Randomized Trials
RCT: Infrequent Zoledronate Infusions Reduce Vertebral Fractures in Early Postmenopausal Women Without Osteoporosis
18 Jan, 2025 | 16:48h | UTCBackground: Osteoporosis prevention typically targets older, higher-risk populations with significantly reduced bone mineral density (BMD). However, many fragility fractures occur in women who do not meet the traditional diagnostic threshold for osteoporosis (T score ≤ –2.5). This study investigated whether infrequent administration of zoledronate could prevent vertebral fractures in early postmenopausal women (50 to 60 years of age) who have BMD values between normal and osteoporotic ranges.
Objective: To determine if administering intravenous zoledronate once at baseline—and again 5 years later—could reduce the incidence of morphometric vertebral fractures and other fracture types over a 10-year period in early postmenopausal women without osteoporosis.
Methods:
- Design: A 10-year, prospective, double-blind, randomized, placebo-controlled trial.
- Population: 1054 women (mean age 56.0) within 10 years post-menopause, with lumbar spine or hip T scores <0 but >–2.5, recruited from the electoral roll in Auckland, New Zealand.
- Interventions: Participants were randomly assigned (1:1:1) to receive:
- Zoledronate 5 mg at baseline and again at Year 5 (zoledronate–zoledronate)
- Zoledronate 5 mg at baseline and placebo at Year 5 (zoledronate–placebo)
- Placebo infusions at baseline and Year 5 (placebo–placebo)
- Follow-up: 10 years, with repeated BMD and spine X-ray assessments at baseline, Year 5, and Year 10.
- Primary Endpoint: Incidence of new morphometric vertebral fractures, defined by semiquantitative radiographic methods.
- Secondary Endpoints: Fragility fracture, any fracture, major osteoporotic fracture, changes in BMD, and bone-turnover markers.
Results:
- Vertebral Fractures: Over 10 years, 6.3% of participants in the zoledronate–zoledronate group and 6.6% in the zoledronate–placebo group experienced a new morphometric vertebral fracture, versus 11.1% in placebo–placebo. After imputation, the relative risks versus placebo–placebo were 0.56 (95% CI, 0.34–0.92; p=0.04) and 0.59 (95% CI, 0.36–0.97; p=0.08), respectively.
- Other Fractures: The zoledronate–zoledronate group had a 30% reduced risk of any fracture (RR, 0.70; 95% CI, 0.56–0.88), and zoledronate–placebo showed a 23% reduction (RR, 0.77; 95% CI, 0.62–0.97), both compared with placebo–placebo.
- Bone Mineral Density: At Year 10, the zoledronate–zoledronate group had sustained BMD gains (~7–9 percentage points above placebo), whereas the zoledronate–placebo group retained a moderate advantage (~5–6 percentage points above placebo).
- Bone-Turnover Markers: Markers remained suppressed in the zoledronate–zoledronate group through Year 10, while in the zoledronate–placebo group, they gradually rose after Year 5 but stayed below baseline levels.
- Safety: Few adverse events were reported. Uveitis or episcleritis after the first infusion occurred in 1.1% of zoledronate recipients. No cases of osteonecrosis of the jaw or atypical femoral fractures were observed.
Conclusions: A single 5-mg dose of zoledronate, with an optional additional dose at five years, reduced the incidence of morphometric vertebral fractures and helped preserve BMD in younger postmenopausal women without osteoporosis. Both zoledronate regimens showed notable fracture-risk reductions and sustained effects on bone turnover.
Implications for Practice: These findings extend the potential role of zoledronate in fracture prevention to younger, early postmenopausal women without osteoporosis. Infrequent infusions are attractive because of their prolonged pharmacologic action and generally favorable safety profile. However, caution is warranted before broadly implementing this strategy for all postmenopausal women, as the data come from a relatively homogenous population and do not address other risk factors or comorbidities. Real-world adherence, healthcare resource allocation, and patient preferences must all be considered. Moreover, further evaluation of cost-effectiveness is essential, especially if expanding use to large populations. Longer follow-up in broader and more diverse groups may reveal less common adverse events that were not detected in this trial. Clinicians should therefore weigh individual risk–benefit profiles and await additional data before making universal recommendations.
Study Strengths and Limitations:
- Strengths: The trial’s 10-year duration, double-blind design, and high retention rate enhance its internal validity. Using radiographic assessments for vertebral fractures adds objectivity and robustness.
- Limitations: The trial predominantly involved healthy, early postmenopausal women of European descent, limiting the applicability of the findings to other ethnicities, older populations, or those with complex comorbidities. Only two zoledronate infusions at a five-year interval were evaluated, leaving the optimal dosing frequency unresolved. Further, while adverse events appeared uncommon here, the sample size and population profile may not adequately capture rare or long-latency adverse outcomes.
Future Research: Larger trials in more diverse demographic and clinical settings are necessary to determine whether infrequent zoledronate can safely and effectively reduce fracture risk across broader patient groups. Studies comparing different dosing schedules, as well as investigations into cost-effectiveness and logistics of administration, would be highly valuable. Longer-term surveillance in real-world cohorts should help clarify the incidence of uncommon adverse events. Ultimately, such additional evidence will guide whether infrequent zoledronate infusions might be integrated into routine practice for fracture prevention in postmenopausal women without osteoporosis.
Reference:
- Bolland MJ, Nisa Z, Mellar A, et al. Fracture Prevention with Infrequent Zoledronate in Women 50 to 60 Years of Age. New England Journal of Medicine. 2025;392:239-248. DOI: http://doi.org/10.1056/NEJMoa2407031
- Chapurlat R. Infrequent Zoledronate — Small Individual Gain, Larger Population Gain. New England Journal of Medicine. 2025;392:281-283. DOI: http://doi.org/10.1056/NEJMe2415376
RCT: High-Flow Nasal Oxygen Noninferior to Noninvasive Ventilation for Most Acute Respiratory Failure Causes
13 Jan, 2025 | 13:11h | UTCBackground: Acute respiratory failure (ARF) arises from diverse etiologies and can manifest as hypoxemic or hypercapnic events. High-flow nasal oxygen (HFNO) and noninvasive ventilation (NIV) are common noninvasive respiratory support modalities, but robust comparative data in various ARF subgroups have been limited. Prior research suggests NIV may benefit chronic obstructive pulmonary disease (COPD) exacerbations and acute cardiogenic pulmonary edema (ACPE), yet for hypoxemic failure (including COVID-19 and immunocompromised populations), HFNO is often favored for its comfort and physiological advantages. The RENOVATE trial was designed to assess whether HFNO is noninferior to NIV for preventing intubation or death among five distinct groups of patients with ARF.
Objective: To determine if HFNO is noninferior to NIV in terms of the composite outcome of endotracheal intubation or death within seven days in patients with ARF, categorized into five subgroups: (1) nonimmunocompromised with hypoxemic ARF, (2) immunocompromised with hypoxemic ARF, (3) COPD exacerbation with respiratory acidosis, (4) ACPE, and (5) hypoxemic COVID-19.
Methods: This multicenter, adaptive, noninferiority randomized clinical trial enrolled 1800 hospitalized adults across 33 Brazilian centers. Patients were stratified by ARF etiology and randomized 1:1 to receive either HFNO or NIV. Treatment protocols allowed HFNO escalation to NIV (particularly for COPD or ACPE) if needed. The primary outcome was defined using a Bayesian hierarchical model with dynamic borrowing across subgroups; noninferiority was met if the posterior probability for an odds ratio (OR) below 1.55 reached ≥0.992. Predefined futility and superiority thresholds guided interim analyses, with a maximum sample size of 2000.
Results: Of 1800 randomized patients, 1766 completed the study (mean age 64 years; 40% women). The primary outcome (intubation or death by day 7) occurred in 39.0% (HFNO) vs 38.1% (NIV). HFNO was noninferior in four subgroups:
- Nonimmunocompromised with hypoxemia: 32.5% vs 33.1% (OR 1.02; posterior probability of noninferiority 0.999).
- COPD exacerbation with respiratory acidosis: 28.6% vs 26.2% (OR 1.05; probability 0.992).
- ACPE: 10.3% vs 21.3% (OR 0.97; probability 0.997).
- Hypoxemic COVID-19: 51.3% vs 47.0% (OR 1.13; probability 0.997).
The immunocompromised subgroup stopped enrollment early for futility; final results there did not confirm noninferiority (57.1% vs 36.4%; OR 1.07; probability 0.989). No significant differences in 28- or 90-day mortality emerged, although mortality rates were generally higher than in some previous trials. Comfort scores favored HFNO, and rates of serious adverse events were similar between groups.
Conclusions: In four of five ARF subgroups, HFNO met predefined noninferiority criteria compared with NIV regarding endotracheal intubation or death at seven days. However, immunocompromised patients with hypoxemic ARF remain an area of uncertainty, as do smaller subgroups (e.g., COPD) under non-borrowing analyses. Clinicians may consider HFNO as an alternative initial approach, recognizing that rescue NIV may still be necessary, particularly in COPD exacerbations.
Implications for Practice: These findings support using HFNO for a broad range of ARF etiologies as a first-line therapy. HFNO’s ease of use, patient comfort, and comparable safety profile may make it especially appealing. Nevertheless, clinicians should remain vigilant in immunocompromised patients and in COPD exacerbations when hypercapnia is pronounced. Potential cost variations between HFNO and NIV may influence real-world adoption, and local resources, staff expertise, and patient tolerance should guide final decisions.
Study Strengths and Limitations: Strengths include a large, diverse sample and a robust Bayesian adaptive design that allowed dynamic borrowing across subgroups. This approach increased precision but also introduced heterogeneity concerns. Some patient groups (particularly immunocompromised and COPD) were relatively small, limiting definitive conclusions in those strata. Additionally, early stopping for futility in immunocompromised patients curtailed full enrollment, and the trial compared HFNO only with face-mask NIV (rather than alternatives such as helmet CPAP).
Future Research: Further large-scale studies should refine whether HFNO can supplant NIV in COPD exacerbations and immunocompromised populations. Investigations on cost-effectiveness, patient-centered outcomes (comfort, quality of life), and comparative models (e.g., helmet NIV) are also warranted.
Reference:
• RENOVATE Investigators and the BRICNet Authors. High-Flow Nasal Oxygen vs Noninvasive Ventilation in Patients With Acute Respiratory Failure: The RENOVATE Randomized Clinical Trial. JAMA. Published online December 10, 2024. DOI: http://doi.org/10.1001/jama.2024.26244
• Frat JP, Le Pape S, Thille AW. Editorial: Is High-Flow Oxygen the Standard for All Patients With Acute Respiratory Failure? JAMA. Published online December 10, 2024. DOI: http://doi.org/10.1001/jama.2024.25906
• Freund Y, Vromant A. Editorial: Reevaluating Respiratory Support in Acute Respiratory Failure—Insights From the RENOVATE Trial and Implications for Practice. JAMA. Published online December 10, 2024. DOI: http://doi.org/10.1001/jama.2024.25869
Meta-Analysis: Beta-Blockers Show No Mortality Reduction in Myocardial Infarction with Preserved Ejection Fraction
15 Jan, 2025 | 13:06h | UTCBackground: Beta-blockers have been a cornerstone of care following myocardial infarction (MI), primarily benefiting patients with reduced left ventricular ejection fraction (LVEF). However, the evidence supporting their routine use in patients with a preserved LVEF remains inconsistent, especially in the context of current revascularization strategies and guideline-directed medical therapy.
Objective: This systematic review and meta-analysis aimed to determine whether beta-blockers confer mortality or cardiovascular event benefits among patients with MI and a preserved LVEF in the contemporary reperfusion era.
