Archives
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: Early TAVR Improves Clinical Outcomes in Asymptomatic Severe Aortic Stenosis
29 Oct, 2024 | 13:04h | UTCBackground: Severe aortic stenosis is prevalent among adults aged 65 and older. Current guidelines recommend aortic-valve replacement for symptomatic patients or asymptomatic patients with specific high-risk features. For other asymptomatic patients, routine clinical surveillance is standard due to limited evidence supporting early intervention, particularly with transcatheter aortic-valve replacement (TAVR).
Objective: To determine whether early TAVR reduces the incidence of death, stroke, or unplanned cardiovascular hospitalization compared to standard clinical surveillance in patients with asymptomatic severe aortic stenosis.
Methods: In this prospective, multicenter, randomized controlled trial, 901 asymptomatic patients aged ≥65 years with severe aortic stenosis and preserved left ventricular ejection fraction were randomized 1:1 to undergo early TAVR or to receive guideline-directed clinical surveillance. The mean age was 75.8 years, and the mean Society of Thoracic Surgeons Predicted Risk of Mortality score was 1.8%, indicating low surgical risk. The primary endpoint was a composite of death from any cause, stroke, or unplanned hospitalization for cardiovascular causes.
Results: Over a median follow-up of 3.8 years, the primary endpoint occurred in 26.8% of the TAVR group compared to 45.3% of the surveillance group (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.40–0.63; P<0.001). Individual components showed lower rates in the TAVR group: death (8.4% vs. 9.2%), stroke (4.2% vs. 6.7%), and unplanned cardiovascular hospitalizations (20.9% vs. 41.7%). Early TAVR patients also maintained better quality of life, with 86.6% achieving favorable outcomes at 2 years compared to 68.0% in the surveillance group (P<0.001). By 2 years, 87.0% of patients in the surveillance group underwent aortic-valve replacement, many presenting with advanced symptoms and cardiac damage. Procedural complications and periprocedural adverse events were similar between groups.
Conclusions: Early TAVR significantly reduced death, stroke, and unplanned cardiovascular hospitalizations in asymptomatic patients with severe aortic stenosis compared to clinical surveillance. Early intervention preserved quality of life and cardiac function, suggesting that early TAVR may benefit this patient population.
Implications for Practice: These findings support considering early TAVR in asymptomatic patients with severe aortic stenosis to improve clinical outcomes and quality of life. This may challenge current guidelines that recommend surveillance over early intervention.
Study Strengths and Limitations: Strengths include the randomized design, large sample size, and multicenter participation. Limitations involve the study population being predominantly low surgical risk patients aged ≥65 years with anatomy suitable for transfemoral TAVR, which may limit generalizability to younger patients, those with higher surgical risk, or those unsuitable for TAVR.
Future Research: Further research is needed to assess long-term valve durability, outcomes in diverse patient populations, and comparisons with surgical aortic-valve replacement. Studies on cost-effectiveness and the impact on guidelines are also warranted.
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.
Observational Study: Kidney Transplantation from Donors with HIV Safe for Recipients with HIV
20 Oct, 2024 | 17:30h | UTCBackground: Kidney transplantation improves survival for persons with HIV and end-stage renal disease but is limited by organ shortages. Transplantation from donors with HIV to recipients with HIV is emerging under the HIV Organ Policy Equity (HOPE) Act but is currently approved only for research. The Department of Health and Human Services is considering expanding this practice to clinical care, but data are limited to small case series without control groups.
Objective: To assess whether kidney transplantation from donors with HIV is noninferior to transplantation from donors without HIV regarding safety outcomes in recipients with HIV.
Methods: In an observational, noninferiority study at 26 U.S. centers, 408 transplantation candidates with HIV were enrolled. Of these, 198 received a kidney transplant: 99 from deceased donors with HIV and 99 from deceased donors without HIV. The primary outcome was a composite safety event (death, graft loss, serious adverse event, HIV breakthrough infection, persistent failure of HIV treatment, or opportunistic infection), assessed for noninferiority (upper bound of 95% CI for hazard ratio ≤3.00). Secondary outcomes included overall survival, survival without graft loss, rejection rates, infections, cancer, and HIV superinfection.
