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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.
Multisociety Guidelines for Perioperative Management of GLP-1 Receptor Agonists
3 Nov, 2024 | 14:27h | UTCIntroduction: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed the management of metabolic diseases such as type 2 diabetes, obesity, and heart failure by enhancing glycemic control and promoting satiety. However, their effect of delaying gastric emptying has raised perioperative safety concerns due to the risk of residual gastric contents leading to pulmonary aspiration during anesthesia. Reports of aspiration incidents and gastrointestinal side effects like nausea and vomiting have prompted the need for unified clinical guidance. This multisociety clinical practice guideline aims to provide recommendations for safely managing patients on GLP-1RAs during the perioperative period, balancing metabolic benefits with procedural risks.
Key Recommendations:
- Shared Decision-Making:
- Collaborative Approach: The continuation or discontinuation of GLP-1RAs should involve shared decision-making among the patient, surgical team, anesthesia providers, and prescribing clinicians.
- Risk Assessment: Evaluate factors that elevate the risk of delayed gastric emptying and aspiration, including:
- Dose Escalation Phase: Higher risk during dose escalation compared to maintenance.
- Higher Dosage: Increased gastrointestinal side effects with higher doses.
- Weekly Formulations: Greater side effects with weekly dosing compared to daily formulations.
- Gastrointestinal Symptoms: Presence of nausea, vomiting, abdominal pain, dyspepsia, or constipation.
- Comorbid Conditions: Conditions like gastroparesis, bowel dysmotility, or neurological disorders affecting gastric motility.
- Timing: Conduct risk assessments well in advance of surgery to allow for appropriate preoperative planning.
- Management of GLP-1RA Therapy:
- Continuation in Low-Risk Patients: GLP-1RAs may be continued preoperatively in patients without elevated risk factors.
- Balancing Risks in High-Risk Patients:
- Metabolic vs. Procedural Risks: Weigh the risks of aspiration against potential metabolic complications like hyperglycemia if GLP-1RAs are withheld.
- Avoiding Bias: Decisions should not be based solely on obesity status to prevent bias.
- Discontinuation Guidelines:
- Daily Formulations: Hold on the day of surgery.
- Weekly Formulations: Discontinue one week prior to surgery.
- Day-of-Surgery Assessment: All patients should be evaluated for symptoms of delayed gastric emptying on the day of the procedure, regardless of GLP-1RA usage.
- Minimizing Aspiration Risk:
- Preoperative Dietary Modifications:
- Liquid Diet: Implement a liquid diet for at least 24 hours before surgery, similar to protocols for colonoscopy and bariatric procedures.
- Gastric Content Assessment:
- Point-of-Care Ultrasound: Use gastric ultrasound to assess residual gastric contents when there is concern for delayed emptying, acknowledging potential limitations in resources and expertise.
- Anesthesia Plan Adjustments:
- Rapid Sequence Induction: Consider rapid sequence induction with tracheal intubation to minimize aspiration risk in patients with confirmed or suspected delayed gastric emptying.
- Procedure Continuation vs. Cancellation: Engage in shared decision-making to weigh the benefits of proceeding with the procedure against the risks, aiming to avoid unnecessary cancellations.
- Preoperative Dietary Modifications:
Conclusion: By adopting these recommendations, healthcare providers can enhance patient safety during the perioperative period for those receiving GLP-1RA therapy. The guidelines emphasize individualized care through shared decision-making, considering both metabolic benefits and procedural risks. Implementing these practices is expected to reduce aspiration incidents, optimize surgical outcomes, and ensure equitable care without bias against patients with obesity or metabolic disorders. As new evidence and medications emerge, these guidelines may be updated to reflect best practices.
