Daily Archives: November 24, 2024
RCT: Adjunctive Middle Meningeal Artery Embolization Reduces Reoperation in Subdural Hematoma
24 Nov, 2024 | 13:53h | UTCBackground: Subacute and chronic subdural hematomas are common neurosurgical conditions with a high recurrence rate after surgical evacuation, affecting 8% to 20% of patients. Middle meningeal artery embolization (MMAE) is a minimally invasive procedure targeting the blood supply to these membranes. Preliminary studies suggest that adjunctive MMAE may reduce hematoma recurrence, but its impact on reoperation risk remains unclear.
Objective: To determine whether adjunctive MMAE reduces the risk of hematoma recurrence or progression leading to repeat surgery within 90 days compared to surgery alone in patients with symptomatic subacute or chronic subdural hematoma.
Methods: In this prospective, multicenter, randomized controlled trial, 400 patients aged 18 to 90 years with symptomatic subacute or chronic subdural hematoma requiring surgical evacuation were randomly assigned to receive either MMAE plus surgery (n=197) or surgery alone (n=203). The primary endpoint was hematoma recurrence or progression leading to repeat surgery within 90 days after the index treatment. The secondary endpoint was deterioration of neurologic function at 90 days, assessed using the modified Rankin Scale.
Results: Hematoma recurrence or progression requiring repeat surgery occurred in 8 patients (4.1%) in the MMAE plus surgery group versus 23 patients (11.3%) in the surgery-alone group (relative risk, 0.36; 95% CI, 0.11 to 0.80; P=0.008). Functional deterioration at 90 days was similar between groups (11.9% vs. 9.8%; risk difference, 2.1 percentage points; 95% CI, −4.8 to 8.9). Mortality at 90 days was 5.1% in the MMAE group and 3.0% in the control group. Serious adverse events related to the embolization occurred in 4 patients (2.0%), including disabling stroke in 2 patients.
Conclusions: Adjunctive MMAE combined with surgery significantly reduced the risk of hematoma recurrence or progression requiring reoperation within 90 days compared to surgery alone. However, there was no significant difference in neurologic functional deterioration, and the procedure was associated with procedural risks.
Implications for Practice: MMAE may be considered as an adjunct to surgical evacuation in patients with subacute or chronic subdural hematoma to reduce reoperation risk. Clinicians should carefully weigh the potential benefits against the risks of procedural complications, including stroke.
Study Strengths and Limitations: Strengths include the randomized controlled design and multicenter approach, enhancing generalizability. Limitations involve the open-label design, introducing potential bias since the primary endpoint was based on surgeon judgment. A substantial loss to follow-up (13.2%) could affect results, and the study was not powered to detect differences in mortality or serious adverse events.
Future Research: Further studies with larger sample sizes are needed to fully evaluate the safety and efficacy of MMAE, including long-term outcomes. Research should focus on optimizing patient selection and assessing the procedure’s impact on mortality and serious adverse events.
Cohort Study: Metformin Linked to Fewer Asthma Attacks in Patients with Asthma and Type 2 Diabetes
24 Nov, 2024 | 20:36h | UTCBackground: Patients with asthma frequently have comorbid obesity and type 2 diabetes (T2D), conditions associated with an increased risk of asthma attacks. Experimental studies suggest that metformin and glucagon-like peptide-1 receptor agonists (GLP-1RAs) can reduce airway inflammation and hyperresponsiveness. However, epidemiological evidence supporting these effects is limited.
Objective: To evaluate the association between metformin use, with or without add-on antidiabetic medications, and the risk of asthma attacks in patients with asthma and T2D.
Methods: This study utilized data from the UK Clinical Practice Research Datalink Aurum from 2004 to 2020, employing two analytical approaches: a self-controlled case series (SCCS) of 4,278 new metformin users with asthma who experienced asthma attacks, and a population-based cohort study using inverse probability of treatment weighting (IPTW) including 8,424 patients. The primary exposure was initiation of metformin; secondary exposures included add-on antidiabetic medications. The primary outcome was the first asthma exacerbation—defined as a short course of oral corticosteroids, unscheduled asthma-related hospital attendance, or death—during 12 months of follow-up.
Results: Metformin use was associated with a significant reduction in asthma attacks in both analyses. In the SCCS, metformin initiation was linked to a 32% reduction in risk (incidence rate ratio [IRR], 0.68; 95% CI, 0.62-0.75). In the IPTW cohort, metformin use was associated with a 24% reduction (hazard ratio [HR], 0.76; 95% CI, 0.67-0.85). Addition of GLP-1RAs led to a further reduction in asthma attacks (IRR, 0.60; 95% CI, 0.49-0.73). Associations were consistent regardless of glycemic control, body mass index, asthma severity, or blood eosinophil counts.