Results: The adjusted hazard ratio for the composite primary outcome was 1.00 (95% CI, 0.73 to 1.38), demonstrating noninferiority. Overall survival at 1 year was 94% for recipients of kidneys from donors with HIV and 95% for those from donors without HIV; at 3 years, survival was 85% and 87%, respectively. Survival without graft loss at 1 year was 93% vs. 90%; at 3 years, 84% vs. 81%. Rejection rates were similar at 1 year (13% vs. 21%) and 3 years (21% vs. 24%). The incidence of serious adverse events, infections, surgical or vascular complications, and cancer did not differ significantly between groups. HIV breakthrough infection occurred more frequently among recipients of kidneys from donors with HIV (incidence rate ratio 3.14; 95% CI, 1.02 to 9.63), primarily due to nonadherence to antiretroviral therapy; viral suppression was regained in all cases. One potential HIV superinfection occurred without clinical consequences.
Conclusions: Kidney transplantation from donors with HIV to recipients with HIV was noninferior to transplantation from donors without HIV regarding safety outcomes, supporting the expansion of this practice from research to clinical care.
Implications for Practice: Expanding kidney transplantation involving donors and recipients with HIV to clinical practice could increase organ availability and reduce disparities in transplantation access for persons with HIV. Clinicians should monitor for HIV breakthrough infections and encourage adherence to antiretroviral therapy.
Study Strengths and Limitations: Strengths include a multicenter design and direct comparison groups. Limitations involve the observational design, inability to randomize due to allocation constraints, and heterogeneity in immunosuppression protocols.
Future Research: Further studies are needed to confirm these findings, evaluate long-term outcomes, and assess potential risks such as HIV superinfection.
RCT: Granulocyte Colony-Stimulating Factor (GCSF) Enhances 90-Day Survival and Reduces Complications in Severe Alcohol-Associated Hepatitis
20 Oct, 2024 | 17:23h | UTCStudy Design and Population: This randomized trial evaluated 126 patients with severe alcohol-associated hepatitis (SAH) eligible for steroid treatment, with discriminant function scores between 32 and 90. Patients were randomized into three groups: prednisolone alone, GCSF alone, and combined GCSF plus prednisolone (GPred). Prednisolone was administered at 40 mg/day, while GCSF was given at 150-300 mcg/d for 7 days, then every third day for up to 12 doses over a month.
Main Findings: The GPred group showed significantly higher 90-day survival (88.1%) compared to prednisolone alone (64.3%, P = 0.03) and GCSF alone (78.6%). The 28-day survival was similar across groups. The GPred group also had more steroid responders by day 7 and showed greater improvements in discriminant function and MELDNa scores. Additionally, patients in the GPred group had significantly lower rates of infections, acute kidney injury, hepatic encephalopathy, and rehospitalizations.
Implications for Practice: Adding GCSF to prednisolone improves survival and reduces the risk of infections and complications in patients with severe alcohol-associated hepatitis. This combination therapy could be considered for improving outcomes in steroid-eligible patients with SAH.
RCT: Low-Dose Amitriptyline Effective as Second-Line Treatment for Irritable Bowel Syndrome
20 Oct, 2024 | 15:56h | UTCBackground: Most patients with irritable bowel syndrome (IBS) are managed in primary care. When first-line therapies—such as dietary changes and antispasmodic drugs—are ineffective, the UK National Institute for Health and Care Excellence (NICE) recommends considering low-dose tricyclic antidepressants as second-line treatment. However, their effectiveness in primary care is uncertain, and they are infrequently prescribed in this setting.
Objective: To determine whether titrated low-dose amitriptyline is effective as a second-line treatment for IBS in primary care.
Methods: In a randomized, double-blind, placebo-controlled, phase 3 trial (ATLANTIS) conducted at 55 general practices in England, 463 adults aged 18 years or older with Rome IV IBS and ongoing symptoms despite first-line therapies were randomized 1:1 to receive low-dose oral amitriptyline (10 mg once daily) or placebo for 6 months. Dose titration over 3 weeks up to 30 mg once daily was allowed according to symptoms and tolerability. The primary outcome was the IBS Severity Scoring System (IBS-SSS) score at 6 months. Secondary outcomes included subjective global assessment (SGA) of relief of IBS symptoms, adequate relief for at least 50% of weeks, and adverse events.
