Daily Archives: September 14, 2024
RCT: Tenecteplase Noninferior to Alteplase in Acute Ischemic Stroke
14 Sep, 2024 | 20:03h | UTCBackground: Acute ischemic stroke (AIS) is a leading cause of morbidity and mortality globally, with a particularly high burden in China. Intravenous thrombolysis with alteplase, administered within 4.5 hours of symptom onset, is the current standard of care. Tenecteplase, a genetically modified variant of alteplase with greater fibrin specificity and a longer half-life, allows for single-bolus administration, potentially simplifying and expediting treatment. Prior studies suggest tenecteplase may be as effective as alteplase in AIS, but data specific to Chinese patients are limited.
Objective: To determine whether tenecteplase is noninferior to alteplase in achieving excellent functional outcomes in Chinese patients with AIS treated within 4.5 hours of symptom onset.
Methods:
- Design: Multicenter, randomized, open-label, blinded-endpoint, noninferiority trial conducted at 55 centers in China between July 2021 and July 2023.
- Participants: 1,489 Chinese adults aged ≥18 years with AIS, National Institutes of Health Stroke Scale (NIHSS) scores of 1–25, measurable neurological deficits, and symptom onset within 4.5 hours.
- Interventions: Patients were randomized 1:1 to receive either:
- Tenecteplase: 0.25 mg/kg intravenous single bolus (maximum 25 mg).
- Alteplase: 0.9 mg/kg intravenous (maximum 90 mg), with 10% as an initial bolus and the remainder infused over 1 hour.
- Outcomes:
- Primary Outcome: Proportion of patients achieving a modified Rankin Scale (mRS) score of 0 or 1 at 90 days (indicating no symptoms or no significant disability).
- Secondary Outcomes: Major neurological improvement at 24 hours, mRS scores of 0–2 at 90 days, change in NIHSS score at 90 days, Barthel Index score ≥95 at 90 days.
- Safety Outcomes: Symptomatic intracerebral hemorrhage (sICH) per ECASS III definition and all-cause mortality at 90 days.
Results:
- Participants: 1,465 patients were included in the full analysis set (732 tenecteplase; 733 alteplase). Median age was 66 years, median NIHSS score was 6, and 30.4% were female.
- Primary Outcome:
- 72.7% in the tenecteplase group achieved mRS 0 or 1 at 90 days compared to 70.3% in the alteplase group.
- Adjusted risk ratio (RR): 1.03 (95% CI, 0.97–1.09), meeting the predefined noninferiority margin (RR ≥0.937).
- Secondary Outcomes:
- Major Neurological Improvement at 24 Hours: 48.0% (tenecteplase) vs. 45.0% (alteplase); RR, 1.07 (95% CI, 0.96–1.19).
- mRS 0–2 at 90 Days: 80.9% (tenecteplase) vs. 79.9% (alteplase); RR, 1.01 (95% CI, 0.96–1.06).
- Change in NIHSS Score at 90 Days: Mean change of –3.70 (tenecteplase) vs. –3.02 (alteplase); adjusted difference, –0.45 (95% CI, –1.40 to 0.50).
- Barthel Index ≥95 at 90 Days: 75.7% (tenecteplase) vs. 73.9% (alteplase); RR, 1.02 (95% CI, 0.96–1.08).
- Safety Outcomes:
- sICH: Occurred in 1.2% of patients in both groups; RR, 1.01 (95% CI, 0.37–2.70).
- 90-Day Mortality: 4.6% (tenecteplase) vs. 5.8% (alteplase); RR, 0.80 (95% CI, 0.51–1.23).
Conclusions: Tenecteplase was noninferior to alteplase in achieving excellent functional outcomes (mRS 0 or 1) at 90 days in Chinese patients with AIS treated within 4.5 hours of symptom onset. Safety profiles, including rates of sICH and mortality, were similar between the two treatments. These findings support tenecteplase as a suitable alternative to alteplase for intravenous thrombolysis in AIS.
Implications for Practice:
- Administration Advantage: Tenecteplase’s single-bolus administration could streamline treatment workflows and reduce door-to-needle times.
- Efficacy and Safety: Comparable efficacy and safety profiles suggest tenecteplase can be confidently used in place of alteplase.
- Patient Selection: Results are applicable to a broad range of AIS patients, including those with varying stroke severities and ages.
Study Strengths and Limitations:
- Strengths: Large sample size, multicenter design, and inclusion of a real-world patient population enhance the generalizability of findings.
- Limitations: Open-label design may introduce bias despite blinded endpoint assessments. The relatively low proportion of patients undergoing thrombectomy limits conclusions about combined therapy.
Future Research:
- Further studies could explore the effectiveness of tenecteplase in specific subgroups, such as patients with large vessel occlusions or those requiring endovascular interventions.