Conclusions: The findings suggest that metformin use is associated with a lower rate of asthma attacks among patients with asthma and T2D, with additional benefits when GLP-1RAs are added. These effects appear independent of glycemic control or weight loss and occur across different asthma phenotypes.
Implications for Practice: These results indicate potential for repurposing metformin as an adjunct therapy to reduce asthma attacks in patients with asthma and T2D. However, as observational studies cannot establish causality, clinicians should interpret these findings cautiously. The higher cost and side-effect profile of GLP-1RAs warrant careful consideration before widespread adoption.
Study Strengths and Limitations: Strengths include a large, nationally representative sample and the use of two distinct analytical methods to enhance robustness. Limitations involve the observational design, which cannot confirm causality, and potential residual confounding factors such as medication adherence and dosage. Additionally, possible misclassification of asthma diagnosis and lack of data on changes in weight may affect the findings.
Future Research: Randomized controlled trials are necessary to confirm these findings and elucidate the mechanisms by which metformin and GLP-1RAs may reduce asthma attacks. Further studies should explore the benefits of early pharmacological intervention with antidiabetic medications in patients with asthma and metabolic dysfunction.
Consensus Guideline: Low-Dose Oral Minoxidil for Hair Loss Management
24 Nov, 2024 | 20:27h | UTCIntroduction: Hair loss significantly affects patients’ quality of life, encompassing conditions like androgenetic alopecia, alopecia areata, and telogen effluvium. While topical minoxidil is FDA-approved for certain hair loss types, limitations have led to increased off-label use of low-dose oral minoxidil (LDOM). Recognizing the need for standardized guidance, an international panel of 43 dermatologists from 12 countries developed a consensus statement using a modified Delphi process to inform best practices for prescribing LDOM until more robust evidence emerges.
Key Recommendations:
- Patient Selection:
- Indications: LDOM may benefit adults and adolescents with androgenetic alopecia, age-related thinning, alopecia areata, telogen effluvium, traction alopecia, persistent chemotherapy-induced alopecia, and endocrine therapy–induced alopecia.
- Contraindications: LDOM is contraindicated in patients with hypersensitivity to minoxidil, significant drug interactions, history of pericardial effusion or tamponade, pericarditis, congestive heart failure, pulmonary hypertension with mitral stenosis, pheochromocytoma, and during pregnancy or breastfeeding.
- Precautions: Use cautiously in patients with tachycardia, arrhythmias, hypotension (blood pressure <90/60 mm Hg), impaired kidney function, or those undergoing dialysis.
- Dosing Guidelines:
- Adults:
- Females: Starting dose of 1.25 mg daily; dosing range 0.625 mg to 5 mg daily.
- Males: Starting dose of 2.5 mg daily; dosing range 1.25 mg to 5 mg daily.
- Adolescents (12–17 years):
- Females: Starting dose of 0.625 mg daily; dosing range 0.625 mg to 2.5 mg daily.
- Males: Starting dose of 1.25 mg daily; dosing range 1.25 mg to 5 mg daily.
- Considerations: Dosing influenced by sex, age, risk of systemic adverse effects, and desire to minimize hypertrichosis.
- Adults:
- Monitoring and Evaluation:
- Baseline Assessments: Routine labs and ECGs are not required unless precautions are present; consult specialists if needed.
- Adverse Effects Monitoring: Counsel patients on potential side effects like hypertrichosis, dizziness, tachycardia, and fluid retention; monitor for signs such as swelling or weight gain.
- Efficacy Expectations: Initial effects may be observed at three months; efficacy may take up to six months if transient shedding occurs.
- Adjunctive Therapies:
- Spironolactone: May be co-administered in female patients with hirsutism, acne, or polycystic ovary syndrome to enhance treatment efficacy and manage fluid retention.
- Beta-Blockers: Consider in consultation with specialists, especially for managing tachycardia.
- Preference Over Topical Minoxidil:
- LDOM may be preferred when topical minoxidil causes scalp irritation, is cosmetically unacceptable, ineffective, or when enhanced hypertrichosis is desired.
Conclusion: This consensus provides a structured approach for clinicians considering LDOM as an off-label treatment for hair loss. By outlining patient selection, dosing, monitoring, and when to seek specialist input, these recommendations aim to optimize patient outcomes and safety.
