Family Medicine
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.
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.
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.
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: Total Hip Replacement Superior to Resistance Training for Severe Hip Osteoarthritis
3 Nov, 2024 | 01:23h | UTCBackground: Severe hip osteoarthritis (OA) is often treated with total hip replacement (THR), yet randomized trials comparing THR with nonsurgical interventions like resistance training (RT) are lacking. While exercise is recommended for hip OA, its efficacy relative to surgery remains unclear.
Objective: To compare the effectiveness of THR with RT in patients aged 50 years or older with severe hip OA and an indication for surgery.
Methods: In a multicenter, randomized controlled trial, 109 patients were assigned to undergo THR (n=53) or participate in a 12-week supervised RT program (n=56). The primary outcome was the change in patient-reported hip pain and function from baseline to 6 months, measured by the Oxford Hip Score (OHS; range 0–48, higher scores indicate less pain and better function). Secondary outcomes included measures of pain, function, quality of life, physical activity, and functional performance. Safety was also assessed.
Results: At 6 months, the mean improvement in OHS was 15.9 points in the THR group and 4.5 points in the RT group (between-group difference: 11.4 points; 95% CI, 8.9 to 14.0; P<0.001). Significant improvements favoring THR were also observed in all secondary patient-reported outcomes. Serious adverse events occurred in 12% of patients in the THR group and 9% in the RT group; most were known complications of THR. At 6 months, 9% of patients assigned to THR had not undergone surgery, and 21% of those assigned to RT had undergone THR.
Conclusions: In patients aged 50 years or older with severe hip OA and an indication for surgery, THR resulted in clinically important, superior reductions in hip pain and improvements in function compared to RT at 6 months.
Implications for Practice: These findings support the use of THR over RT for patients with severe hip OA who are surgical candidates, affirming current clinical recommendations. However, RT may still be considered as an initial treatment option for some patients, especially those preferring to delay surgery.
Study Strengths and Limitations: Strengths include the randomized controlled design and multicenter approach. Limitations involve lack of blinding, potential selection bias due to low enrollment (14% of eligible patients), and crossovers between treatment groups, which may underestimate the true treatment effects.
Future Research: Further studies should investigate long-term outcomes, optimal timing of THR, and factors influencing patient choice and response to RT versus surgery.
Review: Chronic Low-Level Lead Poisoning
3 Nov, 2024 | 01:15h | UTCIntroduction: Lead poisoning, historically known as plumbism, remains a significant health concern despite reductions in lead use. Chronic low-level lead exposure has been identified as a critical risk factor for cardiovascular disease in adults and cognitive deficits in children, even at blood lead concentrations previously deemed safe. This review by Lanphear et al. explores the multifaceted effects of chronic, low-level lead poisoning, emphasizing its impact on neurodevelopment, kidney function, and cardiovascular health, and underscores the urgent need for effective prevention strategies.
Key Findings:
- Exposure and Absorption: Lead exposure occurs primarily through ingestion and inhalation, with children absorbing lead more readily than adults. Absorption is enhanced in the presence of iron or calcium deficiency. Once absorbed, lead is predominantly stored in the skeleton, and factors altering bone metabolism can mobilize lead back into the bloodstream.
- Neurodevelopmental Effects: Lead exposure is linked to preterm birth, cognitive deficits, attention deficit–hyperactivity disorder (ADHD), and behavioral disorders in children. Notably, cognitive deficits are proportionately larger at lower blood lead levels, with significant IQ reductions observed even at the lowest measurable concentrations.
- Kidney Disease: Chronic lead exposure is a risk factor for chronic kidney disease. Higher blood lead levels are associated with reduced glomerular filtration rates and an increased risk of developing chronic kidney conditions.
- Cardiovascular Disease: Lead induces hypertension and atherosclerosis through mechanisms such as oxidative stress and endothelial dysfunction. It is a leading risk factor for mortality from cardiovascular disease, with substantial risk increases even at low blood lead concentrations. Studies indicate that lead exposure may have contributed to historical trends in coronary heart disease mortality.
- Global Burden: In 2019, lead exposure accounted for approximately 5.5 million deaths from cardiovascular disease and the loss of 765 million IQ points in children globally. The economic cost associated with lead-related health outcomes is estimated at $6 trillion annually, representing about 7% of the global gross domestic product.