- Investigations into long-term outcomes beyond 90 days and real-world implementation strategies may provide additional insights.
RCT: Liraglutide for Children Aged 6 to <12 Years with Obesity
14 Sep, 2024 | 19:40h | UTCSummary:
A recent phase 3a randomized, double-blind, placebo-controlled trial published in the New England Journal of Medicine examined the efficacy and safety of liraglutide in children aged 6 to less than 12 years with obesity. Currently, no medications are approved for treating nonmonogenic, nonsyndromic obesity in this age group, making this study particularly noteworthy.
Methods:
- Participants: 82 children with obesity (BMI ≥95th percentile for age and sex).
- Design: Participants were randomized in a 2:1 ratio to receive once-daily subcutaneous liraglutide (up to 3.0 mg) or placebo, alongside lifestyle interventions, over a 56-week treatment period, followed by a 26-week follow-up.
- Primary Endpoint: Percentage change in BMI from baseline to week 56.
- Secondary Endpoints: Percentage change in body weight and the proportion achieving a ≥5% reduction in BMI.
Results:
- BMI Reduction: At week 56, the liraglutide group experienced a mean BMI reduction of –5.8%, compared to a +1.6% increase in the placebo group. The estimated difference was –7.4 percentage points (95% CI, –11.6 to –3.2; P<0.001).
- Body Weight: Mean body weight increased by 1.6% in the liraglutide group versus 10.0% in the placebo group, a difference of –8.4 percentage points (95% CI, –13.4 to –3.3; P=0.001).
- BMI Reduction ≥5%: Achieved by 46% of participants in the liraglutide group versus 9% in the placebo group (adjusted odds ratio, 6.3; 95% CI, 1.4 to 28.8; P=0.02).
- Adverse Events: Reported in 89% of the liraglutide group and 88% of the placebo group. Gastrointestinal events were more common with liraglutide (80% vs. 54%).
Discussion:
While the study suggests that liraglutide can lead to a statistically significant reduction in BMI among children aged 6 to less than 12 years with obesity, several considerations should temper our enthusiasm:
- Sample Size and Diversity: The trial included only 82 participants, with a predominantly White population (72%), which may limit the generalizability of the findings to broader, more diverse populations.
- Duration and Long-Term Effects: The study spanned 56 weeks, with a 26-week follow-up. The long-term efficacy and safety of liraglutide in this age group remain uncertain, particularly concerning growth, development, and potential rebound weight gain after discontinuation.
- Clinical Significance: Although the reduction in BMI was statistically significant, the clinical significance—especially regarding long-term health outcomes and obesity-related comorbidities—is less clear. Obesity is a chronic and relapsing condition, and a modest reduction in BMI may not translate into substantial health benefits without sustained intervention.
- Adverse Events: The high incidence of gastrointestinal adverse events raises questions about the tolerability of liraglutide in young children. Managing these side effects in a pediatric population can be challenging and may affect adherence.
- Lack of Consensus on BMI Reduction: There’s no international consensus on what constitutes a clinically meaningful BMI reduction in children, complicating the interpretation of the results.
Conclusion:
This trial provides preliminary evidence that liraglutide, combined with lifestyle interventions, may help reduce BMI in children under 12 with obesity. However, given the limitations—including small sample size, short duration, and safety concerns—it’s prudent to approach these findings with cautious optimism. More extensive studies with longer follow-up periods and more diverse populations are necessary to fully assess the long-term efficacy and safety of liraglutide in this vulnerable age group.
Takeaway:
While liraglutide shows promise as an adjunct therapy for pediatric obesity, it’s essential to weigh the benefits against the potential risks and uncertainties. Clinicians should continue to prioritize established lifestyle interventions and consider pharmacotherapy on a case-by-case basis, pending further evidence.
RCT: PCI Reduces Major Adverse Cardiac Events in Patients Undergoing TAVI with Significant Coronary Artery Disease
14 Sep, 2024 | 19:09h | UTCBackground:
Severe aortic stenosis and coronary artery disease (CAD) frequently coexist, particularly in the elderly population. Approximately 50% of patients undergoing transcatheter aortic valve implantation (TAVI) have concurrent CAD. The optimal management of significant coronary lesions in patients undergoing TAVI remains uncertain, with guidelines providing no clear recommendations. Understanding whether percutaneous coronary intervention (PCI) improves outcomes in this setting is crucial for guiding clinical practice.
Objective:
To evaluate whether routine PCI of physiologically significant coronary lesions improves clinical outcomes compared to conservative management in patients with stable CAD undergoing TAVI.
Methods:
- Design: International, multicenter, open-label, randomized controlled trial (NOTION-3).
- Participants: 455 patients with severe symptomatic aortic stenosis scheduled for TAVI and at least one significant coronary lesion (defined as fractional flow reserve [FFR] ≤0.80 or diameter stenosis ≥90%).
