Pharmacology/Pharmaceutical Industry
Meta-Analysis: Oral Anticoagulant Monotherapy Reduced Bleeding Without Increasing Ischemic Events in AF and Stable CAD
9 Oct, 2024 | 11:13h | UTCBackground: Atrial fibrillation (AF) patients with stable coronary artery disease (CAD) often require both oral anticoagulants (OACs) for stroke prevention and antiplatelet therapy for CAD management. However, dual antithrombotic therapy (DAT) increases bleeding risk. The optimal antithrombotic regimen in this population remains unclear.
Objective: To evaluate whether OAC monotherapy reduces major bleeding without increasing ischemic events compared to DAT in patients with AF and stable CAD.
Methods: This meta-analysis followed PRISMA guidelines, pooling data from three randomized controlled trials (RCTs) involving 3,945 patients with AF and stable CAD. The trials included used various OACs (rivaroxaban, edoxaban, or warfarin/DOAC) and compared them with DAT. The primary outcomes were all-cause death, cardiovascular death, and major bleeding. Secondary outcomes included stroke (ischemic and hemorrhagic) and myocardial infarction (MI).
Results: OAC monotherapy significantly reduced the risk of major bleeding compared to DAT (3.4% vs 5.8%; RR: 0.55; 95% CI: 0.32–0.95; p=0.03). There were no significant differences between groups in all-cause death (4.2% vs 5.4%; RR: 0.85; 95% CI: 0.49–1.48; p=0.57), cardiovascular death (2.4% vs 3.0%; RR: 0.84; 95% CI: 0.50–1.41; p=0.50), any stroke event (2.2% vs 3.1%; RR: 0.74; 95% CI: 0.46–1.18; p=0.21), or myocardial infarction (RR: 1.57; 95% CI: 0.79–3.12; p=0.20).
Conclusions: In patients with AF and stable CAD, OAC monotherapy significantly reduces major bleeding risk compared to DAT without increasing the risk of ischemic events or mortality.
Implications for Practice: OAC monotherapy may be a preferable antithrombotic strategy in patients with AF and stable CAD, balancing effective thromboembolic protection with a lower bleeding risk. Clinicians should consider OAC monotherapy to simplify antithrombotic regimens and reduce bleeding complications, especially beyond one year after coronary events or interventions.
Study Strengths and Limitations: Strengths include the inclusion of recent large-scale RCTs and the focus on a clinically relevant patient population. Limitations involve reliance on study-level data, limited number of trials, and potential heterogeneity among included studies. The duration of DAT was not consistently available, and individual patient data meta-analysis may provide more detailed insights.
Future Research: Additional large-scale RCTs and individual patient data meta-analyses are needed to confirm these findings and to determine the optimal duration and type of antithrombotic therapy in patients with AF and stable CAD.
Umbrella Review: 5-Day Antibiotic Courses Effective for Non-ICU Community-Acquired Pneumonia or Exacerbations of COPD
6 Oct, 2024 | 17:12h | UTCBackground: Respiratory tract infections (RTIs) significantly contribute to global disease burden and antibiotic usage. Optimizing antibiotic treatment duration is crucial for antimicrobial stewardship to minimize resistance. Despite evidence supporting shorter antibiotic courses for RTIs, prolonged treatment durations persist in clinical practice.
Objective: To evaluate the current evidence base for optimal antibiotic treatment durations in RTIs and determine whether shorter courses are supported.
Methods: An umbrella review was conducted by searching Ovid MEDLINE, Embase, and Web of Science up to May 1, 2024, without language restrictions. Systematic reviews comparing antibiotic treatment durations for community-acquired pneumonia (CAP), acute exacerbations of chronic obstructive pulmonary disease (AECOPD), hospital-acquired pneumonia (HAP), acute sinusitis, and streptococcal pharyngitis, tonsillitis, or pharyngotonsillitis in adults were included. Pediatric-focused reviews were excluded. Quality assessments utilized the AMSTAR 2 tool for reviews and the Cochrane risk-of-bias tool (version 1) for randomized controlled trials (RCTs). The GRADE approach determined the overall quality of evidence.
Results: Thirty systematic reviews were included, generally of low to critically low quality. For non-ICU CAP (14 reviews), moderate-quality evidence supports a 5-day antibiotic course, with insufficient data for shorter durations. In AECOPD (eight reviews), a 5-day treatment was non-inferior to longer courses regarding clinical and microbiological cure, with similar or fewer adverse events. Evidence for non-ventilator-associated HAP is lacking. In acute sinusitis, shorter regimens appear effective, but further research is needed for patients requiring antibiotics. For pharyngotonsillitis (eight reviews), evidence supports short-course cephalosporin therapy but not short-course penicillin when dosed three times daily.
Conclusions: Evidence supports a 5-day antibiotic treatment duration for non-ICU CAP and AECOPD in clinically improving patients. Implementing this evidence in practice is essential. High-quality RCTs are needed to assess shorter durations for CAP and AECOPD, establish optimal durations for HAP and acute sinusitis, and evaluate short-course penicillin with optimal dosing in pharyngotonsillitis.
Implications for Practice: Clinicians should adopt 5-day antibiotic courses for non-ICU CAP and AECOPD in patients showing clinical improvement, aligning with antimicrobial stewardship objectives to reduce unnecessary antibiotic exposure and resistance development.
Study Strengths and Limitations: Strengths include a comprehensive search and assessment of systematic reviews and meta-analyses. Limitations involve the generally low quality of included reviews and RCTs, with many studies exhibiting unclear or high risk of bias. Heterogeneity in definitions of short-course treatment and variability in patient populations and settings were also noted.
Future Research: High-quality RCTs are required to investigate antibiotic durations shorter than 5 days for CAP and AECOPD, determine optimal treatment lengths for HAP and acute sinusitis, and assess short-course penicillin therapy with optimal dosing schedules in pharyngotonsillitis.
Summary of the review “Neuroleptic Malignant Syndrome”
6 Oct, 2024 | 16:20h | UTCIn a comprehensive review published in the New England Journal of Medicine, Wijdicks and Ropper discuss neuroleptic malignant syndrome (NMS), a rare but potentially fatal complication of antipsychotic therapy characterized by fever, muscle rigidity, and autonomic dysfunction. Given the widespread use of dopamine-blocking agents across various medical specialties, it is crucial for practicing physicians to recognize and manage this syndrome promptly to improve patient outcomes.