Methods: Researchers conducted a PRISMA-compliant search of PubMed and EMBASE, identifying randomized controlled trials (RCTs) that compared long-term beta-blocker therapy versus no beta-blocker therapy in patients with MI and LVEF ≥40%. Three RCTs (total n = 9512) were included. The primary outcome was a composite of all-cause mortality and recurrent MI. Secondary outcomes included all-cause mortality, cardiovascular mortality, MI, and stroke. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using a random-effects model. Heterogeneity was assessed via I² statistics. Risk of bias was evaluated with the Cochrane RoB 2.0 tool, and the quality of evidence was reviewed according to GRADE recommendations.
Results: Across the three RCTs, beta-blockers did not significantly reduce the composite of all-cause mortality and MI (RR 0.97, 95% CI: 0.84–1.12; p = 0.671; I² = 0%). Secondary endpoints also showed no significant effect: all-cause mortality (RR 0.96, 95% CI: 0.79–1.17), cardiovascular mortality (RR 1.22, 95% CI: 0.87–1.72), recurrent MI (RR 0.97, 95% CI: 0.78–1.19), and stroke (RR 0.96, 95% CI: 0.66–1.38). Sensitivity analyses, including leave-one-out approaches, yielded consistent findings. There was minimal heterogeneity overall, suggesting stable results. Although one trial strictly excluded patients with LVEF <50%, others allowed mildly reduced LVEF (40–50%), highlighting variability in definitions of “preserved” function.
Conclusions: In contemporary patients with MI and preserved LVEF, beta-blockers did not lower overall mortality, recurrent MI, or stroke. These data suggest that, under current revascularization practices and adjunctive therapies, beta-blockers may not offer the same advantage observed in earlier trials among individuals without significant systolic dysfunction.
Implications for Practice: Clinicians managing MI in patients with preserved LVEF should carefully weigh potential side effects and the absence of clear mortality benefit when deciding on beta-blocker therapy. While widely prescribed, beta-blockers may not improve outcomes for this subgroup in modern practice. Guidelines that currently reflect broad beta-blocker use may need refinement to account for these latest findings.
Study Strengths and Limitations: Major strengths include a focus on contemporary, randomized evidence and rigorous risk-of-bias assessment. The analysis is limited by the small number of RCTs, variable definitions of “preserved” ejection fraction, and a predominantly male study population. Underrepresentation of women and patients with borderline LVEF reduces generalizability to broader clinical cohorts.
Future Research: Ongoing RCTs (such as REBOOT-CNIC, BETAMI, and DANBLOCK) will provide further insight into the impact of beta-blockers in patients with normal or mildly reduced LVEF, particularly regarding safety profiles (e.g., bradyarrhythmias, hypotension, respiratory exacerbations) and subgroup analyses by sex. These data may inform more nuanced guideline recommendations.
Reference: Sabina M, Shah S, Grimm M, Daher JC, Campillo P, Boozo MB, Al-Abdouh A, Abusnina W, D’Ascenzo F, Bizanti A. Beta-Blockers in Patients with Myocardial Infarction and Preserved Left Ventricular Ejection: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Journal of Clinical Medicine. 2025;14(1):150. DOI: https://doi.org/10.3390/jcm14010150
RCT: Empagliflozin Lowers Urinary Supersaturation in Nondiabetic Adults With Calcium and Uric Acid Kidney Stones
15 Jan, 2025 | 12:03h | UTCBackground: Kidney stones represent a major health challenge worldwide, with calcium-based (calcium oxalate or phosphate) and uric acid (UA) stones accounting for most cases. Despite multiple preventive measures—including hydration, dietary modification, and, in certain cases, pharmacotherapy—recurrence rates remain high. Recent retrospective analyses suggest sodium-glucose cotransporter 2 (SGLT2) inhibitors may reduce stone episodes in patients with type 2 diabetes. These agents could theoretically lower stone risk by promoting urinary citrate excretion, altering urine pH, and enhancing UA clearance. However, prospective data are lacking in nondiabetic individuals. This phase 2, single-center, double-blind, placebo-controlled, crossover study (SWEETSTONE) explored whether empagliflozin (25 mg daily) modifies urinary relative supersaturation ratios (RSRs)—a validated surrogate of stone risk—in adults without diabetes who have a history of either calcium or UA stones.
Objective: To determine if empagliflozin significantly reduces RSRs for calcium oxalate (CaOx), calcium phosphate (CaP), and UA in nondiabetic adults with recurrent kidney stones and to assess short-term safety.
Methods: A total of 53 participants (28 calcium stone formers, 25 UA stone formers) were randomized to empagliflozin 25 mg once daily or placebo for two weeks, followed by a 2–6-week washout, then crossed over to the alternative treatment. Primary outcomes were changes in RSR CaOx, RSR CaP, and RSR UA. Secondary measures included 24-hour urine pH, citrate, calcium, and UA, as well as key blood parameters. Analyses were performed separately for calcium and UA stone groups using a generalized linear mixed effects model. The per protocol set was used for the main analysis, with additional intention-to-treat assessments for confirmation.
Results: In calcium stone formers, empagliflozin lowered RSR CaP by 36% (95% CI −48% to −21%; p<0.001) compared with placebo but did not significantly change RSR CaOx. Uric acid supersaturation rose modestly, yet nonsignificantly. Among UA stone formers, empagliflozin reduced RSR UA by 30% (95% CI −44% to −12%; p=0.002), with no significant effect on RSR CaOx or RSR CaP. Both groups showed substantial increases in 24-hour urine citrate (60% for calcium stones, 40% for UA stones) and marked reductions in plasma UA levels. Urine calcium rose in some calcium stone formers, but no severe adverse events were reported during the study.
Conclusions: Short-term treatment with empagliflozin produced meaningful decreases in key urinary supersaturation indices among nondiabetic adults with calcium or UA stones, while exhibiting an acceptable safety profile. These favorable laboratory changes offer mechanistic promise but do not establish definitive evidence that long-term stone recurrence is reduced.
Implications for Practice: Although the pronounced improvement in urinary lithogenic profiles is encouraging, it remains unclear whether these shifts will translate into sustained reductions in actual stone formation. Consequently, clinicians should be cautious about recommending off-label SGLT2 inhibition for stone prevention solely on the basis of these short-term biochemical improvements. Larger, longer-duration trials with clinical endpoints (i.e., stone recurrence) are warranted before SGLT2 inhibitors can be broadly endorsed for this indication. In addition, practical considerations—such as cost, insurance coverage, and potential off-target effects—must be weighed in individualized clinical decisions.
Study Strengths and Limitations: Strengths include the randomized crossover design and distinct analyses for calcium and UA stone phenotypes. Nevertheless, the sample size was modest, and the treatment duration too brief to capture definitive impacts on stone recurrence. The predominance of white male participants also limits generalizability to more diverse populations.
Future Research: Extended follow-up is crucial to determine the long-term clinical effectiveness of empagliflozin in preventing stone events. Future work should also explore potential mechanisms in larger cohorts, assess cost-effectiveness in real-world settings, and evaluate whether other SGLT2 inhibitors elicit comparable effects.
Reference: Anderegg MA, Schietzel S, Bargagli M, et al. Empagliflozin in nondiabetic individuals with calcium and uric acid kidney stones: a randomized phase 2 trial. Nature Medicine (2025). DOI: https://doi.org/10.1038/s41591-024-03330-x
RCT: Sequential Oral Agents Not Noninferior to Insulin for Gestational Diabetes
8 Jan, 2025 | 11:05h | UTCBackground: Gestational diabetes mellitus (GDM) affects a growing number of pregnant individuals worldwide. While insulin has long been the standard pharmacological treatment, oral glucose-lowering agents (metformin and glyburide) have gained traction.
Objective: This trial investigated whether a sequential oral glucose-lowering regimen—beginning with metformin and adding glyburide as needed—was noninferior to an insulin-based strategy in reducing the risk of infants born large for gestational age (LGA).
Methods: This open-label, randomized, noninferiority trial enrolled 820 participants with singleton pregnancies at 16 to 34 weeks of gestation across 25 Dutch centers. Participants were randomized 1:1 to either (1) metformin initiated at 500 mg once daily and increased every three days up to 1000 mg twice daily or the highest tolerated dose with glyburide at 2.5 mg 30-60 minutes before each meal (with a dose increase up to a maximum of 5 mg three times per day) added if needed, and insulin added only if both failed, discontinuing glyburide, or (2) standard insulin therapy. The primary outcome was LGA (>90th percentile for gestational age and sex).
Results: Among those allocated to oral therapy (n=409), 79% achieved glycemic control without insulin. However, 23.9% of infants in the oral-therapy group were LGA vs 19.9% in the insulin group (absolute risk difference 4.0%; 95% CI, −1.7% to 9.8%). This exceeded the predefined 8% absolute risk difference noninferiority margin (P = .09 for noninferiority). Maternal hypoglycemia occurred more often with oral agents (20.9% vs 10.9%; absolute risk difference, 10.0%; 95% CI, 3.7%-21.2%), and neonatal intravenous glucose therapy was administered more frequently to those randomized to oral agents (6.4% vs 3.2%). Exploratory analysis not powered for definitive conclusions of participants requiring only metformin (no glyburide) showed a somewhat lower LGA rate (19.7%).
Conclusions: A sequential oral pharmacotherapy strategy—beginning with metformin and adding glyburide if needed—did not meet noninferiority criteria compared to insulin for preventing LGA births in GDM. While oral agents can reduce the overall need for insulin, the higher rate of maternal hypoglycemia, the higher rate of neonatal hypoglycemia requiring intravenous glucose therapy, and the borderline higher LGA incidence underscore the continued importance of insulin-based strategies, especially considering that the results support a larger body of evidence that glyburide is a suboptimal treatment for gestational diabetes. These results reinforce that insulin remains the preferred first-line pharmacological treatment for GDM, in line with current guidelines. Although patient satisfaction can be higher with oral agents, clinicians should carefully weigh the risks. Further research is needed to clarify the role of metformin-only approaches in GDM management.
Strengths and Limitations: Strengths include a large multicenter design and a clear noninferiority framework. Limitations include the open-label design, which introduces the possibility of bias in treatment allocation and outcome assessment, the reliance on local clinical protocols for insulin adjustments, and variations in diagnostic criteria.
Future Research: Ongoing trials are examining whether metformin alone might match insulin’s efficacy for GDM. Further studies should address long-term offspring outcomes.
Reference:
Rademaker D, de Wit L, Duijnhoven RG, et al. Oral Glucose-Lowering Agents vs Insulin for Gestational Diabetes: A Randomized Clinical Trial. JAMA. Published online January 6, 2025. DOI: http://doi.org/10.1001/jama.2024.23410
Powe CE. For Gestational Diabetes Pharmacotherapy, Insulin Reigns Supreme (Editorial). JAMA. Published online January 6, 2025. DOI: http://doi.org/10.1001/jama.2024.27148
RCT: Assessing Procalcitonin-Based Antibiotic Management in Critically Ill Patients With Sepsis
7 Jan, 2025 | 14:00h | UTCBackground: Optimal antibiotic duration for sepsis remains uncertain. Procalcitonin (PCT) and C-reactive protein (CRP) are thought to support shorter courses, but prior research was small-scale or at risk of bias. This multicenter, randomized trial (ADAPT-Sepsis) evaluated whether daily PCT- or CRP-guided protocols could reduce antibiotic use without increasing 28-day all-cause mortality in critically ill adults with suspected sepsis.
Objective: To determine if daily biomarker-guided (PCT or CRP) strategies decrease total antibiotic days among critically ill adults while maintaining acceptable 28-day mortality, compared with standard care.
