Internal Medicine
RCT: Low-Dose Ketamine Enhances Pain Relief When Added to Morphine in ED Patients
20 Nov, 2024 | 14:42h | UTCBackground: Acute pain is a prevalent complaint among emergency department (ED) patients, yet effective pain management remains suboptimal, especially in individuals with current opioid use due to opioid tolerance and hyperalgesia. Low-dose ketamine (LDK) has been proposed as an adjunct to opioids to enhance analgesia through synergistic or additive effects, but its efficacy in patients with and without current opioid use in the ED setting is not well established.
Objective: This randomized controlled trial aimed to determine the effectiveness of LDK as an adjunct to morphine versus morphine alone for acute pain management in ED patients with and without current opioid use.
Methods: In this single-center, double-blind study, 116 adult patients presenting to the ED with acute pain (numeric rating scale [NRS] ≥5) requiring intravenous opioids were randomized to receive either 0.1 mg/kg ketamine or isotonic saline (placebo) as an adjunct to morphine. Patients with and without current opioid use were randomized separately. Pain intensity was measured at baseline and at 10, 20, 30, 45, 60, and 120 minutes post-randomization. The primary outcome was pain reduction from baseline to 10 minutes. Secondary outcomes included pain intensity over 120 minutes, need for rescue opioids, side effects, and patient and provider satisfaction.
Results: The study included 116 patients (median age 51 years; 58% male; 36% with current opioid use). Pain reduction from baseline to 10 minutes was significantly greater in the LDK group compared to placebo (median reduction of 4 [IQR 3–6] vs. 1 [IQR 0–2]; p = 0.001). Pain intensity was significantly lower in the LDK group at 10, 20, and 30 minutes post-administration. There was a higher incidence of nausea, vomiting, and dissociation in the LDK group during the first 10 minutes. No significant differences were observed in the need for rescue opioids or in patient and provider satisfaction between groups.
Conclusions: LDK administered as an adjunct to morphine significantly enhances short-term pain relief in ED patients with acute pain, regardless of current opioid use status. However, the increased risk of transient side effects necessitates careful consideration.
Implications for Practice: LDK may be considered as an adjunct to morphine for acute pain management in the ED, particularly when traditional opioid treatments are insufficient. Clinicians should weigh the benefits against the potential for transient side effects, and LDK should not be universally recommended for all patients with moderate to severe pain.
Study Strengths and Limitations: Strengths of the study include its randomized, double-blind design and the inclusion of patients with current opioid use. Limitations include early termination leading to a smaller sample size, potentially underpowering the stratified analysis, and heterogeneity in patient pain conditions. Additionally, assessing the primary outcome at 10 minutes may not capture the peak effect of morphine.
Future Research: Further studies should focus on optimizing LDK administration protocols, such as exploring bolus versus continuous infusion methods, to achieve sustained pain reduction and minimize side effects.
RCT: Catheter Ablation Superior to Antiarrhythmic Drugs in Ischemic Cardiomyopathy with Ventricular Tachycardia
20 Nov, 2024 | 14:32h | UTCBackground: Patients with ventricular tachycardia and ischemic cardiomyopathy face high risks of adverse outcomes, including death and recurrent arrhythmias. While catheter ablation is commonly used when antiarrhythmic drugs fail to suppress ventricular tachycardia, its effectiveness as a first-line therapy compared to antiarrhythmic drugs remains uncertain.
Objective: To compare the efficacy of catheter ablation versus antiarrhythmic drug therapy as a first-line treatment in patients with ischemic cardiomyopathy and ventricular tachycardia who have an implantable cardioverter–defibrillator (ICD).
Methods: In this multicenter, randomized controlled trial (VANISH2), 416 patients with previous myocardial infarction, clinically significant ventricular tachycardia, and an ICD were randomly assigned to receive catheter ablation within 14 days or antiarrhythmic drug therapy with sotalol or amiodarone based on prespecified criteria. The primary endpoint was a composite of death from any cause during follow-up or, more than 14 days after randomization, ventricular tachycardia storm, appropriate ICD shock, or sustained ventricular tachycardia treated by medical intervention.
Results: Over a median follow-up of 4.3 years, the primary endpoint occurred in 50.7% of patients in the catheter ablation group and 60.6% in the drug therapy group (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.58–0.97; P=0.03). Adverse events within 30 days post-ablation included death in 1.0% and nonfatal events in 11.3% of patients. In the drug therapy group, adverse events attributed to antiarrhythmic drugs included death from pulmonary toxicity in 0.5% and nonfatal events in 21.6% of patients.
Conclusions: Catheter ablation as an initial therapy significantly reduced the risk of the composite primary endpoint compared to antiarrhythmic drug therapy in patients with ischemic cardiomyopathy and ventricular tachycardia.
Implications for Practice: These findings support considering catheter ablation as a first-line treatment option for patients with ischemic cardiomyopathy and ventricular tachycardia, potentially leading to improved clinical outcomes over initial antiarrhythmic drug therapy.
Study Strengths and Limitations: Strengths include the randomized, multicenter design and long-term follow-up. Limitations involve the inability to assess effects on individual components of the primary endpoint, such as mortality. Operator experience with catheter ablation may affect outcomes, potentially influencing the generalizability of the results.
Future Research: Further studies are needed to evaluate the long-term benefits and risks of catheter ablation, particularly with advancements in ablation technology. Research into new antiarrhythmic drugs and alternative ICD programming strategies may also provide additional insights.
Phase 2 RCT: Oral Muvalaplin Significantly Reduces Lipoprotein(a) Levels in High-Risk Patients
20 Nov, 2024 | 14:22h | UTCBackground: Elevated lipoprotein(a) [Lp(a)] levels are an independent risk factor for atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Current therapeutic options to lower Lp(a) are limited, and no approved pharmacotherapies specifically target Lp(a) reduction.
Objective: To evaluate the efficacy and safety of muvalaplin, an oral small-molecule inhibitor of Lp(a) formation, in reducing Lp(a) levels in patients at high risk of cardiovascular events.
Methods: In this phase 2, randomized, double-blind, placebo-controlled trial, 233 adults aged 40 years or older with Lp(a) concentrations of 175 nmol/L or greater and high cardiovascular risk (due to atherosclerotic cardiovascular disease, diabetes, or familial hypercholesterolemia) were enrolled across 43 sites worldwide. Participants were randomized to receive muvalaplin at doses of 10 mg/d (n = 34), 60 mg/d (n = 64), or 240 mg/d (n = 68), or placebo (n = 67) for 12 weeks. The primary endpoint was the placebo-adjusted percentage change from baseline in Lp(a) levels at week 12, measured using both an intact Lp(a) assay and a traditional apolipoprotein(a)-based assay.
Results
At week 12, muvalaplin achieved significant, dose-dependent reductions in Lp(a) levels compared with placebo. Using the intact Lp(a) assay, placebo-adjusted reductions were:
- 47.6% (95% CI, 35.1%-57.7%) for 10 mg/d
- 81.7% (95% CI, 78.1%-84.6%) for 60 mg/d
- 85.8% (95% CI, 83.1%-88.0%) for 240 mg/d
Using the apolipoprotein(a)-based assay, reductions were:
- 40.4% (95% CI, 28.3%-50.5%) for 10 mg/d
- 70.0% (95% CI, 65.0%-74.2%) for 60 mg/d
- 68.9% (95% CI, 63.8%-73.3%) for 240 mg/d
Dose-dependent decreases in apolipoprotein B levels were also observed, with placebo-adjusted reductions ranging from 8.9% to 16.1%. Muvalaplin was well tolerated across all doses, with no significant safety or tolerability concerns reported.
Conclusions: Muvalaplin significantly reduced Lp(a) levels in high-risk patients over a 12-week period and was well tolerated. These findings suggest that muvalaplin could be an effective oral therapy for lowering Lp(a) levels.
Implications for Practice: Muvalaplin may offer a convenient oral option to reduce elevated Lp(a) levels, potentially lowering cardiovascular risk in high-risk patient populations.
Study Strengths and Limitations: Strengths of the study include its randomized, double-blind, placebo-controlled design and the use of both traditional and novel assays to accurately measure Lp(a) levels. Limitations involve the short duration of the trial, the relatively small sample size for each dosage group, and the lack of assessment of long-term cardiovascular outcomes and safety.