Reference: Kindel TL, Wang AY, Wadhwa A, et al. Multisociety clinical practice guidance for the safe use of glucagon-like peptide-1 receptor agonists in the perioperative period. Surgery for Obesity and Related Diseases. 2024; In Press. https://doi.org/10.1016/j.soard.2024.08.033
Clinical Trial Follow-up: Empagliflozin Continues to Reduce Cardiorenal Risks Post-Discontinuation in CKD Patients
3 Nov, 2024 | 13:08h | UTCBackground: Chronic kidney disease (CKD) progression leads to end-stage kidney disease, adversely affecting quality of life, increasing cardiovascular morbidity and mortality, and imposing high economic costs. Previous trials, including the EMPA-KIDNEY trial, demonstrated that empagliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, provides cardiorenal benefits in CKD patients at risk of progression. The persistence of these benefits after discontinuation of the drug remains uncertain.
Objective: To assess how the effects of empagliflozin on kidney disease progression and cardiovascular outcomes evolve after discontinuation in patients with CKD.
Methods: In this randomized, double-blind, placebo-controlled trial, 6,609 patients with CKD were assigned to receive empagliflozin 10 mg daily or placebo and followed for a median of 2 years during the active trial period. Eligible patients had an estimated glomerular filtration rate (eGFR) between 20 and less than 45 ml/min/1.73 m², or between 45 and less than 90 ml/min/1.73 m² with a urinary albumin-to-creatinine ratio of at least 200 mg/g. After the active trial, 4,891 surviving patients consented to a 2-year post-trial follow-up without the trial drug, during which local practitioners could prescribe open-label SGLT2 inhibitors. The primary composite outcome was kidney disease progression or cardiovascular death from the start of the active trial to the end of the post-trial period.
Results: During the combined active and post-trial periods, a primary outcome event occurred in 26.2% of patients in the empagliflozin group and 30.3% in the placebo group (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.72–0.87). During the post-trial period alone, the HR was 0.87 (95% CI, 0.76–0.99), indicating continued benefit after drug discontinuation. The risk of kidney disease progression was 23.5% in the empagliflozin group versus 27.1% in the placebo group (HR, 0.79; 95% CI, 0.72–0.87). Cardiovascular death occurred in 3.8% and 4.9% of patients, respectively (HR, 0.75; 95% CI, 0.59–0.95). No significant effect was observed on death from noncardiovascular causes (5.3% in both groups).
Conclusions: In patients with CKD at risk for progression, empagliflozin continued to confer cardiorenal benefits for up to 12 months after discontinuation. These findings suggest that short-term treatment with empagliflozin has lasting effects on kidney and cardiovascular outcomes.
Implications for Practice: Empagliflozin should be considered for a broad range of CKD patients to slow disease progression and reduce cardiovascular risk, with benefits extending beyond active treatment. Clinicians should initiate empagliflozin therapy in eligible CKD patients to maximize long-term cardiorenal protection.
Study Strengths and Limitations: Strengths include the large sample size, broad eligibility criteria, and high follow-up rates. Limitations involve the exclusion of certain regions during post-trial follow-up and reliance on local eGFR measurements during this period.
Future Research: Further studies are needed to understand the mechanisms behind the sustained benefits of empagliflozin after discontinuation and to explore the long-term effects of extended treatment durations.
RCT: No Significant Difference Between Intraosseous and Intravenous Vascular Access in Out-of-Hospital Cardiac Arrest Outcomes
3 Nov, 2024 | 12:58h | UTCBackground: Out-of-hospital cardiac arrest (OHCA) is a major global health concern, resulting in high mortality rates despite advancements in emergency care. In Denmark alone, approximately 5,000 cases occur annually, with a 30-day survival rate of only about 14%. Rapid vascular access during cardiopulmonary resuscitation (CPR) is crucial for administering medications like epinephrine, as recommended by international guidelines. Both intraosseous (IO) and intravenous (IV) routes are routinely used, but their comparative effectiveness remains unclear. Current guidelines favor IV access for initial attempts, yet this recommendation is based on very low-certainty evidence, highlighting the need for well-designed clinical trials.
Objective: To compare the effectiveness of initial intraosseous versus intravenous vascular access on sustained return of spontaneous circulation (ROSC) in adults experiencing nontraumatic OHCA.