Methods: From 2018 to 2024 (with enrollment paused March–August 2020 due to COVID-19), 2760 adults (≥18 years) on intravenous antibiotics for suspected sepsis (acute organ dysfunction and presumed infection) and likely to continue antibiotics for at least 72 hours were randomized across 41 UK NHS ICUs within 24 hours of antibiotic initiation. They were assigned in a 1:1:1 ratio to (1) daily PCT-guided advice (n=918), (2) daily CRP-guided advice (n=924), or (3) standard care (n=918). Biomarker results were concealed; clinicians received automated daily prompts recommending continuation or discontinuation. The co-primary outcomes were (1) total antibiotic duration (randomization to day 28) and (2) 28-day all-cause mortality. Secondary measures included antibiotic duration for the initial sepsis episode, 90-day mortality, readmissions, and length of stay.
Results: Among 2760 participants (mean age, 60.2 years; 60.3% men; ~50% with septic shock), over 96% provided 28-day data. Patients in the PCT-guided arm had a statistically significant mean reduction in total antibiotic duration vs standard care (9.8 vs 10.7 days; difference, 0.88 days; 95% CI, 0.19–1.58; p=0.01). The PCT strategy met the prespecified 5.4% noninferiority margin for 28-day mortality (20.9% vs 19.4%; absolute difference, 1.57; 95% CI, –2.18 to 5.32; p=0.02), implying noninferiority but not fully excluding a small risk of excess mortality. CRP-guided protocols did not shorten total antibiotic use (10.6 vs 10.7 days; p=0.79) and were inconclusive for noninferiority regarding mortality (21.1% vs 19.4%; difference, 1.69; 95% CI, –2.07 to 5.45; p=0.03). Notably, 90-day mortality also showed no significant differences. A post-trial commentary (PulmCCM) emphasized that some uncertainty remains with the 5.4% margin and warned that patient-level randomization could subtly discourage earlier antibiotic discontinuation in standard care, which received no explicit “stop” prompts.
Conclusions: In critically ill patients with suspected sepsis, a PCT-guided antibiotic discontinuation protocol shortened overall antibiotic use by nearly one day without exceeding the predefined noninferiority threshold for 28-day mortality. However, the chosen 5.4% margin allows for the possibility of clinically relevant harm. A CRP-guided protocol did not reduce total antibiotic use and showed inconclusive mortality findings.
Implications for Practice: Adopting PCT-based stewardship may modestly decrease antibiotic exposure without a clear short-term mortality penalty, potentially limiting antibiotic resistance. Clinicians should remain vigilant, recognizing the risk tolerance implied by the 5.4% margin. PCT results should complement, not replace, comprehensive clinical judgment.
Study Strengths and Limitations: Strengths include the large sample size, multi-center design, blinded biomarker allocation, and distinct emphasis on both effectiveness and safety outcomes. Limitations include the acceptance of a 5.4% potential excess mortality as the noninferiority threshold, uncertainty about rare but significant harms, and the possibility of bias introduced by patient-level randomization. Generalizability to lower-resource settings may also be limited.
Future Research: Further randomized trials with lower noninferiority margins or cluster-level allocation are needed to better define the safety and efficacy of PCT-guided strategies for reducing antibiotic duration in sepsis. Additional investigations are needed for long-term patient-centered outcomes, cost-effectiveness, and the role of alternative biomarkers or combined strategies in sepsis care.
Reference:
Dark P, Hossain A, McAuley DF, et al. Biomarker-Guided Antibiotic Duration for Hospitalized Patients With Suspected Sepsis: The ADAPT-Sepsis Randomized Clinical Trial. JAMA. 2024; published online December 9. DOI: http://doi.org/10.1001/jama.2024.26458
PulmCCM Commentary: “Is procalcitonin ‘safe’ to guide antibiotic use in patients with sepsis? ADAPT-Sepsis tests the strategy in the U.K., with global ambitions.” Jan 02, 2025. https://www.pulmccm.org/p/is-procalcitonin-safe-to-guide-antibiotic
Phase III RCT: Adding Nab-Paclitaxel to Gemcitabine-Cisplatin Fails to Improve Survival in Advanced Biliary Tract Cancers
8 Jan, 2025 | 13:00h | UTCBackground: Biliary tract cancers (BTCs)—including intrahepatic and extrahepatic cholangiocarcinomas and gallbladder carcinoma—are often diagnosed at advanced stages, leaving few curative options. Gemcitabine-cisplatin (GC) has been the longstanding frontline therapy, yielding modest survival benefits. Preclinical research suggested that nab-paclitaxel might enhance drug delivery to desmoplastic tumors, and an encouraging phase II trial (GAP: gemcitabine, nab-paclitaxel, and cisplatin) spurred further investigation.
Objective: SWOG S1815 was designed to determine whether adding nab-paclitaxel (GAP regimen) to standard GC therapy would improve overall survival (OS) for patients newly diagnosed with locally advanced or metastatic BTCs.
Methods: This phase III, randomized, open-label trial enrolled patients with histologically or cytologically confirmed advanced BTC, excluding those with ampullary cancer (no prior systemic therapy for advanced disease). Participants were randomized 2:1 to receive either GAP (gemcitabine 800 mg/m^2, cisplatin 25 mg/m^2, nab-paclitaxel 100 mg/m^2 on days 1 and 8 of a 21-day cycle) or standard GC (gemcitabine 1,000 mg/m^2 plus cisplatin 25 mg/m^2 on days 1 and 8). The primary outcome was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and toxicity. Disease site (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder carcinoma) and stage (locally advanced or metastatic) were key stratification factors.
Results: Among 441 eligible patients, 67% had intrahepatic cholangiocarcinoma, 16% had gallbladder carcinoma, and 17% had extrahepatic cholangiocarcinoma, with 73% presenting metastatic disease. Median OS was 14.0 months (95% confidence interval [CI], 12.4-16.1) in the GAP arm versus 13.6 months (95% CI, 9.7-16.6) in the GC arm (hazard ratio [HR], 0.91; P = .41). Similarly, median PFS did not significantly differ (7.5 months v 6.3 months; HR, 0.89; P = .32). Subset analyses hinted that patients with gallbladder carcinoma and those with locally advanced disease might benefit more from the GAP triplet, but these findings were not statistically conclusive. Although ORR was higher with GAP (31% v 21%; P = .03), this did not translate into improved OS. Treatment-related toxicities were more frequent with the triplet regimen. Grade 3 or higher hematologic adverse events occurred in 60% of GAP patients versus 45% of those on GC (P = .003). Additionally, several grade 3-4 nonhematologic toxicities (such as ALT increase, anorexia, constipation, diarrhea, edema, fatigue, hypomagnesemia, nausea, sepsis, sensory peripheral neuropathy, and vomiting) were significantly more common with GAP. Seven treatment-related deaths occurred in the GAP arm, versus one in the GC arm, underscoring the regimen’s higher toxicity burden.
Conclusions: In this unselected BTC population, adding nab-paclitaxel to standard gemcitabine-cisplatin did not confer an OS advantage. Although higher ORR was observed, the toxicity profile was notably increased. Based on these findings, adding nab-paclitaxel to GC does not improve OS and is associated with increased toxicity. Therefore, GC remains the standard first-line treatment for advanced BTC. However, similar to what was observed in the PRODIGE 38 AMEBICA trial, which compared mFOLFIRINOX to GC, there was no survival advantage with the triplet regimen.
Implications for Practice: From a real-world perspective, the triplet regimen elevates both toxicity and likely treatment costs, without demonstrable survival benefit for the broader BTC population. Clinicians may consider GAP in highly selected subsets (for instance, localized unresectable gallbladder disease) or in research settings. Until further evidence clarifies which patients might benefit, GC remains the standard first-line treatment for advanced BTC.
Study Strengths and Limitations: Strengths include the large, multi-institutional, US-based randomized design and robust accrual (enrollment of a sufficient number of participants).* Limitations involve the heterogeneous nature (diversity) of BTCs and the absence of centralized radiologic review (a process where imaging studies are reviewed by a central group of experts rather than solely by local investigators). Furthermore, the trial did not incorporate cost-effectiveness analyses or routine genomic stratification *(classifying patients based on the genetic characteristics of their tumors), which could have refined patient selection.
Future Research: Ongoing investigations seek to integrate precision oncology—encompassing genetic profiling and circulating tumor DNA—to identify subgroups that may benefit from targeted or intensified cytotoxic strategies. Perioperative or adjuvant approaches with GAP or similar triplets might prove more effective in earlier-stage disease. Studies combining novel immunotherapies or targeted agents with chemotherapy could address the evolving BTC landscape.
Reference: Shroff RT, King G, Colby S, et al. SWOG S1815: A Phase III Randomized Trial of Gemcitabine, Cisplatin, and Nab-Paclitaxel Versus Gemcitabine and Cisplatin in Newly Diagnosed, Advanced Biliary Tract Cancers. Journal of Clinical Oncology.
DOI: https://doi.org/10.1200/JCO-24-01383
Phase 2b/3 QUASAR Program: Guselkumab for Induction and Maintenance Therapy in Moderate-to-Severe Ulcerative Colitis
7 Jan, 2025 | 13:00h | UTCBackground: Ulcerative colitis (UC) is a chronic inflammatory condition affecting the colon’s mucosal surface, frequently accompanied by debilitating symptoms such as bloody diarrhea, urgency, and abdominal discomfort. Despite the availability of corticosteroids, immunosuppressants, and advanced biologic or small-molecule therapies, many patients still experience suboptimal outcomes. Targeting interleukin (IL)-23, a critical cytokine in the inflammatory cascade, has gained increasing attention. Guselkumab, a human IgG1 monoclonal antibody against the IL-23p19 subunit, has shown clinical promise in psoriasis, psoriatic arthritis, and Crohn’s disease. This article reports findings from the phase 2b/3 QUASAR clinical development program evaluating guselkumab in UC.
Objective: To assess the efficacy and safety of intravenous (IV) guselkumab induction therapy (200 mg every 4 weeks) compared to placebo, followed by subcutaneous (SC) maintenance regimens (200 mg every 4 weeks or 100 mg every 8 weeks) compared to placebo (withdrawal) in adults with moderately to severely active UC who had inadequate responses or intolerance to at least one conventional or advanced therapy.
Methods: In these double-blind, randomized, placebo-controlled studies within the QUASAR program, adults with a baseline modified Mayo (mMayo) score of 5–9 (which excludes the physician’s global assessment) and evidence of active UC underwent IV induction with either guselkumab or placebo at Weeks 0, 4, and 8. The primary endpoint of the induction trial was clinical remission at Week 12 in the primary analysis population (patients with mMayo score 5-9), defined by improved stool frequency, rectal bleeding, and endoscopic findings. Responders from both the phase 2b and phase 3 induction studies then entered the maintenance study, randomized to SC guselkumab (either 200 mg Q4W or 100 mg Q8W) or placebo (withdrawal, meaning patients who had previously responded to guselkumab). The primary endpoint for the maintenance phase was clinical remission at Week 44 in the primary analysis population. Key secondary outcomes included endoscopic improvement, histological remission, corticosteroid-free remission, and patient-reported measures.
Results: A total of 701 patients with a baseline mMayo score of 5-9 (primary analysis population) were evaluated in the phase 3 induction study. By Week 12, a higher proportion of those receiving IV guselkumab (23%) achieved clinical remission compared to placebo (8%; p<0.0001). Patients also demonstrated improvement in endoscopic outcomes and had early symptomatic relief (notably a reduction in rectal bleeding as early as Week 1). In the subsequent maintenance phase, 568 guselkumab induction responders from both phase 2b and phase 3 studies (primary analysis population) were randomized. At Week 44, clinical remission was significantly more frequent in patients receiving guselkumab SC (50% on 200 mg Q4W, 45% on 100 mg Q8W) vs 19% on placebo (both p<0.0001). Endoscopic and histological indices indicated improved mucosal healing with active therapy. Most patients in remission were free of corticosteroids, highlighting a significant steroid-sparing effect.