- Screening and Treatment: Screening high-risk populations is recommended, including children in older housing and workers in certain industries. While chelation therapy can reduce body lead burden, its effects on health outcomes are inconsistent, highlighting the importance of primary prevention.
- Prevention Strategies: Eliminating environmental sources of lead through government-funded population strategies is essential. This includes replacing lead-containing infrastructure like water service lines, banning leaded aviation fuel, reducing lead in consumer products, and remediating contaminated soils and older housing with lead-based paints.
Conclusion: Chronic low-level lead poisoning continues to pose a significant global health threat, contributing to cardiovascular disease and neurodevelopmental deficits. The disproportionate effects at even the lowest exposure levels underscore the necessity for robust, population-wide prevention strategies. Implementing stringent regulatory actions to eliminate sources of lead exposure is imperative to reduce the substantial morbidity, mortality, and economic burdens associated with lead poisoning.
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.
Systematic Review: Intensive Blood Pressure Targets Do Not Reduce Mortality or Cardiovascular Events in Hypertensive Patients with Chronic Kidney Disease
20 Oct, 2024 | 17:50h | UTCBackground: Chronic kidney disease (CKD) is a significant independent risk factor for cardiovascular disease and mortality, affecting approximately 10% of the global population. Hypertension is prevalent in CKD patients, ranging from 22% to 80% depending on disease stage. While lowering blood pressure is essential in managing CKD, the optimal blood pressure targets remain uncertain, particularly whether lower-than-standard targets provide additional benefits.
Objective: To compare the effects of standard versus lower-than-standard blood pressure targets on mortality and morbidity outcomes in hypertensive patients with CKD.
Methods: A systematic review and meta-analysis of six randomized controlled trials (RCTs) involving 7348 participants were conducted. Studies included adults with hypertension and CKD randomized to lower blood pressure targets (≤130/80 mmHg) versus standard targets (≤140–160/90–100 mmHg) with at least 12 months of follow-up. Primary outcomes were total mortality, total serious adverse events, total cardiovascular events, cardiovascular mortality, and progression to end-stage renal disease (ESRD). Data were analyzed using GRADE methodology to assess the certainty of evidence.
Results: Over a mean follow-up of 3.6 years, lower blood pressure targets likely resulted in little to no difference in total mortality (risk ratio [RR] 0.90; 95% confidence interval [CI], 0.76 to 1.06; moderate-certainty evidence), total serious adverse events (RR 1.01; 95% CI, 0.94 to 1.08; moderate-certainty), and total cardiovascular events (RR 1.00; 95% CI, 0.87 to 1.15; moderate-certainty) compared to standard targets. Lower targets may result in little to no difference in cardiovascular mortality (RR 0.90; 95% CI, 0.70 to 1.16; low-certainty) and progression to ESRD (RR 0.94; 95% CI, 0.80 to 1.11; low-certainty). Participants in the lower target groups achieved greater reductions in systolic and diastolic blood pressure but required more antihypertensive medications.
Conclusions: Intensive blood pressure targets probably do not reduce total mortality, serious adverse events, or cardiovascular events compared to standard targets in hypertensive patients with CKD, and may have little to no effect on cardiovascular mortality or progression to ESRD.
Implications for Practice: Clinicians should consider that lowering blood pressure below standard targets in hypertensive CKD patients may not provide additional benefit in reducing mortality or cardiovascular events. The increased medication burden and potential for adverse effects with intensive targets should be weighed against the lack of demonstrated benefit.
Study Strengths and Limitations: Strengths include the use of individual participant data from six RCTs and a comprehensive analysis using GRADE methodology. Limitations involve the open-label design of the included studies, potential risk of bias, heterogeneity in blood pressure targets and CKD definitions, and limited adverse event reporting.
Future Research: Further high-quality RCTs are needed to determine optimal blood pressure targets in hypertensive CKD patients, including those with varying levels of proteinuria and using out-of-office blood pressure monitoring. Ongoing studies may provide additional evidence in the near future.