- Interventions:
- PCI Group (n=227): Underwent PCI of all eligible lesions followed by TAVI.
- Conservative Treatment Group (n=228): Received TAVI without prior PCI.
- Primary Endpoint: Major adverse cardiac events (MACE), a composite of death from any cause, myocardial infarction (MI), or urgent revascularization.
- Secondary Endpoints: Included individual components of the primary endpoint, bleeding events, stroke, hospital admissions for heart failure, and procedural complications.
- Follow-Up: Median of 2 years (interquartile range, 1 to 4 years).
Results:
- Baseline Characteristics: Median age was 82 years; 67% were men; median Society of Thoracic Surgeons–Procedural Risk of Mortality (STS-PROM) score was 3%.
- Primary Endpoint (MACE):
- Occurred in 26% of patients in the PCI group versus 36% in the conservative group.
- Hazard Ratio (HR): 0.71 (95% Confidence Interval [CI], 0.51 to 0.99; P=0.04), indicating a 29% relative risk reduction with PCI.
- Components of MACE:
- Myocardial Infarction:
- Lower incidence in the PCI group.
- Urgent Revascularization:
- Reduced need in the PCI group.
- Myocardial Infarction:
- All-Cause Mortality:
- No significant difference between groups.
- Bleeding Events:
- Higher in the PCI group (28% vs. 20%; HR, 1.51; 95% CI, 1.03 to 2.22).
- Bleeding assessed according to Valve Academic Research Consortium–2 criteria.
- Procedural Complications:
- PCI-related complications occurred in 3% of patients in the PCI group.
- Safety Endpoints:
- Similar rates of stroke and stent thrombosis between groups.
- Acute kidney injury was less frequent in the PCI group (5% vs. 11%; HR, 0.45; 95% CI, 0.23 to 0.89).
Conclusions:
In patients with stable CAD and severe symptomatic aortic stenosis undergoing TAVI, performing PCI on significant coronary lesions resulted in a statistically significant reduction in MACE over a median follow-up of 2 years compared to conservative management. The benefit was primarily due to reductions in myocardial infarction and urgent revascularization rates. However, this advantage was accompanied by an increased risk of bleeding events.
Clinical Implications:
- Patient Selection: PCI should be considered in patients with physiologically significant coronary lesions (FFR ≤0.80 or diameter stenosis ≥90%) undergoing TAVI.
- Risk–Benefit Analysis: Clinicians should balance the reduction in MACE against the increased bleeding risk when deciding on PCI.
- Treatment Strategy: The findings support a strategy of routine revascularization in this patient population to improve cardiovascular outcomes.
- Future Considerations: Further research is needed to determine the optimal timing of PCI relative to TAVI and to identify which patient subgroups may derive the most benefit.
Recommendations:
- Guideline Update: The results may inform future guidelines to provide clearer recommendations on managing CAD in patients undergoing TAVI.
- Individualized Care: Decisions regarding PCI should be individualized, considering patient comorbidities, anatomical complexity, and bleeding risk.
- Antithrombotic Therapy: Attention to antiplatelet and anticoagulation strategies is important to mitigate bleeding risks.
Study Limitations:
- Exclusion of patients with recent acute coronary syndromes and left main coronary artery disease limits the generalizability.
- Changes in antithrombotic regimens over the study period reflect evolving clinical practice but may affect outcomes.
- Majority of patients had low to intermediate SYNTAX scores, so results may not apply to those with more complex CAD.
Final Note:
The NOTION-3 trial provides valuable evidence supporting the use of PCI in patients with significant CAD undergoing TAVI, emphasizing the importance of comprehensive cardiovascular care in this high-risk population.
RCT: Comparing Perioperative Chemotherapy Alone to Perioperative Chemotherapy Plus Preoperative Chemoradiotherapy in Resectable Gastric Cancer
14 Sep, 2024 | 18:23h | UTCBackground:
In the management of resectable gastric cancer, perioperative chemotherapy—chemotherapy administered both before (neoadjuvant) and after (adjuvant) surgery—is the standard of care in many Western countries. This approach is based on trials like MAGIC and FLOT4-AIO, which demonstrated improved survival with perioperative chemotherapy compared to surgery alone.
Preoperative chemoradiotherapy (the combination of chemotherapy and radiotherapy before surgery) has shown benefits in other gastrointestinal cancers, such as esophageal cancer, by downstaging tumors and potentially improving surgical outcomes. However, its efficacy in gastric cancer, especially when added to perioperative chemotherapy, has not been well-established.
Objective:
To determine whether adding preoperative chemoradiotherapy to standard perioperative chemotherapy improves overall survival compared to perioperative chemotherapy alone in patients with resectable gastric and gastroesophageal junction adenocarcinoma.
Methods:
- Study Design: International, phase 3, randomized controlled trial (TOPGEAR).