Phase 2 RCT: Zerlasiran Lowers Lipoprotein(a) Levels by Over 80% in Patients With ASCVD
24 Nov, 2024 | 20:18h | UTCBackground: Elevated lipoprotein(a) [Lp(a)] is a genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. Traditional lipid-lowering therapies, including statins and lifestyle modifications, do not effectively reduce Lp(a) levels. Small-interfering RNA (siRNA) therapies targeting hepatic production of apolipoprotein(a) offer a potential approach to lowering Lp(a) concentrations.
Objective: To evaluate the efficacy and safety of zerlasiran, an siRNA targeting apolipoprotein(a) synthesis, in reducing serum Lp(a) concentrations in patients with ASCVD.
Methods: In this randomized, double-blind, placebo-controlled phase 2 trial, 178 adults with stable ASCVD and elevated Lp(a) levels (≥125 nmol/L) were enrolled across 26 sites in Europe and South Africa. Participants were randomized to receive subcutaneous zerlasiran at doses of 450 mg every 24 weeks (n=45), 300 mg every 16 weeks (n=42), or 300 mg every 24 weeks (n=44), or matching placebo every 16 weeks (n=23) or every 24 weeks (n=24). The primary outcome was the time-averaged percent change in Lp(a) concentration from baseline to week 36.
Results: Zerlasiran significantly reduced Lp(a) levels compared to placebo. The placebo-adjusted time-averaged percent reductions were −85.6% (95% CI, −90.9% to −80.3%) for 450 mg every 24 weeks, −82.8% (95% CI, −88.2% to −77.4%) for 300 mg every 16 weeks, and −81.3% (95% CI, −86.7% to −76.0%) for 300 mg every 24 weeks. Median percent reductions at week 36 exceeded 90% in all zerlasiran groups. The most common adverse events were mild injection site reactions, occurring in up to 7.1% of participants. No serious adverse events were attributed to the study drug.
Conclusions: Zerlasiran was well-tolerated and produced substantial reductions in Lp(a) levels over 36 weeks in patients with ASCVD.
Implications for Practice: If validated in larger, long-term studies that assess cardiovascular outcomes, zerlasiran may offer a novel treatment for patients with elevated Lp(a), addressing a significant unmet need in cardiovascular risk management. Clinicians should, however, exercise caution until the impact on hard endpoints such as myocardial infarction and stroke, as well as long-term safety, are confirmed.
Study Strengths and Limitations: Strengths include the randomized, double-blind design and significant Lp(a) reductions observed. Limitations involve the predominantly White, male study population, limiting generalizability. The study did not assess clinical endpoints like cardiovascular events, so the impact on actual cardiovascular risk remains unknown. Additionally, the moderate sample size and duration may not detect rare adverse events or long-term effects, necessitating further investigation.
Future Research: Larger, long-term phase 3 trials are needed to confirm these findings, assess the impact on cardiovascular events, and evaluate efficacy and safety in more diverse populations.
Meta-analysis: Low/Moderate-Intensity Statins with Ezetimibe May Offer Better LDL-C Reduction and Safety over High-Intensity Statins
24 Nov, 2024 | 20:01h | UTCBackground: Despite widespread use of high-intensity statin therapy, achieving target LDL-C levels and reducing cardiovascular events remain challenging in patients with or at high risk of atherosclerotic cardiovascular disease (ASCVD). High-intensity statins can have dose-dependent adverse effects, limiting their tolerability. Combining low/moderate-intensity statins with ezetimibe, a cholesterol absorption inhibitor, may enhance lipid-lowering efficacy with fewer side effects.
Objective: To compare the clinical effectiveness and safety of low/moderate-intensity statins combined with ezetimibe versus high-intensity statin monotherapy in reducing major adverse cardiovascular events (MACEs) and lowering LDL-C levels.
Methods: A systematic review and meta-analysis were conducted according to PRISMA guidelines. Fifteen studies (6 randomized controlled trials [RCTs] and 9 observational studies) encompassing 251,450 participants were included. The primary outcome was a composite of cardiovascular death or major cardiovascular events. Secondary outcomes included lipid-lowering efficacy and safety measures such as muscle-related adverse events and liver enzyme elevations.
Results: Observational studies indicated that combination therapy was associated with lower rates of the primary composite outcome (HR = 0.76; 95% CI [0.73, 0.80]), cardiovascular death (HR = 0.80; 95% CI [0.74, 0.88]), all-cause death (HR = 0.84; 95% CI [0.78, 0.91]), and non-fatal stroke (HR = 0.81; 95% CI [0.75, 0.87]). RCTs showed that combination therapy resulted in a greater number of patients achieving LDL-C levels < 70 mg/dL (RR = 1.27; 95% CI [1.21, 1.34]) and significant reductions in LDL-C (MD = –7.95 mg/dL; 95% CI [–10.02, –5.89]) and total cholesterol (MD = –26.77 mg/dL; 95% CI [–27.64, –25.89]). Combination therapy also reduced muscle-related adverse events (RR = 0.52; 95% CI [0.32, 0.85]) and liver enzyme elevations (RR = 0.51; 95% CI [0.29, 0.89]) in RCTs.