EULAR/PReS Guidelines for the Diagnosis and Management of Still’s Disease
20 Oct, 2024 | 17:41h | UTCIntroduction:
Still’s disease, encompassing systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease (AOSD), is a systemic inflammatory disorder characterized by spiking fevers, rash, arthralgia or arthritis, and elevated inflammatory markers. Historically treated as separate entities, sJIA and AOSD are now recognized as the same disease continuum. To unify and optimize diagnosis and management across all ages, the European Alliance of Associations for Rheumatology (EULAR) and the Paediatric Rheumatology European Society (PReS) have developed comprehensive, evidence-based recommendations.
Key Recommendations:
- Unified Terminology: sJIA and AOSD are the same disease and should be collectively termed “Still’s disease” to standardize diagnosis and treatment. (Recommendation: strong)
- Rapid Diagnosis Using Operational Definitions: Key clinical features include spiking fever ≥39°C lasting ≥7 days, transient rash coinciding with fever spikes, arthralgia or arthritis, and elevated inflammatory markers (CRP, ESR, neutrophils, ferritin). Arthritis is supportive but not essential for diagnosis. (Strong)
- Diagnostic Biomarkers: Elevated serum interleukin-18 (IL-18) and S100 proteins strongly support the diagnosis and should be measured when available. (Moderate)
- Exclude Alternative Diagnoses: Carefully consider infections, malignancies, other immune-mediated inflammatory diseases, and monogenic autoinflammatory disorders to avoid misdiagnosis. (Strong)
- Treatment Goals: The ultimate goal is drug-free remission, defined as clinically inactive disease (CID) maintained for at least 6 months. CID entails absence of disease-related symptoms and normalization of ESR and CRP. Intermediate targets at specific time points guide treatment adjustments. (Strong)
- Early Use of IL-1 and IL-6 Inhibitors: To avoid prolonged glucocorticoid use, prioritize early initiation of interleukin-1 (IL-1) or interleukin-6 (IL-6) inhibitors upon diagnosis. (Strong)
- Glucocorticoid Tapering: Aim to achieve CID without glucocorticoids within 6 months. Maintain CID for 3–6 months before initiating tapering of biologic DMARDs. (Strong)
- Monitor for Complications: Be vigilant for life-threatening complications, including macrophage activation syndrome (MAS) and lung disease (LD), which require prompt recognition and management. (Strong)
- MAS Management: Consider MAS in patients with persistent fever, splenomegaly, elevated ferritin, cytopenias, abnormal liver function tests, coagulopathy, and hypertriglyceridemia. High-dose glucocorticoids are essential; anakinra, ciclosporin, and interferon-γ inhibitors may be added. (Strong)
- LD Screening and Management: Screen patients for LD via clinical assessment and pulmonary function tests; high-resolution CT scans are indicated for symptomatic patients. The presence of LD is not a contraindication for IL-1 or IL-6 inhibitors. (Strong)
Conclusion: Implementing these unified, evidence-based recommendations is expected to improve the diagnosis and management of Still’s disease across all ages, leading to earlier intervention, optimized treatment strategies, reduced complications, and enhanced patient outcomes, including achieving drug-free remission.
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
RCT: Milk Elimination Diet Comparable to Four-Food Elimination in Pediatric EoE
20 Oct, 2024 | 15:04h | UTCBackground: Eosinophilic esophagitis (EoE) is a chronic immune-mediated condition characterized by eosinophil infiltration of the esophageal mucosa, leading to symptoms such as nausea, vomiting, abdominal pain, and dysphagia in children. While elimination of six common food allergens is effective, this approach is highly restrictive and may adversely affect quality of life (QoL). Less restrictive diets could potentially balance efficacy with improved QoL.
Objective: To compare the efficacy of a one-food elimination diet excluding milk (1FED) versus a four-food elimination diet excluding milk, egg, wheat, and soy (4FED) in treating pediatric EoE.
Methods: In this multicenter, randomized, nonblinded trial conducted at ten sites in the United States, 63 children aged 6 to 17 years with histologically active and symptomatic EoE were randomized 1:1 to either 1FED (n = 38) or 4FED (n = 25) for 12 weeks. The primary endpoint was symptom improvement measured by the Pediatric Eosinophilic Esophagitis Symptom Score (PEESS). Secondary endpoints included the proportion achieving histologic remission (<15 eosinophils per high-power field), changes in histologic features (histology scoring system), endoscopic severity (endoscopic reference score), transcriptome profiling (EoE diagnostic panel), QoL scores, and predictors of remission.