Results: Among 463 participants (mean age 48.5 years; 68% female), low-dose amitriptyline was superior to placebo at 6 months, with a significant mean difference in IBS-SSS score between groups (–27.0; 95% CI, –46.9 to –7.1; P = .0079). More participants reported relief of IBS symptoms with amitriptyline compared to placebo (61% vs 45%; odds ratio [OR] 1.78; 95% CI, 1.19–2.66; P = .0050). Adequate relief of IBS symptoms for at least 50% of weeks was higher with amitriptyline (41% vs 30%; OR 1.56; 95% CI, 1.20–2.03; P = .0008). Adverse events were more frequent with amitriptyline, mainly related to anticholinergic effects such as dry mouth (54%) and drowsiness (53%), but most were mild. Withdrawals due to adverse events were slightly higher with amitriptyline (13% vs 9%).
Conclusions: Low-dose amitriptyline was superior to placebo as a second-line treatment for IBS in primary care and was safe and well tolerated.
Implications for Practice: General practitioners should consider prescribing low-dose amitriptyline to patients with IBS whose symptoms do not improve with first-line therapies, providing appropriate support for patient-led dose titration.
Study Strengths and Limitations: Strengths include the large sample size, primary care setting, and extended treatment duration. Limitations involve underrepresentation of patients with IBS with constipation, potential unblinding due to side effects, and a predominantly White participant population.
Future Research: Further trials assessing amitriptyline as a first-line therapy for IBS in primary care and studies on long-term outcomes are recommended.
Reference: Ford AC, Wright-Hughes A, Alderson SL, et al. Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment in Primary Care (ATLANTIS): a Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial. Lancet. 2023; DOI: http://doi.org/10.1016/S0140-6736(23)01523-4
RCT: Five-Fraction SBRT Noninferior to Conventional Radiotherapy in Localized Prostate Cancer
20 Oct, 2024 | 15:46h | UTCBackground: Prostate cancer poses a significant global health challenge, with radiotherapy being a common curative treatment for localized disease. Hypofractionation, delivering higher doses per session over fewer treatments, has potential benefits in efficacy and convenience. While moderately hypofractionated radiotherapy is established, the efficacy of stereotactic body radiotherapy (SBRT) delivering radiation in just five fractions remains uncertain.
Objective: To assess whether five-fraction SBRT is noninferior to conventionally or moderately hypofractionated radiotherapy regarding freedom from biochemical or clinical failure in patients with low-to-intermediate-risk localized prostate cancer.
Methods: In this phase 3, international, open-label randomized controlled trial (PACE-B), 874 men with stage T1–T2 prostate cancer, Gleason score ≤3+4, and prostate-specific antigen (PSA) ≤20 ng/mL were randomized 1:1 to receive SBRT (36.25 Gy in 5 fractions over 1–2 weeks) or control radiotherapy (78 Gy in 39 fractions over 7.5 weeks or 62 Gy in 20 fractions over 4 weeks). Androgen-deprivation therapy was not permitted. The primary endpoint was freedom from biochemical or clinical failure.
Results: Between August 2012 and January 2018, 874 patients were randomized (433 to SBRT and 441 to control radiotherapy) at 38 centers. Median age was 69.8 years, median PSA was 8.0 ng/mL, and 91.6% had intermediate-risk disease. At a median follow-up of 74.0 months, the 5-year incidence of freedom from biochemical or clinical failure was 95.8% in the SBRT group and 94.6% in the control group (unadjusted HR 0.73; 90% CI, 0.48 to 1.12; P=0.004 for noninferiority). Cumulative incidence of late Radiation Therapy Oncology Group (RTOG) grade 2 or higher genitourinary toxic effects at 5 years was higher with SBRT (26.9% vs. 18.3%; P<0.001), while gastrointestinal toxic effects were similar between groups (10.7% vs. 10.2%; P=0.94). Overall survival did not differ significantly (HR for death, 1.41; 95% CI, 0.90 to 2.20).
Conclusions: Five-fraction SBRT was noninferior to conventional or moderately hypofractionated radiotherapy in terms of biochemical or clinical failure in patients with low-to-intermediate-risk localized prostate cancer. SBRT may be an effective treatment option but is associated with a higher incidence of medium-term genitourinary toxic effects.
Implications for Practice: SBRT offers equivalent oncologic efficacy with the convenience of fewer treatment sessions, potentially reducing patient burden and healthcare resource utilization. Clinicians should consider SBRT for eligible patients but must inform them about the increased medium-term risk of genitourinary toxic effects.