Future Research: Long-term studies are necessary to determine whether the reduction in Lp(a) levels with muvalaplin translates into decreased cardiovascular events. Future research should also explore optimal dosing strategies and assess the long-term safety profile of muvalaplin.
Cohort Study: High Rate of Preventable Adverse Events in Surgical Inpatients
16 Nov, 2024 | 17:29h | UTCBackground: Adverse events during hospital admissions, particularly in surgical settings, remain a significant cause of patient harm despite efforts to improve patient safety since the “To Err is Human” report. Advances in surgical techniques and patient care necessitate an updated assessment of the current state of perioperative safety.
Objective: To estimate the frequency, severity, and preventability of adverse events associated with perioperative care in surgical inpatients and to identify the settings and healthcare professionals involved.
Methods: A multicenter retrospective cohort study was conducted across 11 US hospitals in Massachusetts. A weighted random sample of 1,009 patients was selected from 64,121 adults admitted for surgery in 2018. Trained nurses reviewed electronic health records to identify adverse events, which were then adjudicated by physicians. Adverse events were classified by type, severity, preventability, setting, and professions involved.
Results: Adverse events occurred in 38.0% of patients (95% CI, 32.6–43.4%), with major adverse events in 15.9% (12.7–19.0%). Among 593 adverse events identified, 59.5% were potentially preventable, and 20.7% were definitely or probably preventable. The most common events were surgery-related (49.3%), adverse drug events (26.6%), healthcare-associated infections (12.4%), and patient care events (11.2%). Adverse events most frequently occurred in general care units (48.8%) and involved attending physicians (89.5%) and nurses (58.9%).
Conclusions: More than one-third of surgical inpatients experienced adverse events, with nearly half classified as major and most potentially preventable. These findings highlight the critical need for ongoing improvement in patient safety throughout perioperative care involving all healthcare professionals.
Implications for Practice: Healthcare providers should enhance patient safety protocols across all perioperative settings, not just in operating rooms. Emphasis should be placed on preventing surgery-related complications, adverse drug events, and healthcare-associated infections by fostering teamwork and continuous monitoring.
Study Strengths and Limitations: Strengths include a comprehensive review of medical records and systematic classification of adverse events by trained professionals. Limitations involve the study’s confinement to Massachusetts hospitals in 2018, potential variability in documentation practices, and limited sample size affecting generalizability and specialty-specific estimates.
Future Research: Further studies are needed to assess adverse event rates in diverse geographic locations and healthcare systems, explore effective interventions to reduce preventable harm, and evaluate long-term trends in surgical patient safety.
RCT: Intensive Systolic Blood Pressure Target Reduces Cardiovascular Events in Type 2 Diabetes
16 Nov, 2024 | 16:49h | UTCBackground: Patients with type 2 diabetes frequently have elevated systolic blood pressure, heightening their risk for cardiovascular disease. Optimal systolic blood-pressure targets in this population remain unclear due to inconclusive results from previous trials.
Objective: To determine whether intensive treatment targeting a systolic blood pressure of less than 120 mm Hg reduces major cardiovascular events compared to standard treatment targeting less than 140 mm Hg in patients with type 2 diabetes.
Methods: In this randomized controlled trial conducted at 145 sites in China, 12,821 patients aged 50 or older with type 2 diabetes, elevated systolic blood pressure, and increased cardiovascular risk were assigned to intensive treatment (target <120 mm Hg) or standard treatment (target <140 mm Hg). The primary outcome was a composite of nonfatal stroke, nonfatal myocardial infarction, treatment or hospitalization for heart failure, or death from cardiovascular causes.
Results: Over a median follow-up of 4.2 years, the intensive-treatment group achieved a mean systolic blood pressure of 121.6 mm Hg versus 133.2 mm Hg in the standard-treatment group at 1 year. Primary outcome events occurred in 393 patients in the intensive group (1.65 events per 100 person-years) versus 492 patients in the standard group (2.09 events per 100 person-years) (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.69 to 0.90; P<0.001). Serious adverse events were similar between groups, but symptomatic hypotension and hyperkalemia were more frequent in the intensive-treatment group.
Conclusions: Intensive systolic blood-pressure control to less than 120 mm Hg significantly reduced major cardiovascular events in patients with type 2 diabetes compared to standard treatment.
Implications for Practice: These findings support adopting more aggressive systolic blood-pressure targets in patients with type 2 diabetes to prevent cardiovascular events. Clinicians should balance the benefits with potential risks, monitoring for hypotension and hyperkalemia.
Study Strengths and Limitations: Strengths include a large sample size, multicenter design, and sufficient power to detect differences in cardiovascular outcomes. Limitations involve unblinded treatment assignment, which may introduce bias, and reliance on self-reported home blood-pressure measurements during the COVID-19 pandemic, potentially affecting data accuracy. The exclusive enrollment of Chinese patients may limit generalizability to other populations. The increased incidence of hypotension and hyperkalemia raises concerns about the safety of intensive blood-pressure lowering in broader practice.
Future Research: Further studies should assess the long-term safety and efficacy of intensive blood-pressure control in diverse populations and explore strategies to minimize adverse events. Investigations into personalized blood-pressure targets based on patient characteristics may enhance clinical outcomes.
RCT: Tirzepatide Reduces Heart Failure Events and Improves Health Status in Obese HFpEF Patients
16 Nov, 2024 | 16:42h | UTCBackground: Obesity significantly increases the risk of heart failure with preserved ejection fraction (HFpEF) due to visceral adiposity-induced systemic inflammation affecting the myocardium. Tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, induces substantial weight loss. However, its effects on cardiovascular outcomes in obese HFpEF patients were previously unknown.
Objective: To assess the impact of tirzepatide on cardiovascular events and health status in patients with HFpEF and obesity.
Methods: In this international, double-blind, randomized, placebo-controlled trial, 731 patients with HFpEF (ejection fraction ≥50%), a body-mass index (BMI) of at least 30, and New York Heart Association class II–IV symptoms were assigned to receive tirzepatide (up to 15 mg subcutaneously once weekly) or placebo for at least 52 weeks. The two primary endpoints were the composite of adjudicated death from cardiovascular causes or worsening heart-failure events, and the change from baseline to 52 weeks in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS).
Results: Over a median follow-up of 104 weeks, death from cardiovascular causes or worsening heart-failure events occurred in 9.9% of patients in the tirzepatide group versus 15.3% in the placebo group (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.41 to 0.95; P=0.026). Worsening heart-failure events occurred in 8.0% with tirzepatide versus 14.2% with placebo (HR, 0.54; 95% CI, 0.34 to 0.85). At 52 weeks, the mean increase in KCCQ-CSS was 19.5 points in the tirzepatide group compared to 12.7 points in the placebo group (between-group difference, 6.9; 95% CI, 3.3 to 10.6; P<0.001). Adverse events leading to discontinuation occurred in 6.3% of tirzepatide patients versus 1.4% of placebo patients, mainly due to gastrointestinal symptoms.
Conclusions: Tirzepatide significantly reduced the risk of cardiovascular death or worsening heart failure and improved health status in patients with HFpEF and obesity.
Implications for Practice: These findings suggest that tirzepatide may be an effective therapeutic option for reducing heart failure events and enhancing quality of life in obese patients with HFpEF. Its benefits may be attributed to significant weight loss and anti-inflammatory effects, offering a potential new approach in managing this patient population.
Study Strengths and Limitations: Strengths include the randomized, double-blind design and a long median follow-up of 104 weeks. Limitations involve the exclusion of patients with BMI less than 30, which may limit applicability to non-obese HFpEF patients with increased visceral adiposity. Additionally, the higher rate of gastrointestinal adverse events leading to discontinuation in the tirzepatide group warrants cautious consideration.
Future Research: Further studies are needed to evaluate tirzepatide’s effects in HFpEF patients with lower BMI but increased visceral adiposity and to elucidate the mechanisms underlying its cardiovascular benefits.
Retrospective Cohort Study: Midline Catheters Associated with Lower Major Complications Than PICCs in Outpatient Antimicrobial Therapy
16 Nov, 2024 | 14:35h | UTCBackground: Outpatient parenteral antimicrobial therapy (OPAT) requires reliable vascular access for administering intravenous antibiotics post-hospitalization. Peripherally inserted central catheters (PICCs) are commonly used due to their versatility and ease of placement. Recently, midline catheters have emerged as potential alternatives for OPAT, offering less invasive access. However, limited evidence exists comparing the safety and complication rates of midline catheters versus PICCs in OPAT patients.