Methods: This randomized, parallel-group superiority trial was conducted across all five regions of Denmark, covering 5.9 million inhabitants. Adults aged 18 years or older with nontraumatic OHCA requiring vascular access during CPR were randomized to receive either initial IO or IV access. The IO group was further randomized to humeral or tibial access for a secondary comparison. The primary outcome was sustained ROSC, defined as no need for chest compressions for at least 20 minutes. Key secondary outcomes included 30-day survival and survival with favorable neurologic outcome (modified Rankin scale score of 0–3). Procedural outcomes such as success rates of vascular access within two attempts, time to successful access, and time to first epinephrine administration were also assessed.
Results: Among 1,479 patients included in the primary analysis (731 in the IO group and 748 in the IV group), successful vascular access within two attempts was achieved in 92% of the IO group versus 80% of the IV group. Despite the higher success rate with IO access, the time to first successful access and time to first epinephrine dose were similar between groups. Sustained ROSC occurred in 30% of patients in the IO group and 29% in the IV group (risk ratio [RR], 1.06; 95% confidence interval [CI], 0.90–1.24; P=0.49). At 30 days, survival rates were 12% in the IO group and 10% in the IV group (RR, 1.16; 95% CI, 0.87–1.56), with favorable neurologic outcomes observed in 9% and 8% of patients, respectively (RR, 1.16; 95% CI, 0.83–1.62). No significant differences were found in procedural times, adverse events, or quality-of-life measures among survivors.
Conclusions: In adults with nontraumatic OHCA, initial intraosseous vascular access did not result in a significant difference in sustained ROSC compared to intravenous access. Both methods yielded comparable survival rates and neurologic outcomes at 30 days, suggesting that the choice of vascular access route may not critically impact immediate resuscitation success.
Implications for Practice: These findings indicate that emergency medical services can opt for either intraosseous or intravenous vascular access during resuscitation based on provider expertise, patient anatomy, and situational considerations without adversely affecting patient outcomes. Emphasizing flexibility in vascular access approach may facilitate quicker access and streamline resuscitation efforts in the prehospital setting.
Study Strengths and Limitations: Strengths include the randomized design, large sample size, and nationwide implementation, enhancing generalizability. Limitations involve potential crossover between groups, lack of blinding among clinicians, and the study being underpowered to detect small differences in long-term outcomes.
Future Research: Further studies are needed to assess long-term survival and neurologic outcomes, and to explore whether specific patient subgroups may benefit more from one vascular access method over the other during cardiac arrest resuscitation.
Reference: Vallentin MF, Granfeldt A, Klitgaard TL, et al. Intraosseous or Intravenous Vascular Access for Out-of-Hospital Cardiac Arrest. New England Journal of Medicine. 2024 Oct 31; DOI: http://doi.org/10.1056/NEJMoa2407616
RCT: Intraosseous vs. Intravenous Drug Administration in Out-of-Hospital Cardiac Arrest Shows No Difference in 30-Day Survival
3 Nov, 2024 | 12:48h | UTCBackground: Out-of-hospital cardiac arrest requires rapid drug administration, with medications like epinephrine being highly time-dependent. Intravenous access can be challenging prehospital due to environmental and patient factors, potentially delaying treatment. Intraosseous access may offer faster drug delivery, but its impact on clinical outcomes is unclear.
Objective: To compare the effectiveness of an intraosseous-first versus intravenous-first vascular access strategy on 30-day survival in adults experiencing out-of-hospital cardiac arrest requiring drug therapy.
Methods: In this multicenter, open-label, randomized trial across 11 UK emergency medical systems, 6,082 adults were assigned to receive either intraosseous-first or intravenous-first vascular access during resuscitation. The primary outcome was survival at 30 days. Secondary outcomes included return of spontaneous circulation and favorable neurologic function at hospital discharge (modified Rankin scale score ≤3).
Results: At 30 days, survival was 4.5% in the intraosseous group and 5.1% in the intravenous group (adjusted odds ratio [OR], 0.94; 95% confidence interval [CI], 0.68–1.32; P=0.74). Favorable neurologic outcome at discharge was similar between groups (2.7% vs. 2.8%; adjusted OR, 0.91; 95% CI, 0.57–1.47). Return of spontaneous circulation was lower in the intraosseous group (36.0% vs. 39.1%; adjusted OR, 0.86; 95% CI, 0.76–0.97).