Key Aspects Influencing Patient Care:
- Epidemiology and Risk Factors:
- NMS occurs in approximately 0.02 to 3% of patients exposed to dopamine-blocking agents.
- Risk factors include dehydration, high doses of antipsychotics, rapid dose escalation, intramuscular administration, and prior episodes of NMS.
- Both first-generation (typical) and second-generation (atypical) antipsychotics can cause NMS, though it may be less severe with atypical agents.
- Clinical Presentation:
- Hyperthermia: Elevated temperatures often exceeding 40°C.
- Muscle Rigidity: Lead-pipe rigidity leading to rhabdomyolysis and elevated creatine kinase levels.
- Autonomic Dysfunction: Tachycardia, fluctuating blood pressure, diaphoresis.
- Altered Mental Status: Ranges from agitation to stupor or catatonia.
- Laboratory Findings: Leukocytosis, electrolyte imbalances, and signs of renal impairment.
- Diagnosis:
- Based on clinical criteria including recent exposure to dopamine antagonists and presence of key symptoms.
- Important to differentiate from serotonin syndrome, malignant hyperthermia, heat stroke, and severe catatonia.
- Management:
- Immediate Discontinuation of the offending agent.
- Supportive Care in ICU:
- Stabilize vital signs and manage autonomic instability.
- Aggressive hydration to prevent renal failure from rhabdomyolysis.
- Cooling measures for hyperthermia.
- Pharmacologic Interventions:
- Dantrolene: Reduces muscle rigidity and hyperthermia.
- Dopamine Agonists: Bromocriptine or amantadine may reverse dopamine blockade.
- Benzodiazepines: Lorazepam for sedation and muscle relaxation.
- Monitoring for Complications:
- Watch for respiratory failure, renal dysfunction, electrolyte disturbances, and cardiac arrhythmias.
- Electroconvulsive Therapy (ECT):
- Considered in refractory cases unresponsive to medical management.
- Outcome and Prognosis:
- Recovery typically occurs within 7 to 11 days with appropriate treatment.
- Mortality rates have decreased but can reach up to 15% within one year due to complications.
- Rechallenge with Antipsychotics:
- If necessary, reintroduce antipsychotics cautiously after full recovery, using low doses and slow titration.
- Prefer atypical agents and monitor closely for recurrence.
Clinical Implications:
- Early Recognition: Timely identification of NMS is critical for initiating life-saving interventions.
- Interdisciplinary Approach: Collaboration among psychiatrists, intensivists, neurologists, and other specialists enhances patient care.
- Education and Prevention:
- Educate healthcare providers about the signs and risk factors of NMS.
- Monitor patients on antipsychotics closely, especially during dose changes or when using high-potency agents.
Guideline Summary: Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors for Adults with Chronic Kidney Disease
4 Oct, 2024 | 11:14h | UTCIntroduction
A recent clinical practice guideline published in The BMJ titled “Sodium-glucose cotransporter-2 (SGLT-2) inhibitors for adults with chronic kidney disease” provides evidence-based recommendations on the use of SGLT-2 inhibitors in adults with chronic kidney disease (CKD), regardless of diabetes status. The guideline aims to assist clinicians in making informed decisions to improve patient outcomes in CKD management.
Key Recommendations and Patient Care Implications
- Risk Stratification
- Assessment: Patients with CKD should be stratified based on their risk of disease progression and complications using estimated glomerular filtration rate (eGFR) and albuminuria levels, following the Kidney Disease Improving Global Outcomes (KDIGO) classification.
- Clinical Implication: Proper risk stratification guides the intensity of treatment and monitoring.
- Use of SGLT-2 Inhibitors
- Low to Moderate Risk Patients: For adults at low or moderate risk, the guideline suggests administering SGLT-2 inhibitors (weak recommendation in favor).
- Patient Care Impact: Clinicians should discuss potential benefits and risks with patients, considering individual preferences.
- High to Very High Risk Patients: For adults at high or very high risk, a strong recommendation is made to administer SGLT-2 inhibitors.
- Patient Care Impact: Clinicians should prioritize initiating SGLT-2 inhibitors in these patients to reduce risks of mortality and progression to kidney failure.
- Low to Moderate Risk Patients: For adults at low or moderate risk, the guideline suggests administering SGLT-2 inhibitors (weak recommendation in favor).
- Benefits of SGLT-2 Inhibitors
- Outcomes: Reduction in all-cause mortality, cardiovascular mortality, hospitalization for heart failure, kidney failure, non-fatal myocardial infarction, and non-fatal stroke.
- Clinical Implication: SGLT-2 inhibitors provide significant protective effects on cardiovascular and kidney health in CKD patients.
- Potential Harms and Monitoring
- Adverse Effects: Minimal increase in risks of acute kidney injury requiring dialysis, bone fractures, lower limb amputations, ketoacidosis, genital infections, or symptomatic hypovolemia.
- Patient Counseling: Patients should be informed about possible side effects and advised on when to seek medical attention.
- Monitoring: Routine laboratory monitoring is not generally necessary, except in high-risk individuals.
- Practical Considerations for Prescribing
- Initiation: Start SGLT-2 inhibitors in patients with eGFR ≥20 mL/min/1.73 m².
- Continuation: Medications can be continued even if eGFR falls below 20 mL/min/1.73 m² until dialysis is initiated.
- Dosage: Initiate at the highest possible dose without the need for titration.
- Drug Selection: Canagliflozin, dapagliflozin, and empagliflozin are suitable options.
- Concurrent Medications: Review and adjust diuretics to prevent volume depletion.
- Patient Education and Self-Management
- Sick Day Rules: Advise patients to temporarily discontinue SGLT-2 inhibitors during acute illnesses causing dehydration.
- Lifestyle Modifications: Encourage adherence to medication and healthy lifestyle changes to enhance treatment efficacy.
- Applicability and Exceptions
- Applicable Populations: Recommendations apply broadly to adults with CKD, with or without type 2 diabetes.
- Exceptions: Caution or alternative approaches may be necessary for patients:
- Receiving kidney replacement therapy.
- With kidney transplants, polycystic kidney disease, rare kidney diseases.
- With eGFR <20 mL/min/1.73 m² not on replacement therapy.
Conclusion
The guideline underscores the importance of incorporating SGLT-2 inhibitors into the management plan for adults with CKD to improve survival and reduce cardiovascular and kidney-related complications. Clinicians should evaluate each patient’s risk profile and engage in shared decision-making to optimize treatment outcomes.