Objective: To compare the risk of major and minor device complications associated with midline catheters versus PICCs in patients receiving OPAT.
Methods: This retrospective cohort study analyzed data from 2,824 hospitalized patients across 69 Michigan hospitals who received either a midline catheter (n=1,999) or a PICC (n=825) for OPAT between January 2017 and November 2023. Patients receiving vancomycin were excluded. The primary outcome was major device complications, defined as catheter-related bloodstream infection (CRBSI) or catheter-related venous thromboembolism (CR-VTE). Secondary outcomes included minor device complications (e.g., catheter dislodgement, occlusion) and device failure, defined as catheter removal due to any complication.
Results: Midline catheters were associated with a lower risk of major complications compared to PICCs (0.8% vs 3.4%; adjusted hazard ratio [aHR], 0.46; 95% CI, 0.23-0.91; P < .001). This difference was more pronounced for devices with dwell times of 14 days or fewer (aHR, 0.29; 95% CI, 0.12-0.68). There were no significant differences in minor complications (10.3% vs 13.8%; aHR, 1.07; 95% CI, 0.83-1.38) or device failure rates (9.6% vs 12.1%; aHR, 1.26; 95% CI, 0.96-1.65) between midline catheters and PICCs.
Conclusions: Midline catheters are associated with a lower risk of major complications compared to PICCs in patients receiving OPAT, particularly for treatment durations of 14 days or fewer. These findings suggest that midline catheters are a safe and effective alternative to PICCs for short-term OPAT.
Implications for Practice: Clinicians should consider using midline catheters for OPAT when the anticipated therapy duration is 14 days or less and the infusate is peripherally compatible. This may reduce the risk of major complications such as CRBSI and CR-VTE, potentially improving patient outcomes and reducing healthcare costs.
Study Strengths and Limitations: Strengths of this study include a large, diverse patient population across multiple hospitals and rigorous data collection methods. Limitations include its retrospective design, potential for unmeasured confounding, and exclusion of patients receiving vancomycin, which may limit generalizability. Additionally, complications occurring after 30 days or post-device removal may have been missed.
Future Research: Further studies are needed to evaluate the safety and efficacy of midline catheters for OPAT durations exceeding 14 days and to explore factors influencing long-term device performance and patient outcomes.
Test-Negative Study: RSV Vaccine May Reduce Hospitalizations and ED Visits in Adults Aged ≥60
16 Nov, 2024 | 14:18h | UTCBackground: Respiratory syncytial virus (RSV) is a significant cause of morbidity and mortality among older adults in the USA, with an estimated 100,000–160,000 RSV-associated hospitalizations annually in those aged 60 years and older. In 2023, RSV vaccines were recommended for this population, showing efficacy in clinical trials. However, real-world effectiveness data, particularly against severe outcomes like hospitalizations in high-risk groups, are limited.
Objective: To assess the real-world effectiveness of RSV vaccination against RSV-associated hospitalizations and emergency department (ED) encounters among adults aged 60 years and older during the 2023–24 RSV season in the USA.
Methods: A test-negative design analysis was conducted using data from the Virtual SARS-CoV-2, Influenza, and Other Respiratory Viruses Network (VISION), encompassing eight states. Adults aged ≥60 presenting with RSV-like illness and tested for RSV from Oct 1, 2023, to Mar 31, 2024, were included. Vaccination status was determined through electronic health records, immunization registries, and medical claims. Vaccine effectiveness (VE) was estimated by comparing the odds of vaccination among RSV-positive cases and RSV-negative controls, adjusting for age, sex, race and ethnicity, comorbidities, and geographic region.
Results: Among 28,271 hospitalizations for RSV-like illness in immunocompetent adults aged ≥60, VE against RSV-associated hospitalization was 80% (95% CI 71–85). VE against RSV-associated critical illness (ICU admission or death) was 81% (95% CI 52–92). In 8,435 hospitalizations among immunocompromised adults, VE was 73% (95% CI 48–85) against RSV-associated hospitalization. Among 36,521 ED encounters in immunocompetent adults, VE against RSV-associated ED visits was 77% (95% CI 70–83). VE estimates were consistent across age groups and vaccine products.
Conclusions: RSV vaccination effectively prevented RSV-associated hospitalizations and ED visits among adults aged ≥60 during the first season post-approval, including those at highest risk due to advanced age or immunocompromise.
Implications for Practice: These findings support recommending RSV vaccination for adults aged ≥60 to reduce severe RSV-related morbidity and mortality. Clinicians should consider advising eligible patients to receive the RSV vaccine to prevent hospitalizations and critical illness.
Study Strengths and Limitations: Strengths include a large, geographically diverse cohort and integrated medical, laboratory, and vaccination data, allowing robust VE estimates across subgroups. Limitations involve potential misclassification of vaccination status, residual confounding, and reliance on clinician-directed RSV testing, which may introduce bias.
Future Research: Further studies are needed to evaluate the duration of vaccine protection over multiple RSV seasons and to assess VE in other high-risk populations and settings.
Phase 3 RCT: Resmetirom Significantly Improves NASH Resolution and Liver Fibrosis
16 Nov, 2024 | 13:56h | UTCBackground: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatments. It significantly increases the risk of liver-related complications, especially in patients with type 2 diabetes. Resmetirom, a thyroid hormone receptor beta-selective agonist, is being investigated for its potential to treat NASH and liver fibrosis.
Objective: To evaluate the efficacy and safety of resmetirom in resolving NASH and improving fibrosis in adults with biopsy-confirmed NASH and fibrosis stages F1B to F3.
Methods: This double-blind, placebo-controlled phase 3 trial randomized 966 adults with NASH to receive once-daily resmetirom (80 mg or 100 mg) or placebo for 52 weeks. Primary endpoints included (1) NASH resolution with no fibrosis worsening and (2) fibrosis improvement by at least one stage without NAFLD activity score worsening. Secondary outcomes included changes in lipid profiles and liver biomarkers.
Results: At 52 weeks, NASH resolution occurred in 25.9% of patients receiving 80 mg and 29.9% receiving 100 mg of resmetirom, compared with 9.7% in the placebo group (P<0.001 for both doses vs. placebo). Fibrosis improved by at least one stage in 24.2% (80 mg) and 25.9% (100 mg) of resmetirom-treated patients versus 14.2% for placebo (P<0.001). LDL cholesterol reductions were −13.6% (80 mg) and −16.3% (100 mg) at 24 weeks versus 0.1% for placebo (P<0.001). Improvements were also noted in triglycerides, liver enzymes, and imaging biomarkers. Adverse events, primarily mild gastrointestinal symptoms, were more frequent with resmetirom. Serious adverse events were similar across groups (10.9%–12.7%).
Conclusions: Resmetirom significantly improved NASH resolution and fibrosis compared to placebo, demonstrating its potential as a treatment for NASH with liver fibrosis.
Implications for Practice: Resmetirom offers a promising treatment option for NASH, potentially altering the disease course and improving outcomes. Clinicians should monitor for regulatory approval and long-term safety data.
Study Strengths and Limitations: Strengths include robust biopsy-confirmed endpoints and a large sample size. Limitations include short follow-up and lack of clinical-outcome data.
Future Research: Long-term studies are needed to assess durability, safety, and effects on clinical outcomes like cirrhosis and liver-related mortality.
RCT: Once-Weekly Semaglutide Reduces Weight and Knee Osteoarthritis Pain in Obese Patients
16 Nov, 2024 | 13:41h | UTCBackground: Obesity is a major risk factor for the development and progression of knee osteoarthritis, leading to chronic pain and reduced mobility. Weight reduction has been shown to alleviate symptoms, but sustained, non-surgical interventions are limited. Glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide, have demonstrated efficacy in weight management; however, their impact on knee osteoarthritis pain is not well established.
Objective: To assess the efficacy of once-weekly subcutaneous semaglutide (2.4 mg) versus placebo, alongside lifestyle interventions, on body weight reduction and pain related to knee osteoarthritis in adults with obesity.
Methods: In this 68-week, double-blind, randomized, placebo-controlled trial conducted at 61 sites across 11 countries, 407 adults with obesity (BMI ≥30) and moderate knee osteoarthritis with at least moderate pain were enrolled. Participants were randomized in a 2:1 ratio to receive semaglutide or placebo, in addition to counseling on a reduced-calorie diet and increased physical activity. The primary endpoints were the percentage change in body weight and the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score from baseline to week 68.