Conclusions: Guselkumab induction (200 mg IV every 4 weeks) followed by either of the two SC maintenance regimens (200 mg Q4W or 100 mg Q8W) demonstrated substantial efficacy in adults with moderate-to-severe UC, with improved clinical, endoscopic, and histological endpoints relative to placebo. No new safety concerns were observed compared to the known safety profile of guselkumab.
Implications for Practice: Guselkumab offers a new therapeutic option for UC, particularly for individuals who have not responded to, or could not tolerate, other treatments. The study suggests that guselkumab can be considered for both biologic-naive and biologic-experienced patients. As with any novel therapy, careful patient selection and close follow-up are advisable.
Study Strengths and Limitations: Strengths include the rigorous, global, phase 2b/3 design with objective assessments of clinical, endoscopic, and histological response. The large population permitted detailed subgroup analyses (e.g., efficacy was observed in both biologic-naive and biologic-experienced populations). Limitations include the exclusion of certain therapy-refractory cases and lack of active comparator arms. The randomized-withdrawal maintenance design means only induction responders were evaluated further, potentially enhancing observed effect sizes.
Future Research: Extended follow-up will elucidate the durability of remission beyond one year and clarify long-term safety considerations. Head-to-head trials against other IL-23 antagonists or advanced therapies could further guide treatment algorithms. Real-world evidence evaluating diverse populations will be instrumental in determining broader applicability.
Reference: Rubin DT, Allegretti JR, Panés J, Shipitofsky N, Yarandi SS, Huang K-HG, Germinaro M, Wilson R, Zhang H, Johanns J, Feagan BG, Hisamatsu T, Lichtenstein GR, Bressler B, Peyrin-Biroulet L, Sands BE, Dignass A; QUASAR Study Group. Guselkumab in patients with moderately to severely active ulcerative colitis (QUASAR): phase 3 double-blind, randomised, placebo-controlled induction and maintenance studies. The Lancet. 2025;405(10472):33–49. DOI: http://doi.org/10.1016/S0140-6736(24)01927-5
RCT: Camrelizumab Increases Pathological Complete Response in Early or Locally Advanced Triple-Negative Breast Cancer
7 Jan, 2025 | 12:00h | UTCBackground: Triple-negative breast cancer (TNBC) accounts for approximately 15% of all breast malignancies and is known for its aggressive clinical course and limited therapeutic options. Neoadjuvant chemotherapy has become standard of care for many patients with stage II or III TNBC, aiming to downstage tumors and enhance surgical outcomes. Recent trials suggest that adding immune checkpoint inhibitors, such as anti–programmed death 1/ligand 1 (PD-1/PD-L1) agents, to anthracycline- and platinum-based regimens can further improve response rates. Camrelizumab, a humanized monoclonal anti–PD-1 antibody, has shown antitumor activity in various malignancies, including advanced TNBC. This study, the CamRelief trial, evaluated whether camrelizumab combined with intensive chemotherapy (nab-paclitaxel plus carboplatin followed by dose-dense anthracycline-cyclophosphamide) increases pathological complete response (pCR) in patients with early or locally advanced TNBC.
Objective: To determine if the addition of camrelizumab to a platinum-containing neoadjuvant chemotherapy regimen significantly improves pCR in operable or locally advanced TNBC compared with placebo plus the same chemotherapy backbone.
Methods: This randomized, double-blind, phase 3 trial enrolled 441 female patients aged 18 to 75 years from 40 Chinese centers. Eligible participants had stage II or III TNBC (T2N0-1M0/T3N0M0 or T2N2-3M0/T3N1-3M0) and an Eastern Cooperative Oncology Group performance-status score of 0 or 1. Patients were randomized 1:1 to receive camrelizumab (200 mg) or placebo plus chemotherapy. Chemotherapy consisted of nab-paclitaxel (100 mg/m^2) and carboplatin (area under the curve, 1.5) on days 1, 8, and 15 every 28 days for 16 weeks, then epirubicin (90 mg/m^2) and cyclophosphamide (500 mg/m^2) every two weeks for 8 weeks. Camrelizumab or placebo was administered every two weeks during the 24 weeks of chemotherapy. The primary end point was pCR (ypT0/Tis ypN0), assessed by a local pathologist masked to treatment assignment, at the time of surgery. Secondary end points included event-free survival, disease-free survival, distant disease-free survival, and safety.
Results: Of the 441 randomized patients, 89.2% in the camrelizumab-chemotherapy group and 91.3% in the placebo-chemotherapy group proceeded to surgery. Pathological complete response was observed in 56.8% (95% CI, 50.0%-63.4%) of patients receiving camrelizumab-chemotherapy vs 44.7% (95% CI, 38.0%-51.6%) of those receiving placebo-chemotherapy (rate difference, 12.2% [95% CI, 3.3%-21.2%]; 1-sided P = .004). Serious adverse events occurred more frequently with camrelizumab-chemotherapy (34.7% vs 22.8%), including decreased neutrophil count, decreased platelet count, and decreased white blood cell count, but most immune-related events (eg, reactive capillary endothelial proliferation, hypothyroidism) were low grade and manageable. Longer-term outcomes (event-free survival, disease-free survival, distant disease-free survival) remain immature at a median follow-up of 14.4 months, with hazard ratios of 0.80 (95% CI, 0.46-1.42), 0.58 (95% CI, 0.27-1.24), and 0.62 (95% CI, 0.29-1.33), respectively.
Conclusions: In patients with early or locally advanced TNBC, adding camrelizumab to a platinum-containing, dose-dense anthracycline-cyclophosphamide regimen significantly increased pCR rates compared with placebo plus the same chemotherapy backbone. Safety profiles were consistent with known effects of camrelizumab and dose-dense chemotherapy, with no unexpected toxicities detected.
Implications for Practice: These findings support the integration of camrelizumab into an intensive neoadjuvant regimen for TNBC, potentially offering higher rates of tumor eradication across various nodal stages. Clinicians should, however, anticipate and monitor immune-related adverse events, particularly in higher-risk populations. Given the toxicity profile, patient selection and vigilant supportive care are important.
Study Strengths and Limitations: Strengths include the randomized, double-blind design and the inclusion of higher-risk, node-positive cohorts (including N3). The dose-dense chemotherapy backbone further strengthens the applicability of results in more advanced operable disease. Limitations involve the short follow-up time, which precludes conclusive survival analyses, and the study’s restriction to a single geographic population.
Future Research: Longer follow-up is necessary to determine if improved pCR translates into sustained survival benefits. Biomarker-driven approaches, including further PD-L1 and immunogenomic analyses, may refine patient selection. Studies in broader populations and direct comparisons with other checkpoint inhibitors will help define the optimal immunotherapy-partner regimens in TNBC.
Reference:
Chen L, Li H, Zhang H, et al. Camrelizumab vs Placebo in Combination With Chemotherapy as Neoadjuvant Treatment in Patients With Early or Locally Advanced Triple-Negative Breast Cancer: The CamRelief Randomized Clinical Trial. JAMA. Published online December 13, 2024. DOI: http://doi.org/10.1001/jama.2024.23560
Joensuu H. Neoadjuvant Camrelizumab for Triple-Negative Breast Cancer. Editorial. JAMA. Published online December 13, 2024. DOI: http://doi.org/10.1001/jama.2024.25927
RCT: Chlorthalidone Shows No Renal Advantage Over Hydrochlorothiazide Under Equivalent Dosing in Older Adults With Hypertension
3 Jan, 2025 | 09:00h | UTCBackground: Hypertension is a critical factor in chronic kidney disease (CKD) progression and cardiovascular risk. Thiazide-type diuretics, such as chlorthalidone and hydrochlorothiazide, are first-line antihypertensive treatments. However, whether one agent confers stronger renal protection remains contested, especially at doses considered pharmacologically comparable. Prior observational studies suggested potential discrepancies in kidney outcomes and hypokalemia incidence. This secondary analysis of the Diuretic Comparison Project (DCP) further clarifies the comparative effectiveness of chlorthalidone versus hydrochlorothiazide on renal endpoints.
Objective: To evaluate whether chlorthalidone (12.5–25 mg/day) prevents CKD progression more effectively than hydrochlorothiazide (25–50 mg/day) in adults ≥65 years with hypertension and no pre-specified exclusion by renal function.
Methods: The DCP is a pragmatic, open-label randomized clinical trial embedded in Veterans Affairs (VA) facilities across the United States. Between June 1, 2016, and December 31, 2023, patients already receiving hydrochlorothiazide (25 or 50 mg/day) for hypertension were randomized either to continue that medication or switch to chlorthalidone (12.5–25 mg/day), reflecting equivalent potency.
The prespecified primary kidney outcome was a composite of doubling of serum creatinine, a terminal estimated glomerular filtration rate (eGFR) <15 mL/min, or dialysis initiation. Secondary measures included ≥40% eGFR decline, incident CKD (new eGFR <60 mL/min), eGFR slope, and relevant adverse events. Laboratory data were obtained through usual clinical care rather than protocol-driven testing.
Results: Among 13,523 randomized participants, 12,265 had analyzable renal data (mean [SD] age, 71 [4] years; 96.8% male). The mean (SD) follow-up was 3.9 (1.3) years. Chlorthalidone did not demonstrate superiority over hydrochlorothiazide for the composite kidney endpoint (6.0% vs 6.4%; hazard ratio, 0.94; 95% CI, 0.81–1.08; P=.37). Additional analyses showed no differences in CKD incidence, ≥40% eGFR decline, or eGFR slope. Hypokalemia occurred more frequently in chlorthalidone users (overall ~2% higher rate of low potassium measurements), and hospitalizations for hypokalemia also trended higher.
Conclusions: Under dosing regimens designed to achieve equivalent antihypertensive potency, chlorthalidone provided no measurable renal benefit over hydrochlorothiazide but posed a modestly elevated risk of hypokalemia. These findings reinforce the clinical interchangeability of both agents for long-term blood pressure management in older adults, provided serum potassium is monitored.
Implications for Practice: Clinicians can confidently employ either chlorthalidone or hydrochlorothiazide in older patients with hypertension, including those with mild or moderate CKD, since renal deterioration rates did not differ significantly. Importantly, the trial used half the milligram amount of chlorthalidone (12.5–25 mg/day) to match the usual doses of hydrochlorothiazide (25–50 mg/day). Recognizing this equivalence helps guide therapy transitions and dosing decisions. Vigilant monitoring of electrolytes remains essential, particularly when prescribing chlorthalidone, given the slightly higher incidence of hypokalemia.
Study Strengths and Limitations: Strengths include the randomized design, broad participant inclusion, and pragmatic structure that mirrors real-world prescribing. Limitations involve potential underestimation or overestimation of renal events due to reliance on routine (rather than scheduled) lab tests. Also, nearly all participants had prior hydrochlorothiazide exposure, which may have influenced tolerance and adherence patterns.
Future Research: Further clinical trials focusing on more advanced CKD stages, distinct comorbidities, or combination regimens (e.g., with potassium-sparing agents) would expand our understanding of how thiazide-type diuretics influence long-term kidney outcomes. Extended follow-up or additional subgroup analyses could also shed light on the interplay of dose-response effects in highly vulnerable populations.