Study Strengths and Limitations: Strengths include a large sample size, multicenter design, standardized radiotherapy protocols, and exclusion of hormonal therapy, minimizing confounding factors. Limitations involve the applicability of findings only to patients similar to those in the trial; some may now opt for active surveillance, and results may not extend to higher-risk populations.
Future Research: Further studies are needed to evaluate long-term outcomes of SBRT, its role in higher-risk patients, and strategies to mitigate genitourinary toxic effects.
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.
Review: Endovascular Management of Acute Stroke
20 Oct, 2024 | 14:43h | UTCIntroduction: Stroke due to large vessel occlusion (LVO) remains a leading cause of disability and mortality worldwide. Endovascular therapy has revolutionized acute ischemic stroke management by enhancing recanalization rates and improving patient outcomes. This review outlines the evolution of endovascular treatments, expansion of therapeutic indications, current best practices, and ongoing research in the endovascular management of acute stroke.
Key Recommendations:
- Early Time Window Therapy (0–6 Hours): Robust evidence from randomized controlled trials demonstrates that mechanical thrombectomy significantly improves functional outcomes in patients with anterior circulation LVO presenting within 6 hours of symptom onset. Patients are selected based on moderate-to-severe neurological deficits and small infarct cores identified via imaging.
- Extended Time Window Therapy (6–24 Hours): Trials such as DAWN and DEFUSE3 have extended thrombectomy benefits to patients up to 24 hours after symptom onset. Advanced imaging techniques, like CT perfusion and MRI, identify patients with substantial penumbral tissue, indicating potential for recovery.
- Large Ischemic Core Infarcts: Recent studies (e.g., SELECT2, ANGEL-ASPECT) suggest that patients with large core infarcts can benefit from endovascular therapy, challenging previous contraindications. Individualized patient selection is crucial to balance risks and benefits.
- Basilar Artery Occlusion: New evidence supports thrombectomy for basilar artery occlusions, especially in patients with moderate-to-severe symptoms. This intervention improves outcomes in a condition historically associated with high morbidity and mortality.
- Bridging Thrombolysis: The necessity of intravenous thrombolysis before thrombectomy in patients directly admitted to endovascular centers is under debate. Meta-analyses indicate that omitting thrombolysis may not adversely affect outcomes, although it remains standard for patients at non-thrombectomy centers.
- Simplified Imaging for Patient Selection: The use of non-contrast CT and CT angiography alone has proven effective for patient selection, reducing treatment delays and expanding access to thrombectomy, particularly in resource-limited settings.
Conclusion: Advancements in endovascular therapy have markedly improved outcomes for patients with acute ischemic stroke due to LVO. Expanded treatment indications and simplified imaging protocols have broadened patient eligibility for thrombectomy. Ongoing research into adjunctive therapies and optimization of management strategies holds promise for further reducing stroke-related disability and mortality.
Systematic Review: Anifrolumab and Belimumab Improve Disease Control in Systemic Lupus Erythematosus; Voclosporin and Belimumab Effective in Lupus Nephritis
20 Oct, 2024 | 14:26h | UTCBackground: Systemic lupus erythematosus (SLE) management remains challenging due to disease heterogeneity and varying severity. New studies since the 2019 EULAR recommendations necessitate an update to inform clinical practice.
Objective: To analyze new evidence (2018–2022) for SLE management to inform the 2023 update of the European League Against Rheumatism (EULAR) recommendations.
Methods: Systematic literature reviews (SLRs) were conducted in Medline and Cochrane Library databases, covering publications from January 2018 to December 2022. Research focused on five domains: (1) efficacy and safety of SLE treatments, (2) benefits of remission/low disease activity, (3) risks of treatment tapering/withdrawal, (4) management of SLE with antiphospholipid syndrome, and (5) safety of varicella zoster virus (VZV) and SARS-CoV2 immunizations.