Results: Semaglutide treatment resulted in a mean weight reduction of −13.7% compared to −3.2% with placebo (P<0.001). The mean change in WOMAC pain score was −41.7 points with semaglutide versus −27.5 points with placebo (P<0.001), indicating a significant reduction in pain. Additionally, semaglutide led to greater improvements in physical function scores and a decrease in the use of nonsteroidal anti-inflammatory drugs. Serious adverse events were similar between groups; however, gastrointestinal disorders led to more discontinuations in the semaglutide group (6.7% vs. 3.0%).
Conclusions: Once-weekly subcutaneous semaglutide significantly reduces body weight and alleviates pain related to knee osteoarthritis in obese adults, compared to placebo, when combined with lifestyle modifications. These findings support semaglutide as an effective non-surgical intervention for weight management and symptom relief in this population.
Implications for Practice: Semaglutide may be considered as part of a comprehensive treatment strategy for obese patients with knee osteoarthritis, potentially improving pain, physical function, and reducing reliance on analgesics. Clinicians should weigh the benefits against potential gastrointestinal side effects.
Study Strengths and Limitations: Strengths include the randomized, double-blind design and a sizable, diverse cohort. Limitations involve the absence of imaging follow-up, lack of metabolic and inflammatory marker assessments, and no post-treatment outcome data to evaluate the sustainability of benefits after discontinuation.
Future Research: Further studies are warranted to explore the long-term effects of semaglutide on knee osteoarthritis progression, its mechanisms of action on joint pathology, and its effectiveness in broader patient populations.
Meta-analysis: Urea May be Effective for the Treatment of SIADH-Induced Hyponatremia
15 Nov, 2024 | 14:01h | UTCBackground: Hyponatremia, defined as a serum sodium level below 135 mEq/L, is the most common electrolyte disorder in clinical practice, associated with increased mortality and prolonged hospital stays. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a frequent cause of euvolemic hyponatremia, particularly among hospitalized patients. Traditional treatments like fluid restriction and hypertonic saline have limitations, and guidelines are inconsistent regarding their use. Urea, an osmotic diuretic, has been proposed as an alternative therapy but is underutilized due to concerns about efficacy, safety, and patient tolerability.
Objective: To evaluate the effectiveness and safety of urea in treating hyponatremia caused by SIADH.
Methods: A systematic review and meta-analysis were conducted following PRISMA guidelines. Searches of MEDLINE, EMBASE, Cochrane CENTRAL, and Google Scholar up to November 2023 identified studies involving patients with SIADH-related hyponatremia treated with oral or nasogastric urea. Inclusion criteria encompassed clinical trials and observational studies reporting outcomes on serum sodium levels, symptom resolution, or adverse effects.
Results: Sixteen observational studies involving 518 patients (430 treated with urea) met inclusion criteria. Urea treatment significantly increased serum sodium levels (mean difference [MD], 9.21 mEq/L [95% CI, 7.36-11.06]; P < 0.01) despite high heterogeneity (I² = 89%). Subgroup analyses showed significant sodium increases at 24 hours and at 2, 3, 5, 7, 14 days, and 1 year post-treatment. Patients with severe hyponatremia (<120 mEq/L) experienced greater sodium increases (MD, 18.04 mEq/L [95% CI, 13.68-22.39]) compared to those with moderate (120-129 mEq/L) or mild (130-135 mEq/L) hyponatremia. Urea’s efficacy was comparable to fluid restriction (MD, 0.81 mEq/L [95% CI, –0.93 to 2.55]; P = 0.4) and vaptans (MD, –2.43 mEq/L [95% CI, –6.31 to 1.45]; P = 0.2), and superior to no treatment (MD, 7.99 mEq/L [95% CI, 6.25-9.72]; P < 0.01). Adverse events were minor; poor palatability was the most common complaint.
Conclusions: Urea is an effective and safe treatment for SIADH-induced hyponatremia, significantly increasing serum sodium levels, particularly in severe cases. It offers a viable alternative to fluid restriction and vaptans with minimal adverse effects.
Implications for Practice: Urea should be considered a valuable treatment option for SIADH-induced hyponatremia, especially in resource-limited settings or when other therapies are contraindicated or poorly tolerated. Its cost-effectiveness and ease of administration may improve patient outcomes and reduce healthcare costs.
Study Strengths and Limitations: Strengths include a comprehensive search strategy and inclusion of diverse studies across multiple settings. Limitations are the reliance on observational studies due to the absence of randomized controlled trials, significant heterogeneity among studies, and the potential for publication bias.
Future Research: Randomized controlled trials are necessary to confirm urea’s efficacy and safety, establish standardized dosing regimens, and develop strategies to enhance palatability and patient adherence.
Meta-Analysis: Spinal Cord Stimulation May Be Effective for Chronic Back and Leg Pain
15 Nov, 2024 | 13:43h | UTCBackground: Chronic back and leg pain causes significant disability worldwide. Spinal cord stimulation (SCS) offers treatment for patients unresponsive to conventional medical management (CMM). The comparative efficacy of conventional and novel SCS forms versus CMM is debated, requiring thorough evaluation.
Objective: To evaluate the efficacy of conventional and novel SCS therapies compared with CMM in adults with chronic back or leg pain who had not previously used SCS.
Methods: A systematic review and Bayesian network meta-analysis per PRISMA guidelines were performed. MEDLINE, Embase, and Cochrane Library were searched up to September 2, 2022. Thirteen RCTs with 1,561 patients were included. Interventions were conventional SCS, novel SCS modalities (e.g., high-frequency, burst stimulation), and CMM. Primary outcomes were pain intensity (visual analog scale) and responder rates (≥50% pain relief) in back or leg. Secondary outcomes were quality of life (EQ-5D index) and functional disability (Oswestry Disability Index).
Results: At 6 months, both conventional and novel SCS were superior to CMM in five of six outcomes. For back pain responder rates, conventional SCS had an OR of 3.00 (95% CrI, 1.49–6.72) and novel SCS had an OR of 8.76 (95% CrI, 3.84–22.31) versus CMM. Pain intensity in the back decreased significantly with conventional SCS (MD, –1.17; 95% CrI, –1.64 to –0.70) and novel SCS (MD, –2.34; 95% CrI, –2.96 to –1.73). Leg pain intensity also decreased significantly with conventional SCS (MD, –2.89; 95% CrI, –4.03 to –1.81) and novel SCS (MD, –4.01; 95% CrI, –5.31 to –2.75) compared to CMM. Quality of life improved with both SCS therapies (conventional SCS MD, 0.15; 95% CrI, 0.09–0.21; novel SCS MD, 0.17; 95% CrI, 0.13–0.21). Functional disability improved significantly with conventional SCS (MD, –7.10; 95% CrI, –10.91 to –3.36).
Conclusions: Both conventional and novel SCS therapies are associated with significant improvements in pain relief, quality of life, and functional ability compared with CMM in patients with chronic back and leg pain at 6 months.
Implications for Practice: The results support integrating SCS therapies into clinical practice for patients with chronic back and leg pain unresponsive to CMM.
Study Strengths and Limitations: Strengths include inclusion of recent RCTs and use of Bayesian network meta-analysis, allowing comprehensive evidence synthesis with both direct and indirect comparisons, enhancing reliability. Limitations involve potential biases due to challenges in blinding participants and assessors, as patients can perceive whether a device is active. Heterogeneity among studies in patient populations and interventions may affect generalizability. Inability to include long-term efficacy data due to crossover in many trials limits understanding of sustained outcomes.
Future Research: Long-term RCTs are needed to assess sustained efficacy and safety of SCS therapies. Future studies should compare different SCS modalities directly and identify patient subgroups most likely to benefit.
RCT: Tirzepatide Significantly Reduces Weight and Diabetes Risk in Obese Adults with Prediabetes
15 Nov, 2024 | 13:29h | UTCBackground: Obesity is a chronic disease that significantly increases the risk of type 2 diabetes, particularly in individuals with prediabetes. Weight reduction has been shown to improve insulin sensitivity and beta-cell function, potentially delaying or preventing the onset of type 2 diabetes. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated significant weight loss and glycemic control in short-term studies.
Objective: To evaluate the long-term efficacy and safety of tirzepatide in reducing body weight and delaying progression to type 2 diabetes in obese adults with prediabetes over a period of three years.
