high-quality RCTs are needed to assess treatments for specific organ manifestations outside LN. Long-term studies on tapering and withdrawal strategies of immunosuppressive therapies are necessary to guide safe practice.
Cohort Study: Ondansetron Initiation Linked to Increased 10-Day Sudden Cardiac Death Risk in Hemodialysis Patients
20 Oct, 2024 | 14:05h | UTCBackground: Individuals undergoing maintenance hemodialysis have a markedly elevated risk of sudden cardiac death, attributed to structural heart disease, electrolyte imbalances, and polypharmacy. Ondansetron, a commonly used antiemetic known to prolong the QT interval, has been associated with fatal arrhythmias when administered intravenously in the general population. However, its cardiac safety profile in the hemodialysis population remains unclear.
Objective: To assess whether initiation of oral ondansetron, compared to antiemetics with lesser QT-prolonging potential, is associated with a higher 10-day risk of sudden cardiac death among patients receiving maintenance hemodialysis.
Methods: This new-user, active-comparator cohort study analyzed data from the United States Renal Data System between 2012 and 2019. A total of 119,254 patients receiving in-center hemodialysis who initiated either oral ondansetron or comparator antiemetics (promethazine, metoclopramide, or prochlorperazine) were included. Inverse probability of treatment-weighted survival models estimated adjusted hazard ratios (aHR) and risk differences (aRD), using an intention-to-treat approach with non-sudden cardiac death as a competing event.
Results: Among the patients, 64,978 (55%) initiated ondansetron, while 54,276 (45%) initiated comparator antiemetics. Ondansetron initiation was associated with a higher 10-day risk of sudden cardiac death compared to comparator drugs (aHR 1.44; 95% CI, 1.08–1.93; aRD 0.06%; 95% CI, 0.01%–0.11%). The number needed to harm was 1,688. Secondary analyses of additional cardiac outcomes, including ventricular arrhythmias and cardiovascular mortality, yielded consistent findings.
Conclusions: Initiation of oral ondansetron is associated with an increased short-term risk of sudden cardiac death among patients on maintenance hemodialysis compared to initiation of antiemetics with lesser QT-prolonging potential.
Implications for Practice: Clinicians should exercise caution when prescribing ondansetron to hemodialysis patients and consider alternative antiemetics with lower QT-prolonging risks. If ondansetron is necessary, monitoring for cardiac arrhythmias and performing electrocardiograms may be advisable to mitigate potential risks.
Study Strengths and Limitations: Strengths include a large, nationally representative cohort and an active-comparator design that minimizes confounding. Limitations involve potential residual confounding inherent in observational studies, possible misclassification of outcomes, and inability to assess dose-response relationships due to power constraints.
Future Research: Further studies are warranted to confirm these findings, elucidate the underlying mechanisms of increased cardiac risk, and evaluate the safety of ondansetron across different dosages and patient subgroups within the hemodialysis population.
Meta-Analysis: Topiramate and CGRP Monoclonal Antibodies Effective in Medication Overuse Headache
13 Oct, 2024 | 14:07h | UTCBackground: Medication overuse headache (MOH) results from frequent intake of acute pain medications, leading to increased headache frequency and severity. There is ongoing debate regarding the necessity and optimal choice of prophylactic drugs in MOH treatment, with previous studies lacking clear guidance.
Objective: To determine the comparative efficacy and safety of available pharmacological therapies for MOH, including their ability to eliminate medication overuse (MO).
Methods: A systematic review and network meta-analysis of randomized controlled trials were conducted, comparing different pharmacological treatments for MOH. Primary outcomes included the responder rate (≥50% reduction in headache frequency), proportion of patients reverting to no medication overuse (nMO), and reductions in monthly headache days and acute medication intake frequency. The certainty of evidence was assessed using the GRADE framework.
Results: Twenty-eight studies involving 5,527 patients were included. Topiramate demonstrated significant benefits in increasing responder rates (odds ratio [OR] 4.93), reducing headache frequency (weighted mean difference [WMD] –5.53), and decreasing acute medication intake frequency (WMD –6.95), but was associated with more adverse events compared to placebo (OR 0.20). Fremanezumab, galcanezumab, and botulinum toxin type A (BTA) were effective in increasing responder rates (ORs 2.57 to 3.46). For reversion to nMO, eptinezumab, fremanezumab, and BTA were superior to placebo (ORs 1.55 to 2.75). Eptinezumab, fremanezumab, erenumab 140 mg, and BTA were more efficacious than erenumab 70 mg without significant differences in safety and tolerability.