Results: A total of 439 relevant articles were identified, predominantly observational studies of low or moderate quality. High-quality randomized controlled trials (RCTs) documented the efficacy of anifrolumab, a type 1 interferon receptor inhibitor, in non-renal SLE, and belimumab and voclosporin, a novel calcineurin inhibitor, in lupus nephritis (LN) when compared with standard care. For specific organ manifestations outside LN, high-quality data were lacking. Multiple observational studies confirmed the benefits of attaining clinical remission or low disease activity, reducing the risk of adverse outcomes. Two RCTs with some concerns found higher relapse rates in patients who discontinued glucocorticoids or immunosuppressants in SLE and LN, respectively; however, observational studies suggest that treatment withdrawal may be feasible in a subset of patients.
Conclusions: Anifrolumab and belimumab achieve better disease control than standard care in extrarenal SLE, while combination therapies with belimumab and voclosporin showed higher response rates in high-quality RCTs in LN. Remission and low disease activity are associated with favorable long-term outcomes. In patients achieving these targets, glucocorticoids and immunosuppressive therapy may be gradually tapered.
Implications for Practice: Clinicians should consider anifrolumab and belimumab for extrarenal SLE, and belimumab and voclosporin for LN. Monitoring and aiming for remission or low disease activity can reduce adverse outcomes. Gradual tapering of glucocorticoids and immunosuppressants may be considered in patients achieving these targets, with careful monitoring for relapse.
Study Strengths and Limitations: Strengths include comprehensive SLRs and inclusion of recent high-quality RCTs. Limitations involve the predominance of low-quality observational studies, lack of high-quality data for specific organ manifestations, and potential bias in treatment withdrawal studies.
Future Research: Further high-quality RCTs are needed to assess treatments for specific organ manifestations outside LN. Long-term studies on tapering and withdrawal strategies of immunosuppressive therapies are necessary to guide safe practice.
Cohort Study: Ondansetron Initiation Linked to Increased 10-Day Sudden Cardiac Death Risk in Hemodialysis Patients
20 Oct, 2024 | 14:05h | UTCBackground: Individuals undergoing maintenance hemodialysis have a markedly elevated risk of sudden cardiac death, attributed to structural heart disease, electrolyte imbalances, and polypharmacy. Ondansetron, a commonly used antiemetic known to prolong the QT interval, has been associated with fatal arrhythmias when administered intravenously in the general population. However, its cardiac safety profile in the hemodialysis population remains unclear.
Objective: To assess whether initiation of oral ondansetron, compared to antiemetics with lesser QT-prolonging potential, is associated with a higher 10-day risk of sudden cardiac death among patients receiving maintenance hemodialysis.
Methods: This new-user, active-comparator cohort study analyzed data from the United States Renal Data System between 2012 and 2019. A total of 119,254 patients receiving in-center hemodialysis who initiated either oral ondansetron or comparator antiemetics (promethazine, metoclopramide, or prochlorperazine) were included. Inverse probability of treatment-weighted survival models estimated adjusted hazard ratios (aHR) and risk differences (aRD), using an intention-to-treat approach with non-sudden cardiac death as a competing event.
Results: Among the patients, 64,978 (55%) initiated ondansetron, while 54,276 (45%) initiated comparator antiemetics. Ondansetron initiation was associated with a higher 10-day risk of sudden cardiac death compared to comparator drugs (aHR 1.44; 95% CI, 1.08–1.93; aRD 0.06%; 95% CI, 0.01%–0.11%). The number needed to harm was 1,688. Secondary analyses of additional cardiac outcomes, including ventricular arrhythmias and cardiovascular mortality, yielded consistent findings.
Conclusions: Initiation of oral ondansetron is associated with an increased short-term risk of sudden cardiac death among patients on maintenance hemodialysis compared to initiation of antiemetics with lesser QT-prolonging potential.
Implications for Practice: Clinicians should exercise caution when prescribing ondansetron to hemodialysis patients and consider alternative antiemetics with lower QT-prolonging risks. If ondansetron is necessary, monitoring for cardiac arrhythmias and performing electrocardiograms may be advisable to mitigate potential risks.
Study Strengths and Limitations: Strengths include a large, nationally representative cohort and an active-comparator design that minimizes confounding. Limitations involve potential residual confounding inherent in observational studies, possible misclassification of outcomes, and inability to assess dose-response relationships due to power constraints.
Future Research: Further studies are warranted to confirm these findings, elucidate the underlying mechanisms of increased cardiac risk, and evaluate the safety of ondansetron across different dosages and patient subgroups within the hemodialysis population.