Methods: In this phase 3, double-blind, randomized, controlled trial (SURMOUNT-1), 1032 obese adults with prediabetes were randomized 1:1:1:1 to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo, alongside lifestyle intervention, for 176 weeks, followed by a 17-week off-treatment period. The primary endpoints included percent change in body weight and onset of type 2 diabetes during the treatment and follow-up periods.
Results: At week 176, participants receiving tirzepatide achieved significant mean weight reductions of –12.3% (5 mg), –18.7% (10 mg), and –19.7% (15 mg), compared to –1.3% with placebo (P<0.001 for all comparisons). Progression to type 2 diabetes was significantly lower in the tirzepatide groups (1.3%) compared to placebo (13.3%), with a hazard ratio of 0.07 (95% CI, 0.0 to 0.1; P<0.001). After the 17-week off-treatment period, 2.4% of tirzepatide-treated participants and 13.7% of placebo-treated participants had developed type 2 diabetes (hazard ratio, 0.12; 95% CI, 0.1 to 0.2; P<0.001). Common adverse events were gastrointestinal and generally mild to moderate.
Conclusions: Three years of tirzepatide treatment in obese adults with prediabetes resulted in substantial and sustained weight loss and significantly reduced the risk of progression to type 2 diabetes compared to placebo, with an acceptable safety profile.
Implications for Practice: Tirzepatide may be an effective long-term therapeutic option for weight management and diabetes prevention in obese patients with prediabetes, potentially altering clinical approaches to obesity and metabolic disease management.
Study Strengths and Limitations: Strengths include the long duration of the trial and large sample size, providing robust data on long-term efficacy and safety. Limitations involve participant attrition and higher withdrawal rates, especially in the placebo group, which may affect the generalizability of the findings.
Future Research: Further studies are needed to explore the mechanisms of tirzepatide’s effects on beta-cell function and insulin sensitivity, as well as its impact on cardiovascular outcomes and quality of life in diverse populations.
Target Trial Emulation: SGLT-2 Inhibitors May Reduce Recurrent Nephrolithiasis in Patients with Type 2 Diabetes and Pre-existing Nephrolithiasis
10 Nov, 2024 | 18:17h | UTCBackground: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors, initially approved for glycemic control in type 2 diabetes, have demonstrated multiple cardiometabolic and renal benefits, including reducing serum urate levels and lowering gout flare-ups. However, data on the effectiveness of SGLT-2 inhibitors in preventing recurrent nephrolithiasis, especially among patients with concomitant gout, are limited.
Objective: To evaluate the comparative effectiveness of SGLT-2 inhibitors versus glucagon-like peptide-1 (GLP-1) receptor agonists in reducing the recurrence of nephrolithiasis among patients with type 2 diabetes and pre-existing nephrolithiasis, including those with concomitant gout.
Methods: A target trial emulation study was conducted using a population-based cohort from British Columbia, Canada, between January 2014 and June 2022. Adults with type 2 diabetes and pre-existing nephrolithiasis who initiated an SGLT-2 inhibitor or a GLP-1 receptor agonist were included. The primary outcome was recurrent nephrolithiasis events identified from emergency department visits, hospital admissions, or outpatient diagnoses. Inverse probability of treatment weighting was applied to adjust for baseline differences.
Results: After weighting, 14,456 patients initiating SGLT-2 inhibitors and 5,877 initiating GLP-1 receptor agonists were analyzed. The incidence of recurrent nephrolithiasis was significantly lower among SGLT-2 inhibitor users (105.3 per 1000 person-years) compared to GLP-1 receptor agonist users (156.4 per 1000 person-years), with an adjusted rate ratio of 0.67 (95% CI 0.57 to 0.79) and a rate difference of –51 per 1000 person-years (number needed to treat [NNT] = 20).
Conclusions: SGLT-2 inhibitor use is associated with a significant reduction in recurrent nephrolithiasis among patients with type 2 diabetes and pre-existing nephrolithiasis, including those with concomitant gout. These findings suggest that SGLT-2 inhibitors may offer dual benefits in managing nephrolithiasis recurrence and gout comorbidities.
Implications for Practice: In patients with type 2 diabetes and a history of nephrolithiasis, particularly those with concomitant gout, SGLT-2 inhibitors may be a valuable addition to current treatment strategies to reduce the recurrence of kidney stones and manage comorbid conditions.
Study Strengths and Limitations: Strengths include the use of a large, population-based cohort and rigorous statistical methods to emulate a target trial, enhancing causal inference. Limitations involve potential residual confounding due to unmeasured factors such as body mass index and laboratory measures, and the inability to capture nephrolithiasis events not requiring medical attention.
Future Research: Further studies are warranted to explore the mechanisms underlying the nephrolithiasis protective effects of SGLT-2 inhibitors, assess their impact in patients without diabetes, and investigate the effects on different types of kidney stones.
Review: Frailty in Older Adults
10 Nov, 2024 | 18:03h | UTCIntroduction: Frailty is a state of decreased physiological reserve and increased vulnerability to adverse health outcomes, becoming more prevalent with age. This review by Kim and Rockwood outlines definitions, biological mechanisms, measurement, and management of frailty in older adults, aiming to guide clinical practice.
Key Recommendations:
- Definitions of Frailty: Clinicians should recognize two predominant concepts: the Fried frailty phenotype, defining frailty as a clinical syndrome with features like exhaustion, weakness, slowness, inactivity, and weight loss; and the deficit-accumulation model, quantifying frailty based on accumulated health deficits.
- Biology of Frailty: Understanding biological mechanisms—such as chronic inflammation, cellular senescence, mitochondrial dysfunction, deregulated nutrient sensing, and hormonal changes—is essential for identifying modifiable risk factors and developing targeted interventions.
- Measurement of Frailty: Utilize validated assessment tools appropriate to the clinical context. The Fried frailty phenotype and the deficit-accumulation frailty index are widely used; brief screening tools and performance measures like gait speed can be practical, especially in acute care settings.
- Management and Interventions for Frailty: Management should focus on increasing physiological reserve through multicomponent interventions. Exercise (aerobic and resistance training), combined with nutritional support, comprehensive geriatric assessment, and medication optimization, has been shown to ameliorate frailty and improve mobility, strength, and daily functioning.
- Frailty Screening Before Stressful Treatments: In high-risk clinical contexts such as oncology and surgery, pre-treatment frailty assessment can guide decision-making, personalize care plans, and improve outcomes by reducing treatment-related adverse effects.
- Evidence Gaps and Future Directions: More research is needed on effective strategies for frailty identification, interventions to prevent or reverse frailty, and the cost-effectiveness of frailty-guided care models, particularly in primary care settings.
Conclusion: Incorporating frailty assessment into clinical practice enables personalized, holistic care that aligns with older patients’ health goals and needs. Interventions targeting frailty can enhance physiological reserve, reduce vulnerability to stressors, and improve clinical outcomes. Further research is essential to optimize frailty management strategies and fully realize the benefits of frailty-guided care in our aging society.
News Release: Seven-Day Antibiotic Regimen Effective for Bloodstream Infections
10 Nov, 2024 | 17:54h | UTCIntroduction: A recent large-scale, multicenter randomized clinical trial has shown that a seven-day course of antibiotics is as effective as the traditional 14-day regimen for treating hospitalized patients with bloodstream infections (BSIs). This finding addresses a critical need in medical practice to optimize antibiotic use amid rising concerns about antimicrobial resistance and healthcare costs.
Highlights: The Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) trial evaluated 3,608 patients with BSIs across 74 hospitals in seven countries, including the United States, Canada, and Australia. Patients were randomized to receive either a seven-day or a 14-day antibiotic course, with the choice of antibiotic, dosage, and administration route determined by their healthcare team.
- Efficacy Results: The 90-day mortality rates were similar between the two groups—14.5% in the seven-day group versus 16.1% in the 14-day group—demonstrating the non-inferiority of the shorter regimen.
- Secondary Outcomes: Rates of relapse, ICU mortality, hospital mortality, and other clinical markers showed no significant differences between the two groups.
- Patient Demographics: The study included a diverse patient population, with 55% in intensive care units at enrollment. Infections originated from various sources, most commonly the urinary tract (42.2%), abdomen (18.8%), and lungs (13.0%).
- Applicability: Exclusion criteria were minimal, enhancing the generalizability of the findings to everyday clinical practice. Patients with extreme immunosuppression or undrained abscesses were excluded, but those with conditions like renal failure were included.