Conclusions: Topiramate likely has large beneficial effects on increasing responder rates and reducing headache frequency but is associated with lower safety and greater intolerability. Fremanezumab, galcanezumab, and eptinezumab show promise in increasing responder rates. Eptinezumab has a large beneficial effect on reversion to nMO, with fremanezumab and BTA having smaller effects.
Implications for Practice: Clinicians should balance efficacy and tolerability when selecting pharmacological treatments for MOH. While topiramate is effective, its adverse event profile may limit its use. CGRP monoclonal antibodies, such as eptinezumab and fremanezumab, offer promising efficacy with acceptable safety profiles and may be preferred options for some patients.
Study Strengths and Limitations: Strengths include a comprehensive network meta-analysis of multiple pharmacological therapies and the use of GRADE for assessing evidence certainty. Limitations involve variability among included studies, small sample sizes, and heterogeneity in study populations and methodologies, which may affect the generalizability of the findings.
Future Research: High-quality randomized controlled trials are needed to confirm these findings and directly compare different pharmacological treatments in MOH. Future studies should focus on long-term efficacy, safety of newer therapies, and their impact on patient-centered outcomes.
Meta-analysis: Colchicine Reduces Ischemic Stroke and MACE in Patients with Prior Stroke or Coronary Disease
13 Oct, 2024 | 12:10h | UTCBackground: Colchicine is recommended for secondary prevention in cardiovascular disease, but its efficacy in preventing ischemic stroke and benefits in key patient subgroups remain uncertain. Inflammation plays a significant role in stroke and cardiovascular events, and colchicine’s anti-inflammatory properties may confer additional protective effects.
Objective: To evaluate the efficacy of colchicine for secondary prevention of ischemic stroke and major adverse cardiovascular events (MACE) in patients with prior stroke or coronary disease, and to assess its safety profile across key clinical subgroups.
Methods: A trial-level meta-analysis was conducted, including six randomized controlled trials with a total of 14,934 patients with prior stroke or coronary disease. Trials comparing colchicine with placebo or no colchicine for at least three months were included. The primary efficacy outcomes were ischemic stroke and MACE, defined as a composite of ischemic stroke, myocardial infarction, coronary revascularization, or cardiovascular death. Secondary outcomes included serious safety events and mortality.
Results: Colchicine reduced the risk of ischemic stroke by 27% (1.8%] vs. 186 events [2.5%]; RR 0.73, 95% CI 0.58–0.90; P = .004) and MACE by 27% (505 events [6.8%] vs. 693 events [9.4%]; RR 0.73, 95% CI 0.65–0.81; P < .001). The efficacy was consistent across key subgroups, including sex, age (<70 vs. ≥70 years), diabetes status, and statin use at baseline. Colchicine was not associated with an increase in serious safety outcomes, all-cause mortality (201 deaths [2.7%] vs. 181 deaths [2.4%]; RR 1.09, 95% CI 0.89–1.33; P = .39), cardiovascular death, or non-cardiovascular death.
Conclusions: In patients with prior stroke or coronary disease, colchicine significantly reduces the risk of ischemic stroke and MACE without increasing serious adverse events or mortality. These findings support the use of low-dose colchicine as an effective secondary prevention therapy in a broad cardiovascular patient population.
Implications for Practice: Clinicians should consider incorporating low-dose colchicine into secondary prevention regimens for patients with prior stroke or coronary disease, given its demonstrated efficacy and acceptable safety profile. Its affordability and widespread availability make it a practical option for diverse healthcare settings, including low- and middle-income countries.
Study Strengths and Limitations: Strengths include a large pooled sample size and inclusion of multiple trials across various patient populations, enhancing generalizability. Limitations involve potential performance bias in non-placebo-controlled trials, differences in stroke outcome definitions among studies, and the inability to perform individual patient data analyses.
Future Research: Further studies are needed to evaluate the long-term effects of colchicine on vascular events and cognitive decline in stroke patients, assess safety in patients with renal impairment, and explore its impact on non-cardiovascular mortality.