Meta-Analysis: Topiramate and CGRP Monoclonal Antibodies Effective in Medication Overuse Headache
13 Oct, 2024 | 14:07h | UTCBackground: Medication overuse headache (MOH) results from frequent intake of acute pain medications, leading to increased headache frequency and severity. There is ongoing debate regarding the necessity and optimal choice of prophylactic drugs in MOH treatment, with previous studies lacking clear guidance.
Objective: To determine the comparative efficacy and safety of available pharmacological therapies for MOH, including their ability to eliminate medication overuse (MO).
Methods: A systematic review and network meta-analysis of randomized controlled trials were conducted, comparing different pharmacological treatments for MOH. Primary outcomes included the responder rate (≥50% reduction in headache frequency), proportion of patients reverting to no medication overuse (nMO), and reductions in monthly headache days and acute medication intake frequency. The certainty of evidence was assessed using the GRADE framework.
Results: Twenty-eight studies involving 5,527 patients were included. Topiramate demonstrated significant benefits in increasing responder rates (odds ratio [OR] 4.93), reducing headache frequency (weighted mean difference [WMD] –5.53), and decreasing acute medication intake frequency (WMD –6.95), but was associated with more adverse events compared to placebo (OR 0.20). Fremanezumab, galcanezumab, and botulinum toxin type A (BTA) were effective in increasing responder rates (ORs 2.57 to 3.46). For reversion to nMO, eptinezumab, fremanezumab, and BTA were superior to placebo (ORs 1.55 to 2.75). Eptinezumab, fremanezumab, erenumab 140 mg, and BTA were more efficacious than erenumab 70 mg without significant differences in safety and tolerability.
Conclusions: Topiramate likely has large beneficial effects on increasing responder rates and reducing headache frequency but is associated with lower safety and greater intolerability. Fremanezumab, galcanezumab, and eptinezumab show promise in increasing responder rates. Eptinezumab has a large beneficial effect on reversion to nMO, with fremanezumab and BTA having smaller effects.
Implications for Practice: Clinicians should balance efficacy and tolerability when selecting pharmacological treatments for MOH. While topiramate is effective, its adverse event profile may limit its use. CGRP monoclonal antibodies, such as eptinezumab and fremanezumab, offer promising efficacy with acceptable safety profiles and may be preferred options for some patients.
Study Strengths and Limitations: Strengths include a comprehensive network meta-analysis of multiple pharmacological therapies and the use of GRADE for assessing evidence certainty. Limitations involve variability among included studies, small sample sizes, and heterogeneity in study populations and methodologies, which may affect the generalizability of the findings.
Future Research: High-quality randomized controlled trials are needed to confirm these findings and directly compare different pharmacological treatments in MOH. Future studies should focus on long-term efficacy, safety of newer therapies, and their impact on patient-centered outcomes.
RCT: More Frequent Screening with Pressure-Supported SBTs Delayed Extubation in Mechanically Ventilated Adults
13 Oct, 2024 | 13:15h | UTCBackground: Prompt liberation from mechanical ventilation is crucial to reduce complications associated with prolonged ventilator use. The optimal frequency of weaning readiness screening and the most effective spontaneous breathing trial (SBT) technique are not well established.
Objective: To evaluate whether the frequency of screening for weaning readiness (once-daily vs more frequent) and the SBT technique used (pressure-supported vs T-piece) affect the time to successful extubation in adults receiving invasive mechanical ventilation.
Methods: In a multicenter randomized clinical trial with a 2×2 factorial design, 797 critically ill adults who had been mechanically ventilated for at least 24 hours were enrolled. Participants were randomized to either once-daily or more frequent screening for weaning readiness and to undergo either pressure-supported SBTs (pressure support >0 to ≤8 cm H₂O with PEEP >0 to ≤5 cm H₂O) or T-piece SBTs, each lasting 30–120 minutes. The primary outcome was the time to successful extubation, defined as the time from starting unsupported spontaneous breathing that was sustained for at least 48 hours post-extubation.