Reference: Ishani A, Hau C, Raju S, et al. “Chlorthalidone vs Hydrochlorothiazide and Kidney Outcomes in Patients With Hypertension: A Secondary Analysis of a Randomized Clinical Trial.” JAMA Netw Open. 2024;7(12):e2449576. DOI: http://doi.org/10.1001/jamanetworkopen.2024.49576
RCT: Discontinuing First-Line DMT in Long-Term Stable Relapsing MS Leads to Recurrence of Disease Activity
3 Jan, 2025 | 08:00h | UTCBackground: Increasing numbers of patients with relapsing-onset multiple sclerosis (MS) are receiving first-line disease-modifying therapies (DMTs) to control inflammatory lesions and reduce disability progression. Yet, extended therapy raises questions regarding overtreatment, adverse effects, and costs, especially in older or clinically stable individuals.
Objective: This randomized, multicenter, rater-blinded clinical trial (DOT-MS) assessed whether discontinuing first-line DMT in adults with MS who had at least five years of clinical and radiological stability is safe in terms of recurrence of significant inflammatory disease activity.
Methods: Eighty-nine participants (median age 54 years, 67% female) were randomly assigned 1:1 to either continue or discontinue their first-line DMT. Inclusion required relapse-onset MS without new, sizeable brain MRI lesions (≤1 new T2 lesion in the previous five years or ≤3 new T2 lesions in the past ten years). Follow-up included clinical evaluations, gadolinium-enhanced brain MRI at baseline and months 3, 6, 12, 18, and 24, and optional unscheduled visits. The primary endpoint was significant inflammatory disease activity, defined as clinical relapse and/or ≥3 new T2 lesions or ≥2 contrast-enhancing lesions. The trial was prematurely terminated by the data safety monitoring board due to higher-than-expected disease activity in the discontinue arm.
Results: After a median follow-up of 15.3 months, none of the 44 participants in the continue group had significant disease activity, versus 8 of 45 (17.8%) in the discontinue group (95% CI for difference, 0.09–0.32). Nearly all events were MRI-detected new or enhancing lesions, though two participants experienced clinical relapses. Most individuals with reactivation were able to regain stability upon DMT reintroduction. Serum neurofilament light levels rose during episodes of inflammatory activity, but neither NfL nor GFAP levels reliably predicted disease recurrence at baseline. No difference in serious adverse events emerged between groups.
Conclusions: In this trial, discontinuation of first-line DMT in long-term stable MS was associated with a significant risk (about 20%) of inflammatory reactivation, particularly noted in participants under 55 years old. As a result, close clinical and MRI monitoring should be mandatory if discontinuation is attempted, with early DMT reinitiation if necessary.
Implications for Practice: Clinicians may consider stopping first-line DMT in select patients who exhibit prolonged stability, especially in older adults, but must remain vigilant. Rapid detection of any radiological or clinical sign of reactivation is crucial, as reintroducing therapy may reestablish disease control.
Study Strengths and Limitations: Strengths include its randomized design, systematic imaging schedule, and thorough biomarker sampling. Limitations involve early trial termination, restricting subgroup analyses and definitive noninferiority testing. Routine spinal cord imaging was not performed, potentially underestimating subclinical disease activity.
Future Research: Longer-term observational follow-up is ongoing to clarify how these participants fare over time and to identify biomarkers that may better predict risk of rebound activity. Evaluating cost-effectiveness and long-term clinical outcomes will guide future decisions about DMT discontinuation.
Reference: Coerver EME, et al. Discontinuation of First-Line Disease-Modifying Therapy in Patients With Stable Multiple Sclerosis: The DOT-MS Randomized Clinical Trial. JAMA Neurology. 2024. DOI: http://doi.org/10.1001/jamaneurol.2024.4164
Phase 2 RCT: CRISPR-Based Therapy Reduces Attacks in Hereditary Angioedema
2 Jan, 2025 | 10:00h | UTCBackground: Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by unpredictable attacks of angioedema involving cutaneous tissues, the gastrointestinal tract, and, potentially, the larynx, posing a risk of asphyxiation. Current prophylactic treatments require frequent administration, often leading to suboptimal adherence and ongoing disease burden. NTLA-2002 is an in vivo CRISPR-Cas9–based therapy designed to permanently inactivate the KLKB1 gene in hepatocytes, thereby reducing plasma kallikrein levels and, hypothetically, lowering attack frequency in patients with HAE.
Objective: To evaluate whether a single intravenous infusion of NTLA-2002 (25 mg or 50 mg) would safely and effectively decrease HAE attack rates and reduce plasma kallikrein protein levels over a 16-week primary observation period, as compared with placebo.
Methods: This phase 2, randomized, double-blind, placebo-controlled trial included 27 adults with confirmed type 1 or type 2 HAE. Participants were assigned in a 2:2:1 ratio to receive a one-time dose of 25 mg or 50 mg of NTLA-2002 or placebo. The primary endpoint was the investigator-confirmed number of angioedema attacks per month from Week 1 through Week 16. Secondary endpoints included the number of moderate-to-severe attacks, use of on-demand therapy, adverse events, and changes in total plasma kallikrein protein levels (analyzed by immunoassays). Exploratory measures encompassed patient-reported outcomes using the Angioedema Quality of Life (AE-QoL) questionnaire.
Results: During the 16-week period, the mean monthly attack rate decreased by 75% in the 25 mg group and 77% in the 50 mg group relative to placebo (estimated rates of 0.70 vs. 0.65 vs. 2.82 attacks per month, respectively). Notably, 4 of 10 patients (40%) in the 25 mg group and 8 of 11 (73%) in the 50 mg group reported no attacks or further prophylaxis use after dosing. Placebo recipients showed only a 16% reduction from baseline. Adverse events were predominantly mild to moderate; headache, fatigue, and nasopharyngitis were most common. Infusion-related reactions occurred in a few patients but resolved without sequelae. A single transient grade 2 elevation in alanine aminotransferase was recorded in one participant given 25 mg of NTLA-2002. By Week 16, total plasma kallikrein levels decreased by 55% in the 25 mg group and 86% in the 50 mg group, with no meaningful changes in placebo.
Conclusions: A single intravenous infusion of NTLA-2002 significantly lowered attack frequency and reduced total plasma kallikrein levels in HAE. Most patients treated at 50 mg experienced no attacks, suggesting that long-term prophylaxis might be unnecessary for many. Longer observation supports durability, yet cost and potential long-term effects of gene editing warrant cautious interpretation.
Implications for Practice: If confirmed by larger phase 3 trials, this gene-editing approach could alter the management of HAE, reducing or eliminating the need for continuous prophylaxis. However, clinicians must weigh the high upfront cost, possible unpredictable immune responses, and the novelty of CRISPR-based therapies before integrating them into standard care.
Study Strengths and Limitations: Strengths include a placebo-controlled design, meaningful improvement in patient-reported outcomes, and robust plasma kallikrein protein reduction. Limitations are the small sample size, short primary observation period, and uncertain long-term safety in diverse populations.
Future Research: Ongoing phase 3 studies with larger cohorts and extended follow-up are essential to confirm safety, long-term efficacy, and cost-effectiveness.
Reference: Cohn DM, Gurugama P, Magerl M, et al. CRISPR-Based Therapy for Hereditary Angioedema. New England Journal of Medicine. 2024; DOI: http://doi.org/10.1056/NEJMoa2405734
- Editorial: Musunuru K. A Milestone for Gene-Editing Therapies. New England Journal of Medicine. 2024; DOI: http://doi.org/10.1056/NEJMe2412176
RCT: Pembrolizumab with Preoperative Radiotherapy Shows Potential in Stage III Soft Tissue Sarcoma
2 Jan, 2025 | 09:00h | UTCBackground: Patients with locally advanced, high-grade soft tissue sarcomas of the extremity often face a high risk of metastatic disease, despite curative-intent surgery and radiotherapy. Traditional doxorubicin-based chemotherapy provides variable benefits and can cause considerable toxicity, prompting investigations into alternative strategies. Emerging data from smaller trials hinted that immune checkpoint inhibitors might offer targeted benefit in sarcomas, but robust evidence in the neoadjuvant setting remains limited.
Objective: To assess whether adding neoadjuvant and adjuvant pembrolizumab to preoperative radiotherapy and surgical resection could enhance disease-free survival (DFS) in individuals with resectable grade 2 or 3, stage III undifferentiated pleomorphic sarcoma or liposarcoma of the extremity and limb girdle.
Methods: This open-label, randomized trial (SU2C-SARC032) enrolled 143 participants at 20 academic centers in Australia, Canada, Italy, and the USA. Eligible patients were 12 years or older, presented with primary tumors >5 cm, and did not receive chemotherapy as part of this protocol. Participants were randomized 1:1 to standard preoperative radiotherapy (50 Gy/25 fractions) plus surgery (control) or the same radiotherapy combined with pembrolizumab (200 mg every three weeks) in the neoadjuvant setting, followed by up to 14 adjuvant cycles. The primary endpoint was disease-free survival, analyzed in a modified intention-to-treat cohort of 127 evaluable patients, with a median follow-up of 43 months.
Results: The pembrolizumab group demonstrated a higher 2-year DFS rate (67%) compared with controls (52%), suggesting a favorable hazard ratio (0.61) for recurrence or death. Nonetheless, grade 3 or higher adverse events were more common in the pembrolizumab arm (56% vs 31%). Secondary endpoints, including distant disease-free survival and overall survival, also appeared to favor the pembrolizumab arm, but these comparisons were not powered for definitive conclusions.
Conclusions: Neoadjuvant and adjuvant pembrolizumab in combination with radiotherapy and surgery demonstrated a DFS advantage in stage III undifferentiated pleomorphic sarcoma or liposarcoma, reinforcing the potential role of immunotherapy in high-risk settings. However, given the increased incidence of adverse events and the relatively short follow-up for overall survival, cautious interpretation is warranted. Further evidence is required to determine long-term benefits and confirm whether these findings extend to other sarcoma subtypes.
Implications for Practice: These data suggest that incorporating pembrolizumab could be considered in selected patients, particularly those with large, high-grade tumors unresponsive to or unsuitable for traditional chemotherapy. Clinicians must balance the incremental risk of immunotherapy-induced side effects against the observed gains in disease-free survival and the ongoing need for extended follow-up.
Study Strengths and Limitations: Strengths include a multicenter randomized design, focus on a high-risk population, and a robust primary endpoint. Limitations encompass a relatively small sample size, inherent to rare cancers, underpowered subgroup analyses, and absence of long-term survival data. Confirmation of these early signals in larger cohorts and over more extended follow-up periods remains necessary.
Future Research: Additional trials should explore optimal radiotherapy fractionation, potential synergies with cytotoxic or targeted agents, and predictive biomarkers of response. Understanding immune correlates, including circulating tumor DNA and tumor microenvironmental factors, may refine treatment selection and enhance therapeutic outcomes.
Reference: Mowery YM, et al. Safety and efficacy of pembrolizumab, radiation therapy, and surgery versus radiation therapy and surgery for stage III soft tissue sarcoma of the extremity (SU2C-SARC032): an open-label, randomised clinical trial. The Lancet. 2024;404(10467). DOI: http://doi.org/10.1016/S0140-6736(24)01812-9
RCT: Daratumumab Monotherapy Prevents Progression in High-Risk Smoldering Multiple Myeloma
26 Dec, 2024 | 15:44h | UTCBackground: Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder that can progress to active multiple myeloma, especially when risk factors place patients in a high-risk subset. Although daratumumab has been approved for multiple myeloma, no treatments have been approved for high-risk SMM. This study (AQUILA) examined whether subcutaneous daratumumab could prevent or significantly delay progression to symptomatic myeloma.
Objective: To evaluate the effectiveness of subcutaneous daratumumab monotherapy versus active monitoring in prolonging time to disease progression (defined by SLiM–CRAB criteria) or death in patients with high-risk SMM.