Lead investigator Dr. Nick Daneman emphasized, “These findings underscore the effectiveness of a shorter antibiotic regimen in patients with bloodstream infections, which is welcomed as we look to identify evidence-based prescribing guidelines for serious bacterial infections.”
Conclusion: The BALANCE trial provides robust evidence that a seven-day antibiotic course is sufficient for treating BSIs, potentially transforming current clinical practice. Adopting shorter antibiotic regimens can reduce healthcare costs, minimize adverse effects, and combat antimicrobial resistance without compromising patient outcomes. This aligns with antimicrobial stewardship goals and promotes more efficient use of healthcare resources.
Source: This study was presented at IDWeek 2024, the joint annual meeting of the Infectious Diseases Society of America and other related organizations. The research was conducted by a team from Sunnybrook Health Sciences Centre and the University of Toronto, led by Dr. Nick Daneman and Dr. Robert Fowler. More information can be found at: http://www.idsociety.org/news–publications-new/articles/2024/antibiotic-treatment-regimen-for-bloodstream-infections-can-safely-be-cut-by-half
RCT: Preemptive TAVR Does Not Improve Composite Outcomes but May Improve Quality of Life in HFrEF Patients with Moderate Aortic Stenosis
10 Nov, 2024 | 14:18h | UTCBackground: Heart failure with reduced ejection fraction (HFrEF) management emphasizes neurohormonal modulation and afterload reduction. Moderate aortic stenosis (AS) increases afterload, potentially worsening outcomes in HFrEF patients. While transcatheter aortic valve replacement (TAVR) is established for severe AS, its benefit in moderate AS remains uncertain.
Objective: To determine whether TAVR provides clinical benefits over guideline-directed medical therapy (GDMT) in patients with HFrEF and moderate AS.
Methods: In the TAVR UNLOAD randomized controlled trial, 178 symptomatic HFrEF patients (left ventricular ejection fraction 20%-50%) on GDMT with moderate AS were randomized 1:1 to receive TAVR with a balloon-expandable valve or clinical AS surveillance (CASS) with aortic valve replacement upon progression to severe AS. The primary endpoint was the hierarchical occurrence of: (1) all-cause death; (2) disabling stroke; (3) disease-related hospitalizations and heart failure equivalents; and (4) change from baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS).
Results: The mean age was 77 years, 20.8% were female, and 55.6% were in NYHA class III or IV. Median follow-up was 23 months. In the CASS group, 43% underwent TAVR due to progression to severe AS at a median of 12 months. TAVR was not superior to CASS for the primary endpoint (win ratio 1.31; 95% CI: 0.91-1.88; P = 0.14). However, at 1 year, TAVR resulted in a greater improvement in KCCQ-OSS compared with CASS (12.8 ± 21.9 vs 3.2 ± 22.8 points; P = 0.018). There were no significant differences in all-cause mortality or major adverse events between groups.
Conclusions: In HFrEF patients with moderate AS on GDMT, TAVR was not superior to clinical surveillance for the primary composite endpoint but was associated with improved quality of life at 1 year.
Implications for Practice: Preemptive TAVR may offer quality-of-life benefits in select symptomatic HFrEF patients with moderate AS but does not reduce mortality or major cardiovascular events compared to surveillance. Clinicians should weigh patient-specific factors when considering TAVR for moderate AS.
Study Strengths and Limitations: Strengths include being the first randomized trial assessing TAVR in moderate AS with HFrEF. Limitations involve being underpowered due to slow enrollment and protocol changes, and a high crossover rate (43% in the CASS group underwent TAVR), potentially attenuating differences between groups.
Future Research: Larger, adequately powered trials are needed to confirm these findings and identify patients who may benefit most from preemptive TAVR in moderate AS.
Cochrane: Galantamine Improves Cognitive Function in Alzheimer’s Disease but Not in Mild Cognitive Impairment
10 Nov, 2024 | 13:40h | UTCBackground: Alzheimer’s disease is the leading cause of dementia. While incurable, symptomatic treatments like galantamine, a cholinesterase inhibitor, are approved for Alzheimer’s disease.
Objective: To assess the clinical effects and adverse events of galantamine in people with Alzheimer’s disease or mild cognitive impairment.
Methods: A systematic review of double-blind, parallel-group, randomized controlled trials comparing oral galantamine with placebo in people with Alzheimer’s disease or mild cognitive impairment. Outcomes included cognitive function, global function, activities of daily living, functional disability, behavioral function, and adverse events.
Results: Twenty-one studies with 10,990 participants were included. Treatment durations ranged from eight weeks to two years. In Alzheimer’s disease, galantamine at 16 mg to 24 mg/day for six months significantly improved cognitive function compared to placebo (MD –2.86 on ADAS-cog, 95% CI –3.29 to –2.43; six studies, 3049 participants; high-certainty evidence). Functional disability improved (MD 2.12 on DAD, 95% CI 0.75 to 3.49; three studies, 1275 participants), as did behavioral function (MD –1.63 on NPI, 95% CI –3.07 to –0.20; two studies, 1043 participants). Participants receiving galantamine had higher rates of premature discontinuation (OR 1.41, 95% CI 1.19 to 1.68; six studies, 3336 participants) and nausea (OR 2.89, 95% CI 2.40 to 3.49; seven studies, 3616 participants). Death rates were reduced in the galantamine groups (OR 0.56, 95% CI 0.33 to 0.96; six studies, 3493 participants).
In mild cognitive impairment, galantamine did not improve cognitive function (MD –0.21 on ADAS-cog/MCI, 95% CI –0.78 to 0.37; two studies, 1901 participants; low-certainty evidence) or activities of daily living (MD 0.30 on ADCS-ADL-MCI, 95% CI –0.26 to 0.86). Adverse events and discontinuation rates were higher with galantamine.
Conclusions: Galantamine at 16 mg to 24 mg/day improves cognitive function, functional ability, and behavior over six months in Alzheimer’s disease, with clinically meaningful changes. Gastrointestinal adverse events are common and may limit tolerability. Galantamine is not effective in mild cognitive impairment.
Implications for Practice: Galantamine may be considered for symptomatic treatment in mild to moderate Alzheimer’s disease to improve cognition, daily functioning, and behavior, weighing the benefits against the increased risk of gastrointestinal adverse events. It is not recommended for people with mild cognitive impairment.
Study Strengths and Limitations: Strengths include a large sample size and high-certainty evidence for key outcomes in Alzheimer’s disease. Limitations involve high attrition rates and potential bias due to higher discontinuation in galantamine groups. The evidence for mild cognitive impairment is of low certainty due to risk of bias and imprecision.
Future Research: Further trials are needed in more diverse clinical populations, including those with severe Alzheimer’s disease and over longer durations. Research should focus on quality of life outcomes, cost-effectiveness, and subgroup analyses based on individual-level factors.
Meta-analysis: Hemodiafiltration Reduces Mortality in Kidney Failure Patients Compared to Hemodialysis
7 Nov, 2024 | 12:19h | UTCBackground: Kidney failure patients undergoing hemodialysis face high mortality rates, with approximately 50% dying within five years of initiating treatment. Hemodiafiltration, a convection-based therapy that removes a broader spectrum of uraemic toxins, has been proposed to improve survival outcomes. Previous studies have shown mixed results regarding its efficacy, and uncertainties remain about its effects on specific patient subgroups, dose-response relationships with convection volume, and cause-specific mortality.
Objective: To compare the effects of online hemodiafiltration versus standard hemodialysis on all-cause and cause-specific mortality in patients with kidney failure.
Methods: An individual patient data meta-analysis of five randomized controlled trials was conducted, encompassing 4,153 patients (2,083 on hemodiafiltration and 2,070 on hemodialysis). Databases including MEDLINE, Embase, and the Cochrane Central Register were searched up to July 17, 2024. The primary outcome was all-cause mortality. Subgroup analyses based on patient characteristics and dose–response analyses using convection volume were performed.
Results: Over a median follow-up of 30 months, all-cause mortality occurred in 477 patients (23.3%) receiving hemodiafiltration and 559 patients (27.0%) receiving hemodialysis. Hemodiafiltration significantly reduced all-cause mortality (hazard ratio [HR] 0.84, 95% CI 0.74–0.95) compared to hemodialysis. Cardiovascular mortality was also lower in the hemodiafiltration group (HR 0.78, 95% CI 0.64–0.96), particularly deaths due to cardiac causes (HR 0.67, 95% CI 0.50–0.89). No differential effects were observed across predefined patient subgroups. A dose-dependent relationship was found between higher convection volumes and reduced mortality risk.