Results: Among the 797 patients (mean age 62.4 years; 59.2% male), there was no significant difference in time to successful extubation when comparing screening frequencies (hazard ratio [HR] 0.88; 95% CI, 0.76–1.03; P = .12) or SBT techniques (HR 1.06; 95% CI, 0.91–1.23; P = .45) individually. However, a significant interaction between screening frequency and SBT technique was identified (P = .009). Specifically, in patients undergoing pressure-supported SBTs, more frequent screening *delayed* time to successful extubation compared to once-daily screening (HR 0.70; 95% CI, 0.50–0.96; P = .02). Conversely, when T-piece SBTs were used, the frequency of screening did not significantly affect extubation time. The median time to successful extubation was shortest in the once-daily screening with pressure-supported SBT group (2.0 days) and longest in the more frequent screening with pressure-supported SBT group (3.9 days).
Conclusions: More frequent screening combined with pressure-supported SBTs resulted in a *longer* time to successful extubation, suggesting this combination may delay weaning from mechanical ventilation. Once-daily screening with pressure-supported SBTs showed a trend toward faster extubation compared to other strategies, although this was not statistically significant.
Implications for Practice: Clinicians should be cautious about combining more frequent screening with pressure-supported SBTs, as this may unintentionally prolong mechanical ventilation. Adopting once-daily screening with pressure-supported SBTs might facilitate earlier extubation.
Study Strengths and Limitations: Strengths of the study include its large sample size, multicenter design, and high adherence to the intervention protocols. Limitations involve the unexpected significant interaction between interventions, which may limit the generalizability of the results.
Future Research: Additional studies are warranted to confirm the interaction between screening frequency and SBT technique and to explore the mechanisms underlying the delayed extubation with more frequent screening and pressure-supported SBTs.
Guideline: SCAI Expert Consensus on Management of STEMI Patients Undergoing Primary PCI
13 Oct, 2024 | 12:44h | UTCIntroduction: ST-elevation myocardial infarction (STEMI) is a leading cause of morbidity and mortality, requiring rapid diagnosis and timely reperfusion. While primary percutaneous coronary intervention (PCI) is the preferred reperfusion method, existing guidelines lack detailed procedural and technical recommendations for the cardiac catheterization laboratory (CCL). The Society for Cardiovascular Angiography & Interventions (SCAI) presents this expert consensus statement to provide best practices for CCL team readiness, optimal angiography and intervention techniques, management of special circumstances and anatomical subsets, and strategies to improve quality of care in STEMI patients undergoing primary PCI.
Key Recommendations:
- CCL Team Readiness:
- Prehospital notification and ECG transmission expedite care.
- Implement emergency department (ED) bypass when feasible.
- Perform a focused cardiovascular assessment prior to PCI.
- Arterial Access:
- Prefer transradial access over femoral to reduce complications.
- Use ultrasound guidance and contemporary techniques for femoral access when necessary.
- Diagnostic Assessment:
- Conduct complete coronary angiography during the index procedure.
- Measure left ventricular end-diastolic pressure (LVEDP) to guide management.
- Managing Thrombus:
- Assess thrombus burden after wire crossing.
- Use bail-out aspiration thrombectomy selectively for large thrombus burden.
- Consider parenteral or intracoronary antiplatelet agents for refractory thrombus.
- Managing No-Reflow:
- Administer intracoronary vasodilators to the distal bed.
- Enhance coronary perfusion pressure by augmenting mean arterial pressure and reducing LVEDP.
- Intracoronary Imaging:
- Encourage routine use of IVUS or OCT to guide PCI.
- Employ intracoronary imaging to investigate stent thrombosis or suspected nonatherosclerotic causes.
- Special Circumstances:
- In cardiogenic shock, perform right heart catheterization and consider mechanical circulatory support.
- After failed fibrinolysis, proceed with immediate catheterization and rescue PCI.
- In multivessel disease, complete revascularization is recommended.
- Anatomical Subsets:
- Use plaque modification techniques for calcified lesions.
- Prefer a provisional one-stent strategy in bifurcation lesions.
- Focus on restoring flow in coronary aneurysms.
- Nonatherosclerotic STEMI Causes:
- Administer intracoronary nitroglycerin to identify epicardial vasospasm.
- Manage spontaneous coronary artery dissection conservatively if flow is preserved.
- Use thrombectomy for coronary embolism.
- Investigate MINOCA with additional imaging and testing.
- Quality Improvement:
- Track all STEMI cases to assess treatment times and outcomes for continuous improvement.
Conclusion: Adherence to these recommendations is expected to enhance patient outcomes by optimizing procedural strategies, reducing complications, and improving survival in STEMI patients undergoing primary PCI.
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.