Conclusions: Combining low/moderate-intensity statins with ezetimibe may offer superior lipid-lowering effects and better safety profiles compared to high-intensity statin monotherapy. While observational studies suggest improved clinical outcomes, these findings need confirmation from large-scale, long-term RCTs.
Implications for Practice: The combination therapy could be a viable option for patients intolerant to high-intensity statins or those requiring additional LDL-C lowering to reach target levels. However, clinicians should interpret these potential benefits cautiously due to reliance on observational data for clinical outcomes and the lack of robust RCT evidence.
Study Strengths and Limitations: Strengths include a comprehensive search strategy and a large patient population. Limitations involve heavy reliance on observational studies for clinical outcomes.
Future Research: Large, well-designed RCTs with longer follow-up periods are needed to confirm the clinical benefits and safety of the combination therapy over high-intensity statin monotherapy across diverse populations.
Review: Candida auris Infections
24 Nov, 2024 | 19:50h | UTCIntroduction: Candida auris, first identified in Japan in 2009, has rapidly emerged as a global public health threat due to its multidrug resistance and propensity to cause difficult-to-control outbreaks in healthcare settings. This review by Lionakis and Chowdhary aims to provide clinicians with an in-depth understanding of the mycologic features, immune responses, epidemiology, risk factors, clinical manifestations, diagnosis, antifungal resistance, treatment, and prevention strategies associated with C. auris infections to inform effective patient care and containment measures.
Key Points:
- Mycologic Features: C. auris is a budding yeast that thrives in high-salt and high-temperature environments. It is divided into five clades (I–V) with distinct geographic distributions and varying virulence and resistance profiles.
- Immune Response: The interleukin-17 pathway is crucial in reducing skin colonization by C. auris, while phagocytes like monocytes, macrophages, and neutrophils are essential for clearing bloodstream and organ infections.
- Epidemiology: Reported in over 45 countries, C. auris is known for causing outbreaks in healthcare facilities due to its persistence on skin and surfaces and challenges in accurate identification. The CDC classifies it as an urgent threat, and the WHO places it in the “critical” group of human fungal pathogens.
- Risk Factors: Key risk factors include advanced age, indwelling medical devices, immunocompromised states, diabetes, recent surgery, use of broad-spectrum antibiotics or antifungals, prolonged hospitalization, and severe COVID-19.
- Clinical Manifestations: Primarily causing invasive infections like candidemia, C. auris is associated with high morbidity and mortality rates (30–60%). Up to 25% of critically ill colonized patients may develop invasive infections.
- Diagnosis: Accurate identification is challenging due to misidentification with other Candida species on conventional tests. Reliable methods include MALDI-TOF mass spectrometry, sequencing of rDNA regions, and molecular assays like PCR.
- Antifungal Resistance: C. auris exhibits clade-specific multidrug resistance, with most strains resistant to fluconazole and some resistant to echinocandins and amphotericin B. Resistance mechanisms involve mutations in the ERG11 and FKS1 genes.
- Treatment: Echinocandins are recommended as first-line treatment for invasive C. auris infections. Close monitoring is essential due to potential treatment failure and emergence of resistance. Amphotericin B formulations may be used in neonates or if echinocandin resistance is present.
- Prevention: Strict infection control measures are critical, including contact precautions, environmental cleaning with EPA-registered disinfectants effective against C. auris, surveillance screening, and cohorting of patients to prevent nosocomial transmission.
Conclusion: The rapid global spread of multidrug-resistant C. auris presents significant challenges for clinical management and infection control. Early and accurate diagnosis, appropriate antifungal therapy, and stringent prevention strategies are essential to improve patient outcomes and prevent further dissemination of this pathogen.
Review: Target Trial Emulation in Observational Studies
24 Nov, 2024 | 19:43h | UTCIntroduction:
Randomized controlled trials (RCTs) are the gold standard for evaluating medical interventions but are often resource-intensive. Observational studies using real-world data (RWD) from electronic health records (EHRs) or claims data offer advantages like larger sample sizes and timely availability. However, they are prone to biases. “Target trial emulation” aligns observational studies with hypothetical RCTs to improve validity and causal inference.
Key Recommendations:
- Design Alignment with RCTs: Observational studies should replicate key trial design elements like eligibility, treatment strategies, follow-up, and outcome measures. This reduces biases and clarifies treatment-effect definitions.