Conclusions: Hemodiafiltration significantly reduces all-cause and cardiovascular mortality in patients with kidney failure compared to standard hemodialysis. The mortality benefit is dose-dependent, with higher convection volumes associated with greater risk reductions.
Implications for Practice: These findings support the adoption of online hemodiafiltration as a superior alternative to conventional hemodialysis. Clinicians should consider implementing high-dose hemodiafiltration to improve survival outcomes in patients with kidney failure.
Study Strengths and Limitations: Strengths include the large sample size and use of individual patient data, allowing for comprehensive subgroup and dose–response analyses. Limitations involve heterogeneity among the included studies and potential biases due to open-label designs. The lack of blinding may have influenced outcome reporting.
Future Research: Further studies are needed to evaluate the long-term benefits of hemodiafiltration on patient-reported outcomes, cost-effectiveness, and environmental impacts. Investigations into the optimal convection volumes and the mechanisms underlying the observed mortality reductions are also warranted.
News Release: CLEAR SYNERGY Trial Finds No Cardiovascular Benefit of Colchicine Post-Myocardial Infarction
7 Nov, 2024 | 11:55h | UTCIntroduction: The international CLEAR SYNERGY (OASIS 9) trial investigated the long-term cardiovascular effects of colchicine in patients undergoing percutaneous coronary intervention (PCI) following acute myocardial infarction (MI). Colchicine, an anti-inflammatory agent, had previously shown promise in reducing cardiovascular events in patients with coronary artery disease. This study aimed to evaluate whether colchicine could improve outcomes in a high-risk post-MI population.
Highlights:
- Study Design: Over 7,000 patients with acute MI (95% with STEMI) were enrolled and randomized to receive either colchicine 0.5 mg daily or placebo, in addition to standard care. The trial featured a 2×2 factorial design, also assessing spironolactone versus placebo.
- Primary Outcome: After a median follow-up of 3.5 years, the primary endpoint—a composite of cardiovascular death, MI, stroke, or ischemia-driven revascularization—occurred in 9.1% of the colchicine group and 9.3% of the placebo group (Hazard Ratio [HR] 0.99; 95% Confidence Interval [CI] 0.85-1.16; p=0.93), indicating no significant difference.
- Secondary Outcomes: There were no significant differences in individual components of the primary endpoint, including cardiovascular death (3.3% vs. 3.2%), MI (2.9% vs. 3.1%), or ischemia-driven revascularization (4.6% vs. 4.7%). All-cause mortality was slightly lower in the colchicine group but not statistically significant.
- Safety Profile: Colchicine was associated with a higher incidence of diarrhea (10.2% vs. 6.6%; p<0.001). Serious infections were similar between groups.
- Comparison with Previous Studies: The findings contrast with earlier trials like COLCOT and LoDoCo2, which reported cardiovascular benefits with colchicine in similar patient populations. Possible reasons for the discrepancy include differences in patient characteristics, study design, and the impact of external factors such as the COVID-19 pandemic.
Conclusion: The CLEAR SYNERGY trial concludes that routine use of colchicine following PCI for acute MI does not reduce the risk of major adverse cardiovascular events. These results suggest reevaluating the role of colchicine in post-MI management and may influence future guideline recommendations. Clinicians should consider these findings when prescribing colchicine, balancing the lack of cardiovascular benefit against the potential for gastrointestinal side effects.
Source: This research was conducted by the Population Health Research Institute and presented at the Transcatheter Cardiovascular Therapeutics (TCT) conference on October 29, 2024. Detailed results are available through the American College of Cardiology (https://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2024/10/25/04/34/clear-synergy) and TCTMD (https://www.tctmd.com/news/colchicine-surprise-no-help-post-mi-large-clear-synergy-trial-shows).
Guideline: Management of Urinary Tract Infections in Pediatrics and Adults
5 Nov, 2024 | 18:59h | UTCIntroduction: Urinary tract infections (UTIs) are among the most common infections worldwide, significantly impacting patient quality of life and imposing substantial clinical and economic burdens. Despite advancements in diagnosis and treatment, UTIs continue to cause high morbidity and mortality, ranging from simple cystitis to life-threatening sepsis. Addressing the discrepancy between evidence quality and recommendation strength in existing guidelines, the WikiGuidelines Group has developed a consensus statement. This guideline aims to provide evidence-based recommendations for the prevention, diagnosis, and management of UTIs across diverse clinical settings.
Key Recommendations:
- Cranberry Products:
- Recommendation: Cranberry juice or supplements are recommended for preventing symptomatic, culture-verified UTIs in women with recurrent UTIs, children, and individuals susceptible after interventions.
- Quality of Evidence: Moderate
- Recommendation Strength: Strong
- Methenamine Hippurate:
- Recommendation: Methenamine hippurate is recommended as an alternative to prophylactic antibiotics for preventing recurrent UTIs in patients with intact bladder anatomy.
- Quality of Evidence: Moderate
- Recommendation Strength: Strong
- Topical Estrogen:
- Recommendation: Vaginal estrogen therapy is recommended for postmenopausal women to reduce recurrent UTIs by restoring the vaginal microbiome.
- Quality of Evidence: High
- Recommendation Strength: Strong
- Empirical Treatment Regimens:
- Recommendation: For uncomplicated cystitis, nitrofurantoin is recommended as a first-line agent. For pyelonephritis, trimethoprim/sulfamethoxazole or a first-generation cephalosporin are reasonable first-line agents, depending on local resistance rates.
- Quality of Evidence: Moderate
- Recommendation Strength: Strong
- Treatment Duration for Acute Cystitis in Adults:
- Recommendation:
- Nitrofurantoin: 5 days
- Trimethoprim/sulfamethoxazole: 3 days
- Oral fosfomycin: Single dose
- Quality of Evidence: High
- Recommendation Strength: Strong
- Recommendation:
- Treatment Duration for Acute Pyelonephritis in Adults:
- Recommendation:
- Fluoroquinolones: 5–7 days
- Dose-optimized β-lactams: 7 days
- Quality of Evidence: High
- Recommendation Strength: Strong
- Recommendation:
- Antimicrobial Stewardship:
- Recommendation: De-escalation of antibiotics and the use of mostly or all oral treatment regimens are recommended to optimize antimicrobial use and reduce adverse effects.
- Quality of Evidence: High
- Recommendation Strength: Strong
Conclusion: The consensus highlights a significant lack of high-quality prospective data in many areas related to UTIs, limiting the ability to provide clear recommendations. Implementing these evidence-based guidelines can enhance patient care by promoting effective prevention strategies, accurate diagnosis based on clinical symptoms, appropriate treatment durations, and robust antimicrobial stewardship. This approach is expected to improve clinical outcomes, reduce antimicrobial resistance, and preserve the effectiveness of current treatments.
RCT: Lipoprotein(a) and LDL-C as Independent Cardiovascular Risk Factors in Statin Trials
5 Nov, 2024 | 17:50h | UTCBackground: Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) [Lp(a)] are both known risk factors for atherosclerotic cardiovascular disease (ASCVD). However, the interaction between Lp(a) and LDL-C levels in relation to ASCVD risk, especially in the context of LDL-C-lowering treatments like statins, remains unclear. This study aimed to clarify if LDL-C reduction impacts Lp(a)-associated ASCVD risk.
Objective: This meta-analysis examined whether LDL-C reduction with statins affects ASCVD risk mediated by elevated Lp(a) levels.
Methods: Data from 27,658 participants across six statin trials were analyzed, including both placebo and statin groups. ASCVD risk was assessed using multivariable Cox proportional hazards models with adjustments for various cardiovascular risk factors. The study evaluated continuous associations between Lp(a) levels, LDL-C levels, and ASCVD risk.
Results: Elevated Lp(a) levels were associated with higher ASCVD risk across all LDL-C levels, even among patients with the lowest LDL-C achieved through statin therapy. Statin-treated patients with Lp(a) >50 mg/dL exhibited a significantly higher ASCVD risk, even in the lowest quartile of achieved LDL-C (HR 1.38, 95% CI 1.06–1.79). The highest risk was observed in individuals with both elevated Lp(a) and LDL-C levels (HR 1.90, 95% CI 1.46–2.48).