Summary of “Dialysis for Chronic Kidney Failure: A Review”
3 Oct, 2024 | 22:46h | UTCIn their comprehensive review published in JAMA on October 2, 2024, Dr. Jennifer E. Flythe and Dr. Suzanne Watnick discuss current evidence regarding the pathophysiology, diagnosis, and management of dialysis-dependent chronic kidney failure. The article emphasizes clinical considerations that directly impact patient care, particularly in the initiation and management of dialysis therapy.
Key Aspects Influencing Patient Care
- Initiation of Dialysis
- No Specific eGFR Threshold: There is no recommended estimated glomerular filtration rate (eGFR) for starting dialysis. Decisions should be individualized, focusing on persistent uremic symptoms (e.g., nausea, fatigue), volume overload (e.g., dyspnea, peripheral edema), worsening eGFR, metabolic acidosis, and hyperkalemia.
- Shared Decision-Making: The timing of dialysis initiation should involve a collaborative approach between clinicians and patients, considering symptoms, laboratory trends, and patient preferences.
- No Mortality Benefit from Early Initiation: A randomized clinical trial found no mortality advantage in starting dialysis at higher eGFR levels (10–14 mL/min/1.73 m²) compared to lower levels (5–7 mL/min/1.73 m²).
- Dialysis Modalities
- Hemodialysis vs. Peritoneal Dialysis: Observational data indicate no significant difference in 5-year mortality rates between the two modalities.
- Modality Selection Factors: Decisions should consider patient lifestyle, comorbid conditions, availability of home support, and resource accessibility.
- Common Complications
- Cardiovascular Risks: Cardiovascular complications, such as arrhythmias and cardiac arrest, are leading causes of death among dialysis patients.
- Infections:
- Hemodialysis: Catheter-related bloodstream infections occur at rates of 1.1 to 5.5 episodes per 1000 catheter-days.
- Peritoneal Dialysis: Peritonitis occurs at a rate of 0.26 episodes per patient-year.
- Systemic Complications: Anemia, hyperphosphatemia, hypocalcemia, and hypertension are prevalent and often require pharmacologic intervention.
- Dialysis-Related Issues: Hypotension during dialysis, muscle cramps, itching, and vascular access malfunction can hinder effective treatment.
- Management Strategies
- Anemia: Initiate intravenous iron and/or erythropoietin-stimulating agents when hemoglobin is below 10 g/dL, aiming to maintain levels between 10 and 11.5 g/dL.
- Mineral and Bone Disorders: Use dietary phosphorus restrictions and phosphorus binders; monitor and manage parathyroid hormone levels to mitigate fracture risk.
- Hypertension: Implement dietary salt restriction, adjust ultrafiltration, and prescribe antihypertensive medications, recognizing there’s no specific BP target in dialysis patients.
- Practical Considerations for Clinicians
- Medication Management: Avoid nephrotoxic agents like NSAIDs and iodinated contrast media in patients with residual kidney function. Adjust dosages for medications excreted renally.
- Symptom Control: Address common symptoms such as pruritus with appropriate therapies such as oral antihistamines and moisturizers. Difelikefalin is a new agent that can also be used.
- Patient Education: Counsel on dietary restrictions (salt, fluid, potassium) and ensure vaccinations are up to date, including hepatitis B, pneumococcal, COVID-19, and RSV vaccines.
Conclusion
For the over 540,000 patients in the U.S. receiving maintenance dialysis, individualized care plans that involve shared decision-making are crucial. Understanding when to initiate dialysis, selecting the appropriate modality, managing complications, and addressing patient-specific needs can significantly influence outcomes and quality of life.
Network Meta-Analysis: Eletriptan, Rizatriptan, Sumatriptan, and Zolmitriptan Most Effective for Acute Migraine Episodes
23 Sep, 2024 | 22:34h | UTCBackground: Migraine, a highly prevalent neurological disorder, is a leading cause of disability, especially among women aged 15 to 49. Effective acute management is critical, with current guidelines recommending non-steroidal anti-inflammatory drugs (NSAIDs) and triptans for moderate to severe episodes. However, the relative efficacy of various drug interventions remains unclear, especially with newer treatments like lasmiditan and gepants entering the market.
Objective: To evaluate and compare the efficacy and tolerability of all licensed oral drugs for the acute treatment of migraine episodes in adults.
Methods: A systematic review and network meta-analysis was conducted, including 137 randomized controlled trials (RCTs) involving 89,445 participants. The study analyzed 17 drug interventions, including NSAIDs, triptans, ditans, and gepants, and compared them with placebo. Primary outcomes included pain freedom at two hours post-dose and sustained pain freedom from two to 24 hours post-dose. Certainty of evidence was assessed using the CINeMA framework, and sensitivity analyses were conducted to confirm the robustness of the findings.
Results: All active interventions outperformed placebo for pain freedom at two hours, with odds ratios ranging from 1.73 (95% CI 1.27 to 2.34) for naratriptan to 5.19 (4.25 to 6.33) for eletriptan. The most effective drugs for sustained pain freedom were eletriptan and ibuprofen. Among head-to-head comparisons, eletriptan was the most effective for pain freedom at two hours, followed by rizatriptan, sumatriptan, and zolmitriptan. Newer drugs like lasmiditan, rimegepant, and ubrogepant were less effective than the triptans and showed adverse effects like dizziness and nausea.
Conclusions: Triptans—specifically eletriptan, rizatriptan, sumatriptan, and zolmitriptan—demonstrated superior efficacy and tolerability profiles compared to newer treatments like lasmiditan and gepants. Given their efficacy, these triptans should be prioritized in acute migraine management. However, triptans are underused, and barriers to access should be addressed to ensure broader utilization. Lasmiditan and gepants may still serve as alternatives for patients contraindicated for triptans due to cardiovascular risks.
Implications for Practice: Clinicians should prioritize triptans, particularly eletriptan, rizatriptan, sumatriptan, and zolmitriptan, in managing acute migraine episodes due to their superior efficacy. Careful consideration is needed when selecting newer drugs like lasmiditan and gepants, as they may be less effective and have higher costs and adverse event risks. Cost-effectiveness and patient cardiovascular profiles should guide decision-making.
Study Strengths and Limitations: Strengths include the comprehensive inclusion of both published and unpublished data, as well as the large sample size and robust methodological framework. Limitations include moderate heterogeneity and low confidence in some comparisons due to reporting biases and imprecise treatment effects in older studies.