- Specification of “Time Zero”: Clearly define the start of eligibility, treatment assignment, and follow-up to prevent immortal time and selection bias. Proper alignment ensures comparable treatment groups.
- Addressing Bias and Confounding: Observational studies remain vulnerable to confounding from unmeasured variables. Researchers must use matching, sensitivity analyses, and robust methods to assess findings’ reliability.
- Data Quality Challenges: Using RWD requires careful validation of completeness, consistency, and accuracy. Missing or inconsistent data can affect results. Clear descriptions of data sources and quality metrics are essential.
- Best Practices:
- Protocols and SAPs: Pre-specify protocols and statistical plans (SAPs) to enhance transparency and mitigate bias.
- Clear Reporting: State the observational nature of the study to avoid confusion with RCTs. Use tables to outline target trial elements.
- Sensitivity Analyses: Explore unmeasured confounding and perform negative control outcomes to ensure robustness.
Limitations:
Despite emulating RCTs, observational studies cannot fully eliminate biases inherent in nonrandomized designs. Confounding, selection bias, and data quality issues remain risks. Careful design, pre-specification, and transparency are essential for credible results.
Conclusion:
Target trial emulation enhances observational study design by aligning it with RCT principles, mitigating biases, and improving the reliability of findings. However, it is not a substitute for randomization. Rigorous implementation and interpretation are critical for improving patient care and outcomes.
Reference:
Hubbard RA, Gatsonis CA, Hogan JW, et al. “Target Trial Emulation” for Observational Studies — Potential and Pitfalls. New England Journal of Medicine. 2024 Nov 23. DOI: http://doi.org/10.1056/NEJMp2407586
RCT: Fezolinetant Reduces Vasomotor Symptoms in Menopausal Individuals Unfit for Hormone Therapy
24 Nov, 2024 | 19:29h | UTCBackground: Vasomotor symptoms (VMS), including hot flushes and night sweats, are prevalent and often debilitating during menopause. Hormone therapy (HT) is effective but contraindicated or unsuitable for many due to medical conditions or personal choice, creating a need for safe, non-hormonal treatments.
Objective: To evaluate the efficacy and safety of fezolinetant, a non-hormonal neurokinin 3 receptor antagonist, in treating moderate to severe VMS in menopausal individuals unsuitable for HT.
Methods: This phase 3b, randomized, double-blind, placebo-controlled trial was conducted across 16 countries. A total of 453 individuals aged 40-65 years with moderate to severe VMS unsuitable for HT were randomized 1:1 to receive fezolinetant 45 mg once daily or placebo for 24 weeks. The primary endpoint was the mean change in daily frequency of moderate to severe VMS from baseline to week 24. Secondary endpoints included changes in VMS severity, sleep disturbance, and safety evaluations.
Results: Of the 452 participants who received at least one dose of the study drug (fezolinetant n=226, placebo n=226), 370 (81.7%) completed the study. The mean age was 54.5 years, and most participants were white (96.7%) and categorized as either HT averse or requiring caution with HT. At week 24, fezolinetant significantly reduced the frequency of VMS compared with placebo (least squares mean difference [LSMD] –1.93 episodes/day; 95% CI –2.64 to –1.22; P<0.001). It also significantly reduced VMS severity (LSMD –0.39; 95% CI –0.57 to –0.21; P<0.001) and improved sleep disturbance scores (LSMD –2.5; 95% CI –3.9 to –1.1; P<0.001). Improvements were observed as early as week 1 and sustained throughout the study. The incidence of treatment-emergent adverse events (TEAEs) was similar between the fezolinetant and placebo groups (65.0% vs. 61.1%, respectively). No significant safety concerns, including liver toxicity, were identified.
Conclusions: Fezolinetant was effective and well-tolerated over 24 weeks in reducing moderate to severe VMS in menopausal individuals unsuitable for HT.
Implications for Practice: Fezolinetant offers a promising alternative for managing VMS in individuals who cannot or choose not to use HT. Clinicians should consider this option but remain cautious due to limited long-term safety data. Individual patient preferences, risk factors, and the novelty of the medication should be weighed in clinical decision-making.
Study Strengths and Limitations: Strengths include the large sample size and extended placebo-controlled duration. Limitations involve the predominantly white study population, potentially limiting generalizability to more diverse groups. The exclusion of individuals over 65 years old and the lack of direct comparison with other non-hormonal treatments also constrain the applicability of the findings.
Future Research: Further studies are needed to assess the long-term safety and efficacy of fezolinetant, particularly in diverse populations and older individuals.