Methods: In this open-label phase 3 trial, 390 patients with high-risk SMM were randomly assigned (1:1) to either daratumumab (1800 mg subcutaneously) or active monitoring. Daratumumab was administered weekly for cycles 1–2, every two weeks for cycles 3–6, and then every four weeks for up to 39 cycles (36 months) or until confirmed disease progression. Active monitoring followed the same schedule for disease evaluations without any specific therapy. The primary endpoint was progression-free survival (PFS), assessed by an independent committee. Secondary endpoints included overall survival, response rates, and time to subsequent therapy.
Results: After a median follow-up of 65.2 months, disease progression or death occurred in 34.5% of patients in the daratumumab group compared to 50.5% in the active-monitoring group (HR, 0.49; 95% CI, 0.36–0.67; p<0.001). At five years, the PFS rate was 63.1% with daratumumab and 40.8% with active monitoring. Overall survival was also higher in the daratumumab arm: 93.0% versus 86.9% at five years (HR for death, 0.52; 95% CI, 0.27–0.98). Treatment discontinuation due to adverse events was low (5.7%), and no new safety signals emerged. Grade 3 or 4 adverse events, primarily hypertension (5.7% vs. 4.6%), occurred at similar rates in both arms. Infections of grade 3 or 4 were more frequent with daratumumab (16.1% vs. 4.6%), including COVID-19 pneumonia, yet overall tolerability remained acceptable. Patient-reported outcomes, including quality-of-life measures, were largely preserved in both groups during the study.
Conclusions: Subcutaneous daratumumab monotherapy substantially delayed progression to symptomatic multiple myeloma and improved overall survival among patients with high-risk SMM. The safety profile was consistent with prior daratumumab studies, suggesting a favorable risk–benefit balance. Early intervention with daratumumab may thus alter the disease trajectory for select patients, sparing them from end-organ damage and improving long-term clinical outcomes.
Implications for Practice: While active monitoring has been the standard of care for high-risk SMM, these findings support early therapeutic intervention for patients with multiple high-risk features. Clinicians should remain cautious, however, when generalizing across different risk stratification models. Additional research on optimal treatment durations, combination strategies, and real-world outcomes will further refine patient selection and management of high-risk SMM.
Study Strengths and Limitations: This trial featured robust follow-up (median of over five years) and clear outcome definitions. However, the classification of high-risk features has evolved, and certain populations (e.g., Black patients) were underrepresented. These factors may limit the generalizability of the findings in broader clinical settings.
Future Research: Ongoing trials are investigating alternative dosing schedules, combination regimens (e.g., daratumumab-based quadruplets), and the role of minimal residual disease monitoring to optimize patient outcomes. Additional studies will clarify whether more intense or shorter treatments might maintain efficacy with fewer side effects.
Reference: Dimopoulos MA, Voorhees PM, Schjesvold F, Cohen YC, Hungria V, Sandhu I, Lindsay J, +29, for the AQUILA Investigators. Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma. New England Journal of Medicine. 2024; DOI: http://doi.org/10.1056/NEJMoa2409029
Three Phase 3, Placebo-Controlled Trials Show Rapid Benefits of Oral Atogepant for Migraine Prevention
26 Dec, 2024 | 12:17h | UTCBackground: Preventive therapies for migraine often require long titration and may take weeks to achieve their full effect. This analysis integrates data from three randomized, placebo-controlled Phase 3 trials (ADVANCE, ELEVATE, PROGRESS) assessing atogepant 60 mg once daily (QD) over 12 weeks, focusing on the first four weeks. A key point is that atogepant was compared only to placebo, not to other well-established migraine preventives.
Objective: To determine whether atogepant provides early efficacy in reducing migraine frequency and improving functional outcomes within the initial weeks of therapy, for both episodic and chronic migraine.
Methods: All three studies enrolled participants aged 18–80 years with a ≥1-year history of migraine. ADVANCE and ELEVATE focused on episodic migraine (EM; 4–14 monthly migraine days), while PROGRESS studied chronic migraine (CM; ≥15 monthly headache days, ≥8 of which met migraine criteria). In ELEVATE, participants had previously failed 2–4 classes of oral migraine preventives. Throughout each trial, patients recorded daily migraine-related data and completed validated functional assessments (AIM-D and EQ-5D-5L). For this pooled analysis, only the atogepant 60 mg QD and placebo arms were examined.
Results: Atogepant recipients had a significantly lower proportion of patients with a migraine day on day 1 in all three trials, suggesting a rapid onset of benefit. Reductions in weekly migraine days (WMDs) emerged as early as week 1 and remained consistently greater than placebo over the first four weeks. Functional measures improved within this same timeframe, with patients on atogepant reporting reductions in activity impairment and enhanced self-rated health. These positive findings were observed in EM (with or without prior prophylaxis failures) and in CM populations.
Conclusions: Atogepant 60 mg QD was linked to early and significant reductions in migraine days, as well as enhancements in physical functioning and daily activities, across three placebo-controlled studies. The data suggest that atogepant may offer clinically meaningful, rapid-onset prophylactic benefits.
Implications for Practice: Clinicians may consider atogepant for patients seeking a preventive migraine therapy that demonstrates a potentially faster impact on symptom frequency and daily functioning. However, direct comparisons with established active treatments are lacking, and appropriate caution in interpreting the early onset of benefit is recommended.
Study Strengths and Limitations: Major strengths include robust, double-blind methodologies and consistent findings across diverse migraine populations. A key limitation is the exclusive use of placebo as the comparator, so the relative advantage over standard preventives remains unknown. The predominantly female and White study cohorts also restrict generalizability.
Future Research: Further investigations should evaluate atogepant in direct comparisons with existing active migraine preventives, examine long-term outcomes, and recruit more diverse populations. Such efforts could better define the therapy’s place in routine migraine care.
Reference: Lipton RB, et al. Early Improvements With Atogepant for the Preventive Treatment of Migraine: Results From 3 Randomized Phase 3 Trials. Neurology. 2025;104(2). DOI: https://doi.org/10.1212/WNL.0000000000210212
RCT: Avoiding Prophylactic Drain Increases Postoperative Invasive Procedures After Gastrectomy
25 Dec, 2024 | 12:47h | UTCBackground: Prophylactic abdominal drainage following gastrectomy for gastric cancer has been debated for decades. While some Enhanced Recovery After Surgery (ERAS) guidelines discourage routine drains, many surgeons still advocate their use to detect and manage intra-abdominal collections before they become severe. Previous trials were small and underpowered, thus failing to provide robust evidence regarding the real need for prophylactic drains.
Objective: To determine whether omitting a prophylactic drain in gastric cancer surgery leads to a higher likelihood of postoperative invasive procedures (reoperation or percutaneous drainage) within 30 days.
Methods: In this multicenter randomized clinical trial, 404 patients from 11 Italian centers were randomly assigned to either prophylactic drain placement or no drain at the end of subtotal or total gastrectomy. Both academic and community hospitals participated. The primary composite outcome was the rate of reoperation or percutaneous drainage within 30 postoperative days, analyzed via a modified intention-to-treat approach. Secondary endpoints included overall morbidity, anastomotic leaks, length of hospital stay, and 90-day mortality. A parallel invited commentary addressed methodological and clinical perspectives.
Results: Among the 390 patients who underwent resection, 196 had a prophylactic drain and 194 did not. By postoperative day 30, 7.7% of patients in the drain group required reoperation or percutaneous drainage, compared with 15% in the no-drain group. This statistically significant difference was driven by a higher reoperation rate in patients without drains. Both groups had similar anastomotic leak rates (approximately 4% overall). However, patients without prophylactic drains had a higher in-hospital mortality (4.6% vs 0.5%) and were more likely to require escalation of care. There were few drain-related complications, indicating a low risk associated with drain placement. Length of hospital stay and readmission rates were comparable between groups.
Conclusions: Omitting prophylactic drains in gastrectomy was associated with an increased need for postoperative invasive interventions, particularly reoperations. While prior guidelines have recommended against routine drain placement, these findings challenge that stance for total and even subtotal gastrectomies. Surgeons may wish to revisit existing protocols, especially in facilities with fewer resources or lower patient volumes, given the potential reduction in reoperation risk associated with prophylactic drainage.
Implications for Practice: Clinicians should carefully balance possible benefits (earlier detection of fluid collections and reduced reoperations) against potential drawbacks of drain usage. Routine placement may be reconsidered, at least in higher-risk cases or in institutions less equipped for complex salvage procedures.
Study Strengths and Limitations: Key strengths include its robust sample size and standardized criteria for complications. Limitations involve the unblinded nature of postoperative management and the lack of drain fluid amylase measurements to guide removal protocols. Additionally, differentiating total from subtotal gastrectomies might refine selection criteria for prophylactic drainage.
Future Research: Further studies could focus on stratified risk profiles for total vs subtotal gastrectomy and on biomarkers in drain fluid to identify subgroups most likely to benefit from prophylactic drainage.
RCT: Early Restrictive vs Liberal Oxygen Strategy in Severe Trauma – No Significant Outcome Difference
22 Dec, 2024 | 17:21h | UTCBackground: The Advanced Trauma Life Support (ATLS) guidelines recommend providing supplemental oxygen to severely injured patients in the early phase after trauma, although the evidence base is limited. Observational research suggests that liberal oxygen administration may raise the risk of death and respiratory complications. Therefore, the TRAUMOX2 trial examined whether an 8-hour restrictive oxygen strategy (targeting an SpO₂ of 94%) could improve outcomes compared with a liberal strategy (12–15 L/min or FiO₂ 0.6–1.0) initiated prehospital or upon trauma center admission.
Objective: To determine whether an early restrictive oxygen approach, as compared with a liberal approach, reduces the composite outcome of death and/or major respiratory complications (pneumonia or ARDS) within 30 days in severely injured adults.
Methods: This investigator-initiated, international, multicenter, open-label, randomized controlled trial enrolled patients aged 18 years or older with blunt or penetrating trauma requiring full trauma team activation and anticipated hospital stay of at least 24 hours. Randomization occurred either prehospital or upon trauma center arrival in a 1:1 ratio to restrictive (lowest dose of oxygen to maintain SpO₂ at 94%) versus liberal therapy (12–15 L/min via nonrebreather mask or FiO₂ 0.6–1.0). The intervention lasted 8 hours, with all other management per standard care. The primary outcome—death or major respiratory complications (pneumonia per CDC criteria or ARDS per the Berlin definition)—was evaluated by blinded assessors within 30 days. Statistical analyses employed logistic regression, adjusted for stratification variables.
Results: Among 1979 randomized patients, 1508 completed the study (median age, 50 years; Injury Severity Score [ISS], 14). The composite primary outcome occurred in 16.1% (118/733) of restrictive-group patients and 16.7% (121/724) of liberal-group patients (odds ratio, 1.01; 95% CI, 0.75–1.37; p=0.94). Mortality alone (8.6% vs 7.3%) and major respiratory complications alone (8.9% vs 10.8%) showed no significant differences between groups. Adverse and serious adverse events were similar, except atelectasis was less frequent in the restrictive group (27.6% vs 34.7%).
Conclusions: In severely injured trauma patients, an 8-hour restrictive oxygen strategy did not significantly reduce death or major respiratory complications compared with a liberal strategy. Both approaches produced similar 30-day outcomes. Nevertheless, restricting oxygen may limit atelectasis and could be a reasonable alternative to giving high-flow oxygen to all trauma patients.
Implications for Practice: Clinicians may choose to target approximately 94% SpO₂ in the early trauma phase without compromising major outcomes. This approach potentially avoids the risks of hyperoxia, though no definitive survival benefit was identified. Pragmatic implementation of a conservative oxygen strategy seems feasible in diverse prehospital and hospital settings.