Future Research: Future studies should focus on re-evaluating the cardiovascular contraindications of triptans to ensure broader access. Additional research is also needed to assess the cost-effectiveness of newer treatments like lasmiditan and gepants, particularly in patients for whom triptans are unsuitable.
Phase 2 RCT: Ponsegromab Shows Promise for the Treatment of Cancer Cachexia
23 Sep, 2024 | 21:48h | UTCBackground: Cancer cachexia is a multifactorial syndrome characterized by weight loss, muscle wasting, and reduced quality of life. Elevated levels of growth differentiation factor 15 (GDF-15), a cytokine, have been associated with cachexia. Ponsegromab, a monoclonal antibody that inhibits GDF-15, has shown potential in reversing cachexia in early studies by improving weight, appetite, and physical activity. This phase 2, randomized, double-blind trial aimed to assess the efficacy and safety of ponsegromab in patients with cancer cachexia and elevated GDF-15 levels.
Objective: To evaluate the impact of ponsegromab on body weight, cachexia symptoms, appetite, physical activity, and safety in cancer cachexia patients with elevated GDF-15 levels.
Methods: In this 12-week study, 187 patients with non-small-cell lung cancer, pancreatic cancer, or colorectal cancer and elevated GDF-15 levels (≥1500 pg/mL) were randomized into four groups: ponsegromab 100 mg, 200 mg, 400 mg, or placebo, administered subcutaneously every four weeks. The primary endpoint was the change in body weight from baseline to week 12. Secondary outcomes included appetite and cachexia symptoms, physical activity measured via digital devices, and safety. The trial also included exploratory endpoints like changes in skeletal muscle mass.
Results:
At 12 weeks, patients treated with ponsegromab showed significant weight gain compared to placebo. The median weight gain differences were 1.22 kg in the 100-mg group, 1.92 kg in the 200-mg group, and 2.81 kg in the 400-mg group. Significant improvements in appetite and cachexia symptoms were observed in the 400-mg group compared to placebo. Physical activity, measured by nonsedentary time, also increased by 72 minutes per day in the 400-mg group. Adverse events were reported by 70% of ponsegromab patients and 80% of placebo patients. Serious adverse events occurred at similar rates across groups, but none were deemed related to treatment. No significant safety concerns were identified.
Conclusions: Ponsegromab effectively increased body weight and improved cachexia symptoms in patients with cancer cachexia and elevated GDF-15 levels, supporting GDF-15’s role as a key driver of cachexia. The findings suggest that ponsegromab may be a promising therapeutic option for managing cancer cachexia, with a favorable safety profile.
Implications for Practice: Ponsegromab could represent a targeted therapy for cancer cachexia, addressing weight loss, appetite, and physical function. Clinicians may consider its use for patients with advanced cancers experiencing cachexia, particularly those with elevated GDF-15 levels.
Study Strengths and Limitations: Strengths of the study include its randomized, double-blind design and the use of objective measures such as digital physical activity tracking. Limitations include the relatively short trial duration, and missing physical activity data for some patients. Additionally, the efficacy of ponsegromab across different baseline levels of GDF-15 requires further investigation.
Future Research: Larger and longer-term trials are necessary to confirm the therapeutic benefit of ponsegromab in cancer cachexia. Future research should explore its impact on survival and assess whether GDF-15 inhibition benefits other conditions associated with elevated GDF-15, such as heart failure and chronic kidney disease.
Summary of the review “Lipoprotein(a) and Cardiovascular Disease”
23 Sep, 2024 | 21:22h | UTCSummary of the review “Lipoprotein(a) and Cardiovascular Disease“
By Prof Børge G Nordestgaard and Anne Langsted
Key Takeaways for Practicing Physicians:
- Significance of Lipoprotein(a) [Lp(a)]:
- Causal Risk Factor: Elevated Lp(a) is a genetically determined causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis.
- Prevalence: Approximately 1 in 5 individuals globally have high Lp(a) levels, increasing their cardiovascular risk.
- Genetic Determinants and Ethnic Variations:
- Genetic Influence: Over 90% genetically determined with minimal lifestyle impact.
- Ethnic Differences:
- Lowest levels: East Asians, Europeans, Southeast Asians.
- Intermediate levels: South Asians, Middle Easterners, Latin Americans.
- Highest levels: Individuals of African descent.
- Sex Differences: Postmenopausal women have about 17% higher Lp(a) levels than men.
- Clinical Measurement and Interpretation:
- When to Measure:
- Once in a Lifetime: Recommended for all individuals to measure Lp(a) at least once.
- High-Risk Patients: Especially important in those with premature ASCVD, familial hypercholesterolaemia (FH), family history of elevated Lp(a) or early ASCVD.
- Stability of Levels: Lp(a) levels are stable after age two and are unaffected by most lifestyle factors.
- Interpreting Levels:
- Elevated Risk Thresholds:
- >30 mg/dL (≥62 nmol/L): Increased risk begins.
- >50 mg/dL (≥105 nmol/L): Clinically significant high risk.
- >90 mg/dL (≥190 nmol/L): Severe risk, comparable to FH.
- Elevated Risk Thresholds:
- Laboratory Considerations:
- Assay Selection: Use isoform-independent assays with standardized calibration.
- Reporting Units: Preferably in nmol/L; however, mg/dL is acceptable with appropriate conversion.
- When to Measure:
- Impact on Patient Care:
- Risk Stratification:
- Independent Risk Factor: High Lp(a) increases ASCVD risk independent of other lipids.
- Reclassification: Can reclassify patients into higher risk categories, influencing management decisions.
- Management Strategies:
- Current Limitations: No approved therapies specifically targeting Lp(a) reduction.
- Aggressive Risk Factor Control:
- LDL Cholesterol: Intensive lowering with high-intensity statins, ezetimibe, and PCSK9 inhibitors.
- PCSK9 Inhibitors: Lower Lp(a) by ~25% and reduce cardiovascular events.
- Lifestyle Modifications: Emphasize smoking cessation, healthy diet, physical activity, and weight management.
- Blood Pressure and Diabetes Management: Optimize control per guidelines.
- LDL Cholesterol: Intensive lowering with high-intensity statins, ezetimibe, and PCSK9 inhibitors.
- Avoid Unproven Therapies: Niacin is not recommended due to side effects and lack of cardiovascular benefit.