Conclusions: An intraosseous-first vascular access strategy did not improve 30-day survival compared to an intravenous-first strategy in adults with out-of-hospital cardiac arrest. The intraosseous route was associated with a lower rate of return of spontaneous circulation.
Implications for Practice: Paramedics should consider that intraosseous access may not offer a survival advantage over intravenous access and may be linked to a reduced return of spontaneous circulation. This finding may influence decisions on vascular access during resuscitation efforts.
Study Strengths and Limitations: Strengths include a large, multicenter randomized design; limitations involve early termination reducing statistical power and inability to blind prehospital providers.
Future Research: Further studies should investigate why intraosseous access is associated with lower return of spontaneous circulation and assess if specific intraosseous techniques or sites affect outcomes.
RCT: Transcatheter Tricuspid-Valve Replacement Improves Symptoms and Quality of Life in Severe Tricuspid Regurgitation
3 Nov, 2024 | 12:37h | UTCBackground: Severe tricuspid regurgitation is associated with debilitating symptoms and increased mortality. Surgical intervention is infrequently performed due to high operative risks and late patient presentation, leading to poor outcomes. Transcatheter tricuspid-valve replacement offers a less invasive alternative versus surgical intervention, but data on its efficacy are limited.
Objective: To compare the safety and effectiveness of transcatheter tricuspid-valve replacement plus medical therapy versus medical therapy alone in patients with severe symptomatic tricuspid regurgitation.
Methods: In this international, multicenter randomized controlled trial, 400 patients with severe symptomatic tricuspid regurgitation despite optimal medical therapy were randomized in a 2:1 ratio to receive transcatheter tricuspid-valve replacement plus medical therapy (valve-replacement group, n=267) or medical therapy alone (control group, n=133). The primary outcome was a hierarchical composite of death from any cause, implantation of a right ventricular assist device or heart transplantation, postindex tricuspid-valve intervention, hospitalization for heart failure, and improvements in the KCCQ-OS score by at least 10 points, NYHA functional class by at least one class, and 6-minute walk distance by at least 30 meters.
Results: At one year, the win ratio favoring valve replacement was 2.02 (95% confidence interval [CI], 1.56 to 2.62; P<0.001), indicating superiority over medical therapy alone. Patients in the valve-replacement group had significant improvements in quality of life, with 66.4% achieving an increase of at least 10 points in the KCCQ-OS score compared to 36.5% in the control group. Improvement of at least one NYHA class was observed in 78.9% of the valve-replacement group versus 24.0% of the control group. Reduction of tricuspid regurgitation to mild or less was achieved in 95.2% of patients in the valve-replacement group, compared to 2.3% in the control group. Severe bleeding occurred more frequently in the valve-replacement group (15.4% vs. 5.3%; P=0.003), as did new permanent pacemaker implantation (17.8% vs. 2.3%; P<0.001).
Conclusions: Transcatheter tricuspid-valve replacement significantly improved clinical outcomes, symptoms, functional capacity, and quality of life in patients with severe tricuspid regurgitation compared to medical therapy alone, despite higher risks of severe bleeding and pacemaker implantation.
Implications for Practice: Transcatheter tricuspid-valve replacement offers a promising therapeutic option for patients with severe symptomatic tricuspid regurgitation who are at high surgical risk. Clinicians should consider this intervention to improve patient symptoms and quality of life, while carefully weighing the procedural risks, particularly bleeding and arrhythmias requiring pacemaker implantation.
Study Strengths and Limitations: Strengths of the study include its randomized controlled design and comprehensive evaluation of both clinical and patient-reported outcomes. Limitations involve the smaller control group due to the 2:1 randomization and a one-year follow-up period that may not capture long-term benefits or risks.
Future Research: Further studies with longer follow-up are needed to assess the durability of transcatheter tricuspid-valve replacement, its long-term impact on survival and hospitalization rates, and strategies to minimize procedural complications.
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.