Results: Out of 63 participants, 51 completed the study (1FED, n = 34; 4FED, n = 17). The 4FED group showed a greater improvement in mean PEESS scores compared to the 1FED group (−25.0 vs. −14.5; P = .04). However, histologic remission rates were similar between 4FED and 1FED (41% vs. 44%; P = 1.00). Changes in the histology scoring system (−0.25 vs. −0.29; P = .77), endoscopic reference score (−1.10 vs. −0.58; P = .47), and QoL scores were comparable between groups. The withdrawal rate was higher in the 4FED group compared to the 1FED group (32% vs. 11%; P = .0496).
Conclusions: While the 4FED moderately improved symptoms more than the 1FED, both diets resulted in similar histologic, endoscopic, QoL, and transcriptomic outcomes. Given its comparable effectiveness, better tolerability, and simplicity, the 1FED is a reasonable first-choice therapy for pediatric EoE.
Implications for Practice: Eliminating cow’s milk alone may be preferable as initial dietary therapy for children with EoE due to its simplicity and similar efficacy compared to more restrictive diets. Clinicians should consider starting with a milk elimination diet before progressing to more restrictive elimination diets if necessary.
Study Strengths and Limitations: Strengths of the study include its randomized, multicenter design; standardized treatment instructions; and use of validated symptom and QoL instruments. Limitations include early termination due to low enrollment, a higher withdrawal rate in the 4FED group, nonblinded interventions, and potential bias from participant expectations.
Future Research: Further large-scale, randomized studies are needed to confirm these findings and to identify biomarkers that predict response to dietary therapy in pediatric EoE.
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.
ATS Guideline: Evaluation and Management of Obesity Hypoventilation Syndrome
12 Oct, 2024 | 23:04h | UTCIntroduction: Obesity Hypoventilation Syndrome (OHS) is a serious condition characterized by obesity (BMI ≥30 kg/m²), sleep-disordered breathing, and daytime hypercapnia (PaCO₂ ≥45 mm Hg), after excluding other causes of hypoventilation. Recognizing the need for standardized evaluation and management, the American Thoracic Society (ATS) has developed comprehensive guidelines. These aim to improve early recognition, optimize treatment strategies, and reduce variability in clinical practice to enhance patient outcomes.
Key Recommendations:
- Screening for OHS:
- Serum Bicarbonate Measurement: For patients with low to moderate probability of OHS (<20%), a serum bicarbonate level can guide the need for arterial blood gas (ABG) analysis. A bicarbonate level <27 mmol/L suggests that measuring PaCO₂ may be unnecessary, while levels ≥27 mmol/L indicate that ABG measurement is warranted. (Quality of evidence: very low; Recommendation: conditional)
- PaCO₂ Measurement: In patients with a high pretest probability of OHS, direct measurement of PaCO₂ is recommended over relying on serum bicarbonate or oxygen saturation levels. (Quality of evidence: very low; Recommendation: conditional)
- Positive Airway Pressure (PAP) Therapy:
- Use of PAP: Stable ambulatory patients diagnosed with OHS should be treated with PAP during sleep to improve gas exchange and alleviate symptoms. (Quality of evidence: very low; Recommendation: conditional)
- Choice of Modality: For patients with OHS and coexisting severe obstructive sleep apnea (OSA) (apnea–hypopnea index ≥30 events/hour), continuous positive airway pressure (CPAP) is suggested as the first-line treatment over noninvasive ventilation (NIV). (Quality of evidence: very low; Recommendation: conditional)
- Hospitalized Patients:
- Discharge Planning: Patients hospitalized with respiratory failure suspected of having OHS should be discharged with NIV therapy until outpatient diagnostic evaluations and PAP titration can be completed, ideally within 2–3 months. (Quality of evidence: very low; Recommendation: conditional)
- Weight Loss Interventions:
- Significant Weight Reduction: Patients with OHS are advised to engage in weight-loss interventions aiming for a sustained loss of 25–30% of actual body weight to resolve hypoventilation. Bariatric surgery may be considered to achieve this goal when appropriate. (Quality of evidence: very low; Recommendation: conditional)
Conclusion: Implementing these guidelines is expected to enhance the early detection and standardized management of OHS. By following these recommendations, healthcare providers can improve patient care, reduce morbidity and mortality associated with OHS, and promote better clinical outcomes.