- Risk Stratification:
- Familial Hypercholesterolaemia (FH):
- Dual Risk: Elevated Lp(a) often coexists with FH, compounding cardiovascular risk.
- Screening: Measure Lp(a) in all patients with FH and consider cascade screening in families.
- Emerging Therapies:
- Gene-Silencing Drugs:
- Pelacarsen, Olpasiran, Lepodisiran: Lower Lp(a) levels by 80–98%.
- Administration: Subcutaneous injections, varying from monthly to quarterly.
- Small Molecule Inhibitors:
- Muvalaplin: Oral agent reducing Lp(a) by ~65%.
- Clinical Trials:
- Phase 3 Trials Ongoing: Evaluating cardiovascular outcomes with significant Lp(a) reduction.
- Potential Change in Practice: These therapies may soon provide effective options for patients with high Lp(a).
- Gene-Silencing Drugs:
- Practical Recommendations:
- Include Lp(a) in Lipid Panels: Encourage laboratories to add Lp(a) measurements to standard profiles.
- Patient Communication:
- Educate on Risks: Explain the significance of high Lp(a) and its genetic nature.
- Lifestyle Advice: Reinforce the importance of modifiable risk factor control.
- Family Screening: Consider evaluating first-degree relatives due to genetic inheritance patterns.
- Monitoring and Follow-Up:
- Re-measurement: Generally, one measurement suffices unless a significant event (e.g., menopause) occurs.
- Acute Phase Reactant Consideration: Be cautious interpreting levels during acute illness; recheck once stabilized.
Conclusion:
Elevated Lp(a) is a significant and prevalent cardiovascular risk factor that is largely genetic and stable throughout life. While direct treatments are on the horizon, current management focuses on aggressive modification of other cardiovascular risk factors. Measurement of Lp(a) should become a routine part of cardiovascular risk assessment, guiding more personalized and effective patient care.
RCT: PACAP Monoclonal Antibody Lu AG09222 Reduced Migraine Days in Patients with Refractory Migraine
20 Sep, 2024 | 17:56h | UTCBackground: Migraine affects approximately 1 billion people worldwide and is a leading cause of disability. While calcitonin gene–related peptide (CGRP)-targeted therapies have advanced migraine prevention, many patients do not achieve sufficient benefit. Pituitary adenylate cyclase–activating polypeptide (PACAP) is implicated in migraine pathogenesis, and blocking its signaling may offer a new therapeutic target.
Objective: To assess the efficacy and safety of Lu AG09222, a monoclonal antibody against PACAP, for migraine prevention in adults who failed two to four prior preventive treatments.
Methods: In a phase 2, double-blind, randomized, placebo-controlled trial (HOPE), 237 adults aged 18–65 years with migraine (mean baseline of 16.7 migraine days per month) were randomized 2:1:2 to receive a single intravenous infusion of 750 mg Lu AG09222, 100 mg Lu AG09222, or placebo. The primary endpoint was the mean change from baseline in migraine days per month over weeks 1–4 in the 750 mg Lu AG09222 group compared to placebo. Secondary endpoints included the proportion achieving ≥50% reduction in migraine days per month and change in headache days per month.
Results: Of 237 participants, 97 received 750 mg Lu AG09222, 46 received 100 mg, and 94 received placebo. Over weeks 1–4, the 750 mg Lu AG09222 group had a mean reduction of 6.2 migraine days per month versus 4.2 days in the placebo group (difference –2.0 days; 95% CI, –3.8 to –0.3; P=0.02). A ≥50% reduction in migraine days per month was achieved by 32% in the 750 mg group versus 27% with placebo. The most common adverse events in the 750 mg group compared to placebo were COVID-19 (7% vs 3%), nasopharyngitis (7% vs 4%), and fatigue (5% vs 1%).
Conclusions: A single intravenous infusion of 750 mg Lu AG09222 significantly reduced migraine frequency over 4 weeks compared to placebo in patients with migraine refractory to prior preventive treatments.
Implications for Practice: Lu AG09222, by targeting PACAP signaling, may provide a novel preventive therapy for patients who have not responded to existing treatments, including CGRP antagonists.
Study Strengths and Limitations: Strengths include the randomized, double-blind, placebo-controlled design. Limitations encompass the short trial duration, small sample size, single-dose administration, predominantly White and European study population, and exclusion of patients with significant cardiovascular disease.
Future Research: Long-term studies are needed to evaluate the sustained efficacy and safety of Lu AG09222, optimal dosing strategies, and its effectiveness in diverse patient populations.
Summary: Perioperative Management of Patients Taking Direct Oral Anticoagulants
19 Sep, 2024 | 21:12h | UTCDirect oral anticoagulants (DOACs)—including apixaban, rivaroxaban, edoxaban, and dabigatran—are increasingly used for stroke prevention in atrial fibrillation and for treating venous thromboembolism. Effective perioperative management of DOACs is essential to minimize bleeding and thromboembolic risks during surgical and nonsurgical procedures. Below are practical recommendations focused on the perioperative management of patients taking DOACs, based on a recent JAMA review article.
Elective Surgical or Nonsurgical Procedures
Classify Bleeding Risk of Procedures:
- Minimal Risk:
- Minor dental procedures (e.g., cleaning, extractions)
- Minor dermatologic procedures (e.g., skin lesion removal)
- Cataract surgery
- Low to Moderate Risk:
- Endoscopic procedures without high-risk interventions
- Cholecystectomy
- Inguinal hernia repair
- High Risk:
- Major surgery (e.g., cancer surgery, joint replacement)
- Procedures involving neuraxial anesthesia
- Endoscopic procedures with high-risk interventions (e.g., large polyp removal)
DOAC Management Strategies:
- Minimal Bleeding Risk Procedures:
- Option 1: Continue DOACs without interruption.
- Option 2: For added safety, withhold the morning dose on the day of the procedure (especially for twice-daily DOACs like apixaban and dabigatran).
- Low to Moderate Bleeding Risk Procedures:
- Preoperative:
- Discontinue DOACs 1 day before the procedure.
- This allows approximately 2 half-lives for drug clearance.
- Postoperative:
- Resume DOACs 1 day after the procedure, ensuring adequate hemostasis.
- Preoperative:
- High Bleeding Risk Procedures:
- Preoperative:
- Discontinue DOACs 2 days before the procedure.
- This allows approximately 4-5 half-lives for drug clearance.
- Postoperative:
- Resume DOACs 2-3 days after the procedure, based on bleeding risk and hemostasis.