- Participants: 574 patients with resectable adenocarcinoma of the stomach or gastroesophageal junction (Siewert type II or III), clinical stage T3 or T4, and considered suitable for curative surgery.
- Interventions:
1. Perioperative Chemotherapy Group (Control Group):
- Definition of Perioperative Chemotherapy: Chemotherapy administered both before (preoperative/neoadjuvant) and after (postoperative/adjuvant) surgery.
- Chemotherapy Regimens:
- Before 2017: Patients received three cycles before surgery and three cycles after surgery of either:
- ECF: Epirubicin, Cisplatin, and continuous-infusion Fluorouracil.
- ECX: Epirubicin, Cisplatin, and Capecitabine (an oral prodrug of fluorouracil).
- After 2017 Amendment: Patients received four cycles before surgery and four cycles after surgery of:
- FLOT: Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel.
- Before 2017: Patients received three cycles before surgery and three cycles after surgery of either:
2. Perioperative Chemotherapy Plus Preoperative Chemoradiotherapy Group (Experimental Group):
- Modifications to Chemotherapy:
- Received one less cycle of preoperative chemotherapy compared to the control group to accommodate the addition of radiotherapy.
- Postoperative chemotherapy was the same as in the control group.
- Preoperative Chemoradiotherapy:
- Chemoradiotherapy Definition: Concurrent administration of chemotherapy and radiotherapy before surgery.
- Radiotherapy Regimen:
- Total dose of 45 Gy, delivered in 25 fractions over 5 weeks (1.8 Gy per fraction, 5 days per week).
- Target Area: Entire stomach, any perigastric tumor extension, and regional lymph nodes.
- Concurrent Chemotherapy During Radiotherapy:
- Continuous infusion of Fluorouracil (200 mg/m² per day) 7 days a week during radiotherapy.
- Alternatively, Capecitabine (825 mg/m² twice daily on days 1–5 of each radiotherapy week) could be used.
- Surgical Procedure:
- Surgery was performed 4–6 weeks after completion of preoperative therapy.
- Recommended surgery included total gastrectomy, subtotal distal gastrectomy, or esophagogastrectomy with D2 lymphadenectomy (removal of additional lymph node stations beyond the immediate perigastric nodes).
Endpoints:
- Primary Endpoint: Overall survival (time from randomization to death from any cause).
- Secondary Endpoints: Progression-free survival, pathological complete response rate (no residual tumor in the resected specimen), treatment-related toxic effects, and quality of life.
Results:
- Pathological Findings:
- Pathological Complete Response Rate:
- Higher in the experimental group (preoperative chemoradiotherapy) at 17% compared to 8% in the control group.
- Tumor Downstaging:
- More patients in the experimental group had their tumors downstaged to a lower T category and had fewer involved lymph nodes.
- Pathological Complete Response Rate:
- Survival Outcomes:
- Overall Survival:
- Median Overall Survival:
- Experimental Group: 46 months.
- Control Group: 49 months.
- Hazard Ratio for Death: 1.05 (95% CI, 0.83–1.31), indicating no significant difference between the groups.
- Median Overall Survival:
- Progression-Free Survival:
- Median progression-free survival was similar between the groups (31 months vs. 32 months).
- Overall Survival:
- Treatment Adherence:
- Preoperative Therapy Completion:
- High completion rates in both groups for preoperative chemotherapy.
- Slightly lower in the experimental group due to the addition of radiotherapy.
- Postoperative Chemotherapy Completion:
- Lower completion rates overall, with fewer patients in the experimental group completing postoperative chemotherapy (48% vs. 59%).
- Preoperative Therapy Completion:
- Adverse Events:
- Similar rates of grade 3 or higher toxic effects in both groups.
- No significant differences in surgical complications or postoperative mortality.
Conclusion:
Adding preoperative chemoradiotherapy to standard perioperative chemotherapy did not improve overall survival or progression-free survival in patients with resectable gastric and gastroesophageal junction adenocarcinoma, despite achieving higher pathological complete response rates and increased tumor downstaging. These findings suggest that the routine addition of preoperative chemoradiotherapy to perioperative chemotherapy does not confer additional survival benefits and should not change the current standard of care.
Clinical Implications:
- Standard Treatment Remains Perioperative Chemotherapy:
- Perioperative chemotherapy alone continues to be the standard approach for resectable gastric cancer.
- Regimens like FLOT are preferred due to their demonstrated efficacy.
- Role of Radiotherapy:
- Routine use of preoperative radiotherapy in addition to chemotherapy is not supported by this trial’s findings.
- Radiotherapy may still have a role in specific clinical scenarios, but not as a standard addition to perioperative chemotherapy.
- Future Directions:
- Further research may focus on identifying subgroups of patients who might benefit from chemoradiotherapy.
- Biomarker-driven approaches and personalized treatment strategies could optimize outcomes.