Conclusions: Lp(a) and LDL-C are independent risk factors for ASCVD, with LDL-C lowering alone insufficient to mitigate the risk associated with elevated Lp(a).
Implications for Practice: These findings underscore the need for distinct strategies to manage patients with elevated Lp(a), particularly as LDL-C reduction alone does not fully address the associated ASCVD risk.
Study Strengths and Limitations: This study’s strength lies in its large participant pool and robust statistical analysis; however, variability in Lp(a) measurement methods across trials may limit precision.
Future Research: Investigations into therapies specifically targeting Lp(a) may offer additional ASCVD risk reduction beyond LDL-C lowering alone.
Cohort Study: Late Ventricular Arrhythmias After Primary PCI for STEMI Are Rare but Increase Mortality
5 Nov, 2024 | 15:24h | UTCBackground: Ventricular tachycardia (VT) and ventricular fibrillation (VF) are critical complications following ST-segment elevation myocardial infarction (STEMI). While early VT/VF typically occurs before or shortly after reperfusion, contemporary data on the incidence of late VT/VF post-primary percutaneous coronary intervention (PCI) are limited. Understanding the risk of late VT/VF is essential for optimizing in-hospital monitoring and discharge timing.
Objective: To assess the risk of late VT and VF after primary PCI in patients with STEMI, identify associated factors, and evaluate their impact on in-hospital mortality.
Methods: This cohort study analyzed data from 174,126 adults with STEMI treated with primary PCI between January 1, 2015, and December 31, 2018, using the National Cardiovascular Data Registry Chest Pain–MI Registry. Late VT/VF was defined as events occurring one or more days after PCI. Multivariable logistic regression was employed to identify factors associated with late VT/VF and its association with in-hospital mortality.
Results: Among the patients, 8.9% experienced VT or VF after primary PCI. Late VT/VF occurred in 2.4% of patients overall and 1.7% of those with uncomplicated STEMI. Late VT/VF associated with cardiac arrest was rare, occurring in 0.4% of all patients and 0.1% of patients with uncomplicated STEMI. Decreased left ventricular ejection fraction (LVEF) was the most significant factor associated with late VT/VF with cardiac arrest (adjusted odds ratio [AOR] for every 5-unit decrease ≤40%: 1.67; 95% CI, 1.54–1.85). Late VT/VF was linked to increased odds of in-hospital mortality (AOR, 6.40; 95% CI, 5.63–7.29).
Conclusions: Late VT/VF after primary PCI for STEMI is infrequent, particularly in patients with uncomplicated presentations. However, when late VT/VF occurs, it is associated with a significantly higher risk of in-hospital mortality.
Implications for Practice: While vigilant monitoring remains crucial, patients with uncomplicated STEMI may be candidates for earlier discharge through shared decision-making. Identifying high-risk patients for late VT/VF can enable tailored monitoring strategies to improve outcomes.
Study Strengths and Limitations: Strengths include a large, contemporary cohort and detailed data on in-hospital VT/VF events. Limitations involve the observational design, potential unmeasured confounders, and the inability to differentiate between VT and VF due to registry definitions.
Future Research: Further studies are warranted to develop precise risk prediction models for late VT/VF and to explore effective out-of-hospital monitoring strategies post-STEMI.
2023 VA/DoD Clinical Practice Guidelines for the Management of Headache
3 Nov, 2024 | 18:45h | UTCIntroduction: Headache disorders, notably migraine and tension-type headache (TTH), are among the most prevalent and disabling neurological conditions globally, significantly impacting individuals’ quality of life and imposing substantial societal costs. This 2023 guideline provides primary care clinicians with evidence-based recommendations for the evaluation, treatment, and prevention of migraine and TTH, aiming to enhance patient care and outcomes.
Key Recommendations:
- Acute Migraine Treatment:
- Triptans (eletriptan, frovatriptan, rizatriptan, sumatriptan, zolmitriptan) are strongly recommended for short-term migraine relief. (Strength: Strong for)
- Aspirin–Acetaminophen–Caffeine combination is strongly recommended for acute migraine treatment. (Strength: Strong for)
- Gepants (ubrogepant, rimegepant) are suggested as options for acute migraine management. (Strength: Weak for)
- NSAIDs (aspirin, ibuprofen, naproxen) and acetaminophen are suggested for acute migraine relief. (Strength: Weak for)
- Preventive Migraine Therapy:
- CGRP Monoclonal Antibodies (erenumab, fremanezumab, galcanezumab) are strongly recommended for preventing episodic or chronic migraine. (Strength: Strong for)
- Angiotensin Receptor Blockers (candesartan, telmisartan) are recommended for episodic migraine prevention. (Strength: Strong for)
- Topiramate and valproate are suggested for migraine prevention. (Strength: Weak for)
- Lisinopril, magnesium, memantine, and atogepant are suggested for preventing episodic migraine. (Strength: Weak for)
- OnabotulinumtoxinA injections are suggested for preventing chronic migraine but not episodic migraine. (Strength: Weak for chronic migraine; Weak against for episodic migraine)
- Gabapentin is not recommended for preventing episodic migraine. (Strength: Weak against)
- Tension-Type Headache Management:
- For acute TTH, ibuprofen (400 mg) or acetaminophen (1000 mg) are suggested. (Strength: Weak for)
- Amitriptyline is suggested for preventing chronic TTH. (Strength: Weak for)
- Nonpharmacologic Interventions:
- Physical Therapy is suggested for managing TTH and migraine. (Strength: Weak for)
- Aerobic Exercise or progressive strength training is suggested for preventing TTH and migraine. (Strength: Weak for)
- Injections and Procedures:
- Greater Occipital Nerve Block is suggested for short-term migraine treatment. (Strength: Weak for)
Conclusion: The 2023 VA/DoD Clinical Practice Guideline provides updated, evidence-based recommendations for managing migraine and TTH, incorporating new pharmacologic agents and nonpharmacologic interventions. The inclusion of newer medications, such as CGRP inhibitors, offers additional options for patients who may not respond to traditional therapies.
RCT: Atrasentan Reduces Proteinuria in Patients with IgA Nephropathy
3 Nov, 2024 | 18:29h | UTCBackground: IgA nephropathy is the most common primary glomerular disease worldwide, leading to a substantial risk of kidney failure. Despite treatment with renin–angiotensin system (RAS) inhibitors, many patients experience persistent proteinuria and progressive kidney function decline. Endothelin-1, acting via the endothelin type A receptor, contributes to the disease’s pathophysiology. Atrasentan, a selective endothelin type A receptor antagonist, has shown potential in reducing proteinuria in prior studies.
Objective: To evaluate the efficacy and safety of atrasentan in reducing proteinuria among patients with IgA nephropathy.
Methods: In this phase 3, multinational, double-blind, randomized controlled trial, adults with biopsy-proven IgA nephropathy, urinary protein excretion of at least 1 g/day, and an estimated glomerular filtration rate (eGFR) of at least 30 ml/min/1.73 m² were enrolled. Patients on maximum tolerated doses of ACE inhibitors or ARBs were randomized 1:1 to receive atrasentan (0.75 mg/day) or placebo for 132 weeks. The primary outcome was the change in the 24-hour urinary protein-to-creatinine ratio from baseline to week 36, assessed in a prespecified interim analysis of the first 270 patients.
Results: Among these patients (135 per group), the geometric mean percentage reduction in the urinary protein-to-creatinine ratio at week 36 was significantly greater with atrasentan (−38.1%) compared to placebo (−3.1%), yielding a between-group difference of −36.1 percentage points (95% CI, −44.6 to −26.4; P<0.001). Adverse events were similar between groups. Fluid retention was reported in 11.2% of the atrasentan group and 8.2% of the placebo group but did not lead to discontinuation. No cases of cardiac failure or severe edema occurred.
Conclusions: Atrasentan significantly reduced proteinuria compared to placebo in patients with IgA nephropathy without significant safety concerns.
Implications for Practice: Atrasentan may serve as an effective additional therapy for patients with IgA nephropathy who remain at high risk of progression despite standard care, potentially influencing clinical decision-making toward more aggressive proteinuria reduction strategies.
Study Strengths and Limitations: Strengths include the randomized controlled design and a representative high-risk population. Limitations involve the interim analysis nature of the data and underrepresentation of Black patients, which may limit generalizability.
Future Research: Long-term effects on eGFR decline and the potential benefits of combining atrasentan with other therapies, such as SGLT2 inhibitors, warrant further investigation.