Study Strengths and Limitations: Notable strengths include multicenter design, randomized enrollment in prehospital and in-hospital settings, and blinded outcome assessment. Limitations include postrandomization exclusions of patients with minor injuries, a relatively short intervention period (8 hours), and an overall open-label design. These factors, along with lower-than-expected event rates, may have limited the power to detect differences in mortality. Commentary from https://bit.ly/bottomline_traumox2 also highlights that the median ISS of 14 indicates moderate rather than extremely severe trauma, possibly contributing to the modest event rates.
Future Research: Large-scale studies with extended intervention durations and targeted subgroups (e.g., severe traumatic brain injury) could clarify optimal oxygen thresholds in trauma care. Ongoing trials with larger sample sizes may better capture smaller but clinically meaningful differences in mortality or complications.
RCT: A Single Dose of Ceftriaxone Reduces Early Ventilator-Associated Pneumonia in Acute Brain Injury Patients
17 Dec, 2024 | 12:26h | UTCBackground: Patients with acute brain injury are at increased risk for early ventilator-associated pneumonia (VAP), which can worsen their clinical course. Although short-term antibiotic prophylaxis has been considered, its utility remains uncertain. This study evaluated whether a single early dose of ceftriaxone could reduce the incidence of early VAP in these patients.
Objective: To determine if a single 2-g intravenous dose of ceftriaxone administered within 12 hours of intubation reduces the incidence of early VAP (day 2 to day 7 of mechanical ventilation) in comatose adults (Glasgow Coma Scale ≤12) requiring prolonged mechanical ventilation after acute brain injury.
Methods: This multicenter, randomized, double-blind, placebo-controlled, assessor-masked superiority trial was conducted in nine ICUs across eight French university hospitals. Patients with acute brain injury from trauma, stroke, or subarachnoid hemorrhage who required at least 48 hours of mechanical ventilation were enrolled. Participants received either ceftriaxone 2 g or placebo once, early after endotracheal intubation. All patients received standard VAP prevention measures, but no selective oropharyngeal or digestive decontamination. The primary endpoint was the incidence of early VAP confirmed by blinded assessors using standard clinical, radiological, and microbiological criteria.
Results: Among 319 patients included in the analysis (162 ceftriaxone, 157 placebo), early VAP incidence was significantly lower with ceftriaxone (14%) compared to placebo (32%) (HR 0.60 [95% CI 0.38–0.95]; p=0.030). Patients receiving ceftriaxone had fewer overall VAP episodes, fewer ventilator and antibiotic exposure days, shorter ICU and hospital stays, and reduced 28-day mortality (15% vs 25%). No significant increase in resistant organisms or adverse events attributable to ceftriaxone was observed.
Conclusions: A single early dose of ceftriaxone significantly reduced early VAP risk in acute brain injury patients undergoing mechanical ventilation. This prophylactic approach may improve clinical outcomes without evident safety concerns.
Implications for Practice: Incorporating a single early ceftriaxone dose into VAP prevention protocols for brain-injured patients could mitigate early respiratory infections and potentially enhance clinical outcomes. Nonetheless, clinicians should remain cautious, considering overall antibiotic stewardship and the need for further evidence on long-term microbial resistance patterns.
Study Strengths and Limitations: Strengths include a robust, multicenter, double-blind, placebo-controlled design and blinded adjudication of VAP cases. Limitations include the lack of long-term assessment of the intestinal microbiota and antimicrobial resistance. Further investigation is required to confirm the safety profile regarding microbial ecology and to explore neurological outcomes in greater depth.
Future Research: Future studies should examine the long-term effects of this single-dose approach on resistance patterns, microbial flora, and functional neurological recovery.
RCT: Liberal vs Restrictive Transfusion Yields No Neurologic Outcome Benefit in Aneurysmal Subarachnoid Hemorrhage
16 Dec, 2024 | 11:26h | UTCBackground: Aneurysmal subarachnoid hemorrhage (SAH) is a critical neurologic condition associated with high morbidity and mortality. Anemia is common in this setting and may worsen cerebral oxygenation and outcomes. However, the impact of a liberal transfusion threshold compared with a restrictive approach on long-term neurologic outcomes has been uncertain.
Objective: To determine whether a liberal red blood cell transfusion strategy (transfusion at hemoglobin ≤10 g/dL) improves 12-month neurologic outcomes compared with a restrictive strategy (transfusion at hemoglobin ≤8 g/dL) in patients with aneurysmal SAH and anemia.
Methods: This was a multicenter, pragmatic, open-label, randomized controlled trial conducted at 23 specialized neurocritical care centers. Critically ill adults with a first-ever aneurysmal SAH and hemoglobin ≤10 g/dL within 10 days of admission were randomized to a liberal or restrictive transfusion strategy. The primary outcome was unfavorable neurologic outcome at 12 months, defined as a modified Rankin scale score ≥4. Secondary outcomes included the Functional Independence Measure (FIM), quality of life assessments, and imaging-based outcomes such as vasospasm and cerebral infarction. Outcome assessors were blinded to group allocation.
Results: Among 742 randomized patients, 725 were analyzed for the primary outcome. At 12 months, unfavorable neurologic outcome occurred in 33.5% of patients in the liberal group and 37.7% in the restrictive group (risk ratio 0.88; 95% CI, 0.72–1.09; p=0.22). There were no clinically meaningful differences in secondary outcomes. Mortality at 12 months was similar (approximately 27% in both arms). Radiographic vasospasm was more frequently detected in the restrictive group, though this did not translate into improved functional outcomes in the liberal arm. Adverse events and transfusion reactions were comparable between groups.
Conclusions: In patients with aneurysmal SAH and anemia, a liberal transfusion strategy did not lead to a significantly lower risk of unfavorable neurologic outcome at 12 months compared with a restrictive approach.
Implications for Practice: These findings suggest that routinely maintaining higher hemoglobin levels does not confer substantial long-term functional benefit. Clinicians may consider a more restrictive threshold (≤8 g/dL) to minimize unnecessary transfusions without compromising outcomes. Some skepticism toward adopting a more liberal transfusion policy is warranted given the lack of demonstrable benefit.
Study Strengths and Limitations: Strengths include the randomized, multicenter design, blinded outcome assessment, and a 12-month follow-up. Limitations include potential unmeasured subtle benefits, the inability to blind clinical teams, and the challenge of capturing all aspects of functional recovery with current measurement tools. Further research may clarify if more tailored transfusion strategies can yield modest but meaningful improvements.
Future Research: Future studies should evaluate intermediate hemoglobin thresholds, develop more sensitive measures of functional and cognitive recovery, and consider individualized transfusion strategies based on specific patient factors and biomarkers of cerebral ischemia.
Noninferiority RCT: Omitting Sentinel-Lymph-Node Biopsy Maintains 5-Year Invasive Disease–Free Survival in Early-Stage Breast Cancer
13 Dec, 2024 | 15:15h | UTCBackground: While axillary surgical staging using sentinel-lymph-node biopsy has been a mainstay in early-stage breast cancer management, its necessity in clinically node-negative patients undergoing breast-conserving therapy has been called into question. With tumor biology increasingly guiding treatment decisions, reducing surgical interventions without compromising survival is a major goal.
Objective: To determine whether omitting sentinel-lymph-node biopsy in patients with clinically node-negative, T1 or T2 (≤5 cm) invasive breast cancer undergoing breast-conserving surgery is noninferior to performing sentinel-lymph-node biopsy in terms of 5-year invasive disease–free survival.
Methods: In this prospective, randomized, noninferiority trial, 5502 eligible patients were randomized in a 1:4 ratio to omission of axillary surgery versus sentinel-lymph-node biopsy. The per-protocol population included 4858 patients. All patients received whole-breast irradiation. Invasive disease–free survival, defined as time to any invasive disease event or death, was the primary endpoint. Noninferiority required a 5-year invasive disease–free survival rate ≥85% and a hazard ratio upper limit <1.271.
Results: After a median follow-up of 73.6 months, the 5-year invasive disease–free survival was 91.9% (95% CI, 89.9–93.5) in the omission group and 91.7% (95% CI, 90.8–92.6) in the sentinel-biopsy group (HR, 0.91; 95% CI, 0.73–1.14), meeting noninferiority criteria. Axillary recurrences were slightly higher in the omission group (1.0% vs. 0.3%), though without detrimental effects on overall survival. Patients who omitted axillary surgery experienced lower rates of lymphedema, better arm mobility, and less pain than those undergoing sentinel-lymph-node biopsy.
Conclusions: For appropriately selected patients with clinically node-negative, early-stage breast cancer undergoing breast-conserving surgery, omitting sentinel-lymph-node biopsy did not compromise 5-year invasive disease–free survival and yielded fewer surgical complications and better quality of life outcomes.
Implications for Practice: Omitting axillary staging may be considered in low-risk patients, particularly older individuals with small, hormone receptor-positive, HER2-negative tumors. However, clinicians should balance the lack of nodal information against potential alterations in adjuvant therapy decisions, especially regarding radiotherapy and systemic treatment recommendations.
Study Strengths and Limitations: Strengths include a large patient population, rigorous prospective randomization, and substantial follow-up. Limitations include a predominance of low-risk, small, HR-positive/HER2-negative tumors, potentially limiting generalizability. While omitting sentinel-lymph-node biopsy reduces surgical morbidity, the absence of nodal status may influence adjuvant treatment planning.
Future Research: Further studies should assess the applicability of omission strategies to younger patients, larger tumors, or more aggressive subtypes, and explore whether novel biomarkers or imaging methods can reliably guide treatment decisions without axillary surgery.
RCT: FFR-Guided PCI Plus TAVI is Non-inferior and Superior to SAVR Plus CABG in Patients With Severe Aortic Stenosis and Complex Coronary Disease
8 Dec, 2024 | 21:22h | UTCBackground: Patients with severe aortic stenosis frequently present with concomitant complex coronary artery disease. Current guidelines recommend combined surgical aortic valve replacement (SAVR) and coronary artery bypass grafting (CABG) as first-line therapy. However, transcatheter aortic valve implantation (TAVI) and fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) have emerged as alternative treatments. Assessing their efficacy compared to SAVR plus CABG has been an unmet need.
Objective: To determine whether FFR-guided PCI plus TAVI is non-inferior and, if demonstrated, superior to SAVR plus CABG in patients with severe aortic stenosis and complex or multivessel coronary disease.
Methods: This international, multicenter, prospective, open-label, non-inferiority randomized controlled trial included patients aged ≥70 years with severe aortic stenosis and complex coronary disease who were deemed suitable for either percutaneous or surgical treatment by a Heart Team. Participants were randomized (1:1) to FFR-guided PCI plus TAVI or SAVR plus CABG. The primary endpoint was a composite of all-cause mortality, myocardial infarction, disabling stroke, clinically driven target-vessel revascularization, valve reintervention, and life-threatening or disabling bleeding at 1 year.
Results: Among 172 enrolled patients, 91 were assigned to FFR-guided PCI plus TAVI and 81 to SAVR plus CABG. At 1 year, the primary endpoint occurred in 4% of patients in the PCI/TAVI group versus 23% in the SAVR/CABG group (risk difference –18.5%; 90% CI –27.8 to –9.7; p<0.001 for non-inferiority; p<0.001 for superiority). The difference was driven mainly by lower all-cause mortality (0% vs 10%, p=0.0025) and reduced life-threatening bleeding (2% vs 12%, p=0.010).
Conclusions: In patients with severe aortic stenosis and complex coronary artery disease, FFR-guided PCI plus TAVI was non-inferior and in fact superior to SAVR plus CABG at 1 year, predominantly due to lower mortality and serious bleeding events.