- Preoperative:
Evidence Supporting These Strategies:
- The PAUSE study demonstrated that standardized interruption protocols without heparin bridging result in low rates of:
- Thromboembolism: 0.2%–0.4%
- Major Bleeding: 1%–2%
Postoperative DOAC Resumption:
- Assess surgical-site hemostasis before resuming DOACs.
- Delay resumption if there is ongoing bleeding or concerns about hemostasis.
- For high bleeding risk procedures, consider a longer delay (2–3 days).
Perioperative Heparin Bridging:
- Not recommended for patients on DOACs.
- Bridging increases bleeding risk without reducing thromboembolism.
- DOACs have rapid offset and onset, making bridging unnecessary.
Special Considerations
Patients with Impaired Renal Function:
- For CrCl 30–50 mL/min:
- Dabigatran: Extend preoperative discontinuation by an additional day.
- For CrCl <30 mL/min:
- Dabigatran is contraindicated.
- For other DOACs, consider extending discontinuation to 3–4 days before surgery.
Patients Undergoing Neuraxial Anesthesia:
- Discontinue DOACs for 3 days (apixaban, edoxaban, rivaroxaban) or 4 days (dabigatran) before the procedure.
- Minimizes risk of spinal or epidural hematoma.
Dental Procedures:
- Generally safe to continue DOACs.
- For added safety:
- Omit or delay the dose on the day of the procedure.
- Employ local hemostatic measures (e.g., tranexamic acid mouthwash).
Endoscopic Procedures:
- Low-risk procedures (e.g., diagnostic endoscopy without biopsy):
- Follow standard DOAC interruption for low to moderate bleeding risk.
- High-risk procedures (e.g., polypectomy of large polyps):
- Extend DOAC discontinuation by an additional day pre- and post-procedure.
Patients Unable to Resume Oral Medications Postoperatively:
- Use prophylactic low-molecular-weight heparin (LMWH) until oral intake is possible.
- Avoid therapeutic-dose LMWH due to bleeding risk.
Emergent, Urgent, or Semiurgent Procedures
Risks:
- Higher bleeding risk: Up to 23%
- Thromboembolism risk: Up to 11%
Management Strategies:
- Assess Time Since Last DOAC Dose:
- If within 48 hours, consider that significant anticoagulant effect may persist.
- Laboratory Testing (if available):
- DOAC Level Testing:
- ≥50 ng/mL: Consider using reversal agents.
- <50 ng/mL: May proceed without reversal agents.
- DOAC Level Testing:
- Use of Reversal Agents:
- For Dabigatran:
- Idarucizumab (5 g IV)
- For Factor Xa Inhibitors (apixaban, rivaroxaban, edoxaban):
- Andexanet alfa (dosing based on last dose timing and amount)
- Prothrombin Complex Concentrates (PCCs): If andexanet alfa is unavailable or contraindicated.
- For Dabigatran:
- Proceeding Without Testing:
- If testing is unavailable and last DOAC dose was within 48 hours, consider reversal agents.
- If >48 hours since last dose, may proceed without reversal.
Considerations:
- Reversal agents are expensive and may carry thrombotic risks.
- Use should be judicious, weighing risks and benefits.
- Consult hematology or thrombosis experts when possible.
Key Takeaways
- Elective Procedures:
- Utilize standardized protocols based on procedural bleeding risk.
- Routine preoperative DOAC level testing is unnecessary.
- Avoid heparin bridging.
- Emergent/Urgent Procedures:
- Reversal agents may be appropriate when significant DOAC levels are present.
- Decision to use reversal agents should consider bleeding risk, time since last dose, and availability of DOAC level testing.
- Patient Communication:
- Ensure patients understand the plan for DOAC interruption and resumption.
- Provide clear instructions regarding timing and dosing.
- Interdisciplinary Coordination:
- Collaborate with surgical teams, anesthesiologists, and pharmacists.
- Use electronic medical records and clinical decision support tools to enhance communication.
Conclusion
By applying standardized perioperative management protocols, clinicians can effectively balance the risks of bleeding and thromboembolism in patients taking DOACs who require surgical or nonsurgical procedures. These strategies simplify decision-making, avoid unnecessary interventions like heparin bridging, and promote patient safety.
Phase 2 RCT: Axatilimab Demonstrates Efficacy in Refractory Chronic GVHD by Targeting CSF1R-Dependent Macrophages
19 Sep, 2024 | 16:05h | UTCBackground: Chronic graft-versus-host disease (GVHD) is a significant long-term complication of allogeneic hematopoietic stem-cell transplantation, affecting approximately half of recipients and leading to substantial morbidity and mortality. Standard therapies often fail to induce durable responses in patients with refractory or recurrent disease. CSF1R-dependent monocytes and macrophages are key mediators of chronic GVHD, contributing to inflammation and fibrosis. Axatilimab, a CSF1R-blocking antibody, has shown promising activity in early studies.
Objective: To evaluate the efficacy and safety of axatilimab at three different doses in patients with recurrent or refractory chronic GVHD.
Methods: In this phase 2, multinational, randomized study (AGAVE-201), 241 patients aged ≥2 years with active chronic GVHD after at least two prior systemic therapies were randomized 1:1:1 to receive intravenous axatilimab at 0.3 mg/kg every 2 weeks (n=80), 1 mg/kg every 2 weeks (n=81), or 3 mg/kg every 4 weeks (n=80). Randomization was stratified by chronic GVHD severity and prior use of FDA-approved therapies (ibrutinib, ruxolitinib, or belumosudil). The primary endpoint was overall response rate (complete or partial response) within the first six cycles. The key secondary endpoint was a patient-reported reduction in symptom burden, defined as a decrease of more than 5 points on the modified Lee Symptom Scale (range 0–100).
Results: The overall response rate was 74% (95% CI, 63%–83%) in the 0.3 mg/kg group, 67% (95% CI, 55%–77%) in the 1 mg/kg group, and 50% (95% CI, 39%–61%) in the 3 mg/kg group, exceeding the predefined efficacy threshold in all groups. A clinically meaningful reduction in symptom burden was reported in 60%, 69%, and 41% of patients in the respective dose groups. Median time to response was less than 2 months across all groups. Organ-specific responses were observed in all affected organs, including skin, lungs, joints, and fascia.