Implications for Practice: These findings suggest that a percutaneous strategy may be a viable and potentially preferable alternative to surgery in selected patients. Nevertheless, given this is the first trial of its kind, cautious interpretation is advised, and routine adoption should await further corroboration.
Study Strengths and Limitations: Strengths include a randomized, multicenter design and standardized endpoint assessment. Limitations involve early trial termination resulting in a smaller sample size and the use of a single TAVI device type, limiting generalizability.
Future Research: Larger trials with longer follow-up, evaluation of other TAVI prostheses, and broader patient populations are needed to validate these findings and determine the optimal patient selection criteria.
RCT: Nivolumab Plus Ipilimumab Extends Progression-Free Survival in MSI-H or dMMR Metastatic Colorectal Cancer
4 Dec, 2024 | 11:51h | UTCBackground: Patients with microsatellite-instability–high (MSI-H) or mismatch-repair–deficient (dMMR) metastatic colorectal cancer typically experience poor outcomes with standard chemotherapy. Previous nonrandomized studies suggested that combining nivolumab with ipilimumab may offer clinical benefits in this population.
Objective: To evaluate the efficacy and safety of nivolumab plus ipilimumab compared with chemotherapy in patients with MSI-H or dMMR metastatic colorectal cancer who had not received prior systemic treatment for metastatic disease.
Methods: In this phase 3, open-label, randomized trial, 303 patients with unresectable or metastatic MSI-H or dMMR colorectal cancer were assigned in a 2:2:1 ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy with or without targeted therapies. The primary endpoint assessed in this interim analysis was progression-free survival (PFS) of nivolumab plus ipilimumab versus chemotherapy in patients with centrally confirmed MSI-H or dMMR status.
Results: At a median follow-up of 31.5 months, nivolumab plus ipilimumab significantly improved PFS compared to chemotherapy (P<0.001). The 24-month PFS was 72% (95% CI, 64–79) with nivolumab plus ipilimumab versus 14% (95% CI, 6–25) with chemotherapy. The restricted mean survival time at 24 months was 10.6 months longer with the combination therapy. Grade 3 or 4 treatment-related adverse events occurred in 23% of patients receiving nivolumab plus ipilimumab and 48% of those receiving chemotherapy.
Conclusions: First-line treatment with nivolumab plus ipilimumab significantly prolonged progression-free survival compared to chemotherapy in patients with MSI-H or dMMR metastatic colorectal cancer, with a lower incidence of high-grade treatment-related adverse events.
Implications for Practice: The combination of nivolumab and ipilimumab may represent a new standard of care for first-line treatment in MSI-H or dMMR metastatic colorectal cancer. However, clinicians should weigh the benefits against potential immune-related adverse events, and long-term survival benefits remain to be fully established.
Study Strengths and Limitations: Strengths include the randomized, phase 3 design and central confirmation of MSI-H or dMMR status. Limitations involve the open-label design, potential bias in patient-reported outcomes, underrepresentation of certain populations, and immature overall survival data.
Future Research: Further studies are needed to compare nivolumab plus ipilimumab directly with nivolumab monotherapy and to assess long-term overall survival benefits and quality of life in diverse patient populations.
RCT: Adjunctive Middle Meningeal Artery Embolization Reduces Reoperation in Subdural Hematoma
24 Nov, 2024 | 13:53h | UTCBackground: Subacute and chronic subdural hematomas are common neurosurgical conditions with a high recurrence rate after surgical evacuation, affecting 8% to 20% of patients. Middle meningeal artery embolization (MMAE) is a minimally invasive procedure targeting the blood supply to these membranes. Preliminary studies suggest that adjunctive MMAE may reduce hematoma recurrence, but its impact on reoperation risk remains unclear.
Objective: To determine whether adjunctive MMAE reduces the risk of hematoma recurrence or progression leading to repeat surgery within 90 days compared to surgery alone in patients with symptomatic subacute or chronic subdural hematoma.
Methods: In this prospective, multicenter, randomized controlled trial, 400 patients aged 18 to 90 years with symptomatic subacute or chronic subdural hematoma requiring surgical evacuation were randomly assigned to receive either MMAE plus surgery (n=197) or surgery alone (n=203). The primary endpoint was hematoma recurrence or progression leading to repeat surgery within 90 days after the index treatment. The secondary endpoint was deterioration of neurologic function at 90 days, assessed using the modified Rankin Scale.
Results: Hematoma recurrence or progression requiring repeat surgery occurred in 8 patients (4.1%) in the MMAE plus surgery group versus 23 patients (11.3%) in the surgery-alone group (relative risk, 0.36; 95% CI, 0.11 to 0.80; P=0.008). Functional deterioration at 90 days was similar between groups (11.9% vs. 9.8%; risk difference, 2.1 percentage points; 95% CI, −4.8 to 8.9). Mortality at 90 days was 5.1% in the MMAE group and 3.0% in the control group. Serious adverse events related to the embolization occurred in 4 patients (2.0%), including disabling stroke in 2 patients.
Conclusions: Adjunctive MMAE combined with surgery significantly reduced the risk of hematoma recurrence or progression requiring reoperation within 90 days compared to surgery alone. However, there was no significant difference in neurologic functional deterioration, and the procedure was associated with procedural risks.
Implications for Practice: MMAE may be considered as an adjunct to surgical evacuation in patients with subacute or chronic subdural hematoma to reduce reoperation risk. Clinicians should carefully weigh the potential benefits against the risks of procedural complications, including stroke.
Study Strengths and Limitations: Strengths include the randomized controlled design and multicenter approach, enhancing generalizability. Limitations involve the open-label design, introducing potential bias since the primary endpoint was based on surgeon judgment. A substantial loss to follow-up (13.2%) could affect results, and the study was not powered to detect differences in mortality or serious adverse events.
Future Research: Further studies with larger sample sizes are needed to fully evaluate the safety and efficacy of MMAE, including long-term outcomes. Research should focus on optimizing patient selection and assessing the procedure’s impact on mortality and serious adverse events.
RCT: Twice-Yearly Lenacapavir Reduces HIV Incidence in Men and Gender-Diverse Persons Background
28 Nov, 2024 | 12:38h | UTCBackground: Although preexposure prophylaxis (PrEP) effectively reduces HIV transmission, adherence to daily oral regimens is suboptimal among high-risk populations. Lenacapavir, a long-acting HIV-1 capsid inhibitor administered subcutaneously every six months, has shown efficacy in cisgender women, but its efficacy in men and gender-diverse individuals remains unclear.
Objective: To evaluate the safety and efficacy of twice-yearly subcutaneous lenacapavir compared to background HIV incidence and daily oral emtricitabine–tenofovir disoproxil fumarate (F/TDF) in preventing HIV infection among men and gender-diverse persons.
Methods: In this phase 3, double-blind, randomized trial, 3,271 HIV-negative participants were assigned in a 2:1 ratio to receive subcutaneous lenacapavir every 26 weeks or daily oral F/TDF, with matching placebos. Participants were cisgender men, transgender women and men, and gender-nonbinary persons aged 16 or older who have sex with male-assigned partners. The primary endpoint compared HIV incidence in the lenacapavir group to background incidence; secondary analysis compared lenacapavir to F/TDF.
Results: In the modified intention-to-treat analysis (n=3,265), HIV infections occurred in 2 participants in the lenacapavir group (0.10 per 100 person-years) and 9 in the F/TDF group (0.93 per 100 person-years). The background HIV incidence was 2.37 per 100 person-years. Lenacapavir significantly reduced HIV incidence compared to background (incidence rate ratio [IRR], 0.04; 95% CI, 0.01–0.18; P<0.001) and F/TDF (IRR, 0.11; 95% CI, 0.02–0.51; P=0.002). No significant safety concerns emerged. Injection-site reactions led to discontinuation in 1.2% of lenacapavir recipients and 0.3% of F/TDF recipients.
Conclusions: Twice-yearly subcutaneous lenacapavir significantly reduced HIV incidence compared to both the background incidence and daily oral F/TDF among men and gender-diverse persons. These findings support lenacapavir as an effective PrEP option in this population.
Implications for Practice: The introduction of a long-acting, twice-yearly injectable PrEP option like lenacapavir could improve adherence and uptake among populations challenged by daily oral regimens.
Study Strengths and Limitations: Strengths include a large, diverse participant population with significant representation of transgender and gender-nonbinary persons, and the use of an active comparator. The novel counterfactual design estimating background HIV incidence avoided ethical issues of placebo controls but may have limitations in accuracy. Limitations include a relatively short follow-up and potential impact of injection-site reactions on adherence. The emergence of resistance mutations in participants who acquired HIV while on lenacapavir is a concern needing further investigation.
Future Research: Further studies should assess the long-term safety, efficacy, and resistance patterns associated with lenacapavir use. Research into optimizing injection techniques to minimize injection-site reactions and exploring lenacapavir’s applicability in other at-risk populations is recommended.
Phase 2 RCT: Zerlasiran Lowers Lipoprotein(a) Levels by Over 80% in Patients With ASCVD
24 Nov, 2024 | 20:18h | UTCBackground: Elevated lipoprotein(a) [Lp(a)] is a genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. Traditional lipid-lowering therapies, including statins and lifestyle modifications, do not effectively reduce Lp(a) levels. Small-interfering RNA (siRNA) therapies targeting hepatic production of apolipoprotein(a) offer a potential approach to lowering Lp(a) concentrations.
Objective: To evaluate the efficacy and safety of zerlasiran, an siRNA targeting apolipoprotein(a) synthesis, in reducing serum Lp(a) concentrations in patients with ASCVD.
Methods: In this randomized, double-blind, placebo-controlled phase 2 trial, 178 adults with stable ASCVD and elevated Lp(a) levels (≥125 nmol/L) were enrolled across 26 sites in Europe and South Africa. Participants were randomized to receive subcutaneous zerlasiran at doses of 450 mg every 24 weeks (n=45), 300 mg every 16 weeks (n=42), or 300 mg every 24 weeks (n=44), or matching placebo every 16 weeks (n=23) or every 24 weeks (n=24). The primary outcome was the time-averaged percent change in Lp(a) concentration from baseline to week 36.
Results: Zerlasiran significantly reduced Lp(a) levels compared to placebo. The placebo-adjusted time-averaged percent reductions were −85.6% (95% CI, −90.9% to −80.3%) for 450 mg every 24 weeks, −82.8% (95% CI, −88.2% to −77.4%) for 300 mg every 16 weeks, and −81.3% (95% CI, −86.7% to −76.0%) for 300 mg every 24 weeks. Median percent reductions at week 36 exceeded 90% in all zerlasiran groups. The most common adverse events were mild injection site reactions, occurring in up to 7.1% of participants. No serious adverse events were attributed to the study drug.
Conclusions: Zerlasiran was well-tolerated and produced substantial reductions in Lp(a) levels over 36 weeks in patients with ASCVD.
Implications for Practice: If validated in larger, long-term studies that assess cardiovascular outcomes, zerlasiran may offer a novel treatment for patients with elevated Lp(a), addressing a significant unmet need in cardiovascular risk management. Clinicians should, however, exercise caution until the impact on hard endpoints such as myocardial infarction and stroke, as well as long-term safety, are confirmed.
Study Strengths and Limitations: Strengths include the randomized, double-blind design and significant Lp(a) reductions observed. Limitations involve the predominantly White, male study population, limiting generalizability. The study did not assess clinical endpoints like cardiovascular events, so the impact on actual cardiovascular risk remains unknown. Additionally, the moderate sample size and duration may not detect rare adverse events or long-term effects, necessitating further investigation.
Future Research: Larger, long-term phase 3 trials are needed to confirm these findings, assess the impact on cardiovascular events, and evaluate efficacy and safety in more diverse populations.