The most common adverse events were dose-dependent transient laboratory abnormalities related to CSF1R blockade, such as elevations in liver enzymes and creatine kinase, which were not associated with clinical symptoms or end-organ damage. Periorbital edema occurred more frequently at higher doses. Adverse events leading to discontinuation occurred in 6% of patients in the 0.3 mg/kg group, 22% in the 1 mg/kg group, and 18% in the 3 mg/kg group. Serious infections were reported but were not dose-dependent.
Conclusions: Axatilimab demonstrated significant efficacy in patients with heavily pretreated recurrent or refractory chronic GVHD, with the highest response rates and best tolerability observed at the lowest dose tested (0.3 mg/kg every 2 weeks). Targeting CSF1R-dependent monocytes and macrophages may represent a novel therapeutic strategy in chronic GVHD.
Implications for Practice: Axatilimab offers a potential new treatment option for patients with chronic GVHD refractory to standard therapies, including those who have failed prior FDA-approved treatments. Clinicians should consider axatilimab as a therapeutic option while monitoring for transient laboratory abnormalities associated with CSF1R blockade. The lower dose appears to provide optimal efficacy with fewer adverse events.
Study Strengths and Limitations: Strengths include the randomized, multinational design and inclusion of patients with severe, refractory chronic GVHD who had received multiple prior therapies. Limitations include the lack of a comparator group, which may introduce outcome-reporting bias, and the small sizes of subgroups, limiting the generalizability of certain findings.
Future Research: Further studies are needed to confirm these results, assess long-term outcomes, and explore axatilimab in earlier lines of therapy and in combination with other treatments. Investigations into the use of axatilimab in other autoimmune diseases characterized by CSF1R-driven macrophage-mediated inflammation and fibrosis are also warranted.
RCT: Pembrolizumab Plus Chemotherapy Improved Overall Survival in Early-Stage Triple-Negative Breast Cancer
18 Sep, 2024 | 16:08h | UTCBackground: Early-stage triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options and poor prognosis. The phase 3 KEYNOTE-522 trial previously demonstrated that adding pembrolizumab to chemotherapy improved pathological complete response rates and event-free survival in this population.
Objective: To determine whether neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab improves overall survival compared to neoadjuvant chemotherapy alone in patients with early-stage TNBC.
Methods: In this multicenter, randomized, double-blind, placebo-controlled phase 3 trial (KEYNOTE-522), 1174 patients with previously untreated stage II or III TNBC were randomized 2:1 to receive neoadjuvant pembrolizumab (200 mg every 3 weeks) plus chemotherapy (paclitaxel and carboplatin, followed by doxorubicin–cyclophosphamide or epirubicin–cyclophosphamide) or placebo plus the same chemotherapy regimen. After surgery, patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles. The primary endpoints were pathological complete response and event-free survival; overall survival was a key secondary endpoint.
Results: After a median follow-up of 75.1 months, the estimated 5-year overall survival was 86.6% in the pembrolizumab–chemotherapy group versus 81.7% in the placebo–chemotherapy group (hazard ratio for death, 0.66; P=0.002). The 5-year event-free survival was 81.2% versus 72.2%, respectively (hazard ratio for event or death, 0.65; 95% CI, 0.51–0.83). Grade 3 or higher treatment-related adverse events occurred in 77.1% of patients receiving pembrolizumab–chemotherapy and 73.3% receiving placebo–chemotherapy. Serious treatment-related adverse events occurred in 34.1% and 20.1% of patients, respectively.
Conclusions: Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab significantly improved overall survival compared to chemotherapy alone in patients with early-stage TNBC.
Implications for Practice: The addition of pembrolizumab to standard neoadjuvant chemotherapy, followed by adjuvant pembrolizumab, should be considered a new standard of care for patients with high-risk, early-stage TNBC, offering a significant survival benefit.
Study Strengths and Limitations: Strengths include the large, international, randomized design, the use of a placebo control, and long-term follow-up. Limitations include the inability to isolate the effects of neoadjuvant versus adjuvant pembrolizumab and the exclusion of adjuvant capecitabine from the treatment protocol.
Future Research: Further studies should focus on identifying biomarkers predictive of response to pembrolizumab, optimizing the sequencing and duration of immunotherapy, and evaluating the addition of other agents to improve outcomes in early-stage TNBC.
RCT: Perioperative Durvalumab Plus Neoadjuvant Chemotherapy Improved Survival in Muscle-Invasive Bladder Cancer
18 Sep, 2024 | 15:22h | UTCBackground: Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy is the standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer (MIBC). Despite this approach, approximately 50% of patients experience recurrence within 3 years. Combining immunotherapy with chemotherapy may enhance outcomes, and durvalumab, a PD-L1 inhibitor, has shown promise when added to chemotherapy in previous studies.
Objective: To evaluate whether perioperative durvalumab combined with neoadjuvant gemcitabine–cisplatin improves event-free survival (EFS) and overall survival (OS) compared to neoadjuvant chemotherapy alone in cisplatin-eligible patients with operable MIBC.
Methods: In the phase 3, open-label, randomized NIAGARA trial, 1063 cisplatin-eligible patients with MIBC (clinical stage T2-T4aN0-1M0) were randomized 1:1 to receive either perioperative durvalumab plus neoadjuvant gemcitabine–cisplatin followed by radical cystectomy and adjuvant durvalumab (durvalumab group, n=533) or neoadjuvant gemcitabine–cisplatin followed by radical cystectomy alone (comparison group, n=530). The primary endpoints were EFS and pathological complete response (pCR). The key secondary endpoint was OS.
Results: At a median follow-up of 42.3 months, the estimated EFS at 24 months was 67.8% (95% CI, 63.6–71.7) in the durvalumab group versus 59.8% (95% CI, 55.4–64.0) in the comparison group (hazard ratio [HR] for progression, recurrence, not undergoing cystectomy, or death, 0.68; 95% CI, 0.56–0.82; P<0.001). The estimated OS at 24 months was 82.2% (95% CI, 78.7–85.2) in the durvalumab group versus 75.2% (95% CI, 71.3–78.8) in the comparison group (HR for death, 0.75; 95% CI, 0.59–0.93; P=0.01). Grade 3 or 4 treatment-related adverse events occurred in 40.6% of patients in the durvalumab group and 40.9% in the comparison group. Radical cystectomy was performed in 88.0% of patients in the durvalumab group and 83.2% in the comparison group.
Conclusions: Perioperative durvalumab combined with neoadjuvant chemotherapy significantly improved event-free and overall survival compared to neoadjuvant chemotherapy alone in cisplatin-eligible patients with operable MIBC.
Implications for Practice: Adding perioperative durvalumab to neoadjuvant chemotherapy may represent a new option for cisplatin-eligible patients with MIBC, offering improved survival outcomes without increasing significant adverse events or delaying surgery.
Study Strengths and Limitations: Strengths include the large sample size and randomized, phase 3 design. Limitations encompass the open-label design and inability to isolate the effects of neoadjuvant versus adjuvant durvalumab. Additionally, the trial was conducted before the widespread use of adjuvant nivolumab, potentially affecting the generalizability of the results.
Future Research: Further studies are needed to delineate the relative contributions of neoadjuvant and adjuvant durvalumab and to explore biomarkers such as circulating tumor DNA to guide treatment decisions.
RCT: Nivolumab Plus Ipilimumab Shows Sustained 10-Year Survival Benefit in Advanced Melanoma
18 Sep, 2024 | 15:06h | UTCBackground: Advanced melanoma historically had a poor prognosis, with median survival under 12 months before 2011. The advent of immune checkpoint inhibitors like nivolumab (anti–PD-1) and ipilimumab (anti–CTLA-4) has significantly improved outcomes. Previous results from the CheckMate 067 trial showed longer overall survival with nivolumab plus ipilimumab or nivolumab alone compared to ipilimumab alone. As patients now live beyond 7.5 years, longer-term data are needed to address new clinical questions about survival and disease progression.
Objective: To assess the final 10-year outcomes of overall survival, melanoma-specific survival, and response durability in patients with advanced melanoma treated with nivolumab plus ipilimumab, nivolumab monotherapy, or ipilimumab monotherapy.
Methods: In the phase 3 CheckMate 067 trial, 945 patients with untreated, unresectable stage III or IV melanoma were randomized 1:1:1 to receive:
- Nivolumab plus ipilimumab: Nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) every 3 weeks for four doses, then nivolumab (3 mg/kg) every 2 weeks.
- Nivolumab monotherapy: Nivolumab (3 mg/kg) every 2 weeks plus placebo.
- Ipilimumab monotherapy: Ipilimumab (3 mg/kg) every 3 weeks for four doses plus placebo.
Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. Randomization was stratified by BRAF mutation status, metastasis stage, and PD-L1 expression. Primary endpoints were overall survival and progression-free survival; secondary endpoints included objective response rates and subgroup analyses.
Results: After 10 years, median overall survival was:
- 71.9 months with nivolumab plus ipilimumab,
- 36.9 months with nivolumab,
- 19.9 months with ipilimumab.
Hazard ratios for death were 0.53 (95% CI, 0.44–0.65; P<0.001) for nivolumab plus ipilimumab vs. ipilimumab, and 0.63 (95% CI, 0.52–0.76; P<0.001) for nivolumab vs. ipilimumab. Ten-year overall survival rates were 43% with combination therapy, 37% with nivolumab, and 19% with ipilimumab. Median melanoma-specific survival was not reached (>120 months) with combination therapy (37% alive at study end), 49.4 months with nivolumab, and 21.9 months with ipilimumab. Among patients alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with combination therapy, 97% with nivolumab, and 88% with ipilimumab. No new safety signals were observed over the extended follow-up.
Conclusions: Nivolumab plus ipilimumab demonstrated a sustained 10-year survival benefit over ipilimumab monotherapy in advanced melanoma. Nivolumab monotherapy also improved survival compared to ipilimumab, though the combination provided the greatest benefit.
Implications for Practice: These 10-year results support nivolumab plus ipilimumab as a preferred first-line treatment for advanced melanoma, offering potential for long-term survival and possible cure. Clinicians should balance improved efficacy against higher adverse event rates with combination therapy and monitor patients accordingly.
Study Strengths and Limitations: Strengths include the large, randomized, multicenter design and extended follow-up, providing robust survival data. Limitations include the trial not being powered for formal comparison between combination and monotherapy, and potential confounding from subsequent therapies on long-term outcomes.
Future Research: Further studies should aim to identify biomarkers predicting long-term response, optimize patient selection for combination therapy, and develop treatments for patients unresponsive to current immune checkpoint inhibitors.
Meta-analysis: Perioperative Colchicine Reduced Postoperative Atrial Fibrillation After CABG
18 Sep, 2024 | 13:33h | UTCBackground: Coronary artery disease (CAD) remains a leading cause of mortality worldwide. Inflammation is a key factor in the development and progression of CAD, and anti-inflammatory therapies have shown potential in improving cardiovascular outcomes. Colchicine, traditionally used to treat gout, has demonstrated efficacy in reducing cardiovascular events in patients with chronic CAD. Previous individual studies have suggested that perioperative colchicine may decrease the incidence of postoperative atrial fibrillation (POAF) in patients undergoing coronary artery bypass grafting (CABG), but a comprehensive analysis is needed to confirm these findings.
Objective: To evaluate the effect of perioperative colchicine administration on the incidence of POAF in patients undergoing isolated CABG surgery through a meta-analysis of randomized controlled trials (RCTs).
Methods: A systematic search was conducted across MEDLINE, Web of Science, and The Cochrane Library to identify RCTs comparing perioperative colchicine administration with standard care in patients undergoing CABG. Inclusion criteria encompassed studies involving isolated CABG patients randomized to receive colchicine or standard care without colchicine. The primary outcome was the incidence of POAF during short-term follow-up.
Results: Five RCTs published between 2014 and 2022 met the inclusion criteria, including a total of 839 patients undergoing isolated CABG. Perioperative colchicine administration was associated with a significant reduction in POAF rates compared to standard care (relative risk [RR], 0.54; 95% confidence interval [CI], 0.40–0.73; p < 0.01). Other outcomes, such as graft patency, myocardial infarction, or long-term mortality, were not uniformly reported and, therefore, not analyzed.
Conclusions: Perioperative administration of colchicine is associated with a significant reduction in the incidence of POAF in patients undergoing CABG surgery.
Implications for Practice: Colchicine may be considered as a prophylactic strategy to reduce POAF in patients undergoing CABG, potentially improving both short- and long-term outcomes. Given the association of POAF with increased perioperative morbidity and long-term adverse events, implementing colchicine could have substantial clinical benefits in this high-risk population.
Study Strengths and Limitations: Strengths of this meta-analysis include the exclusive inclusion of randomized controlled trials and the use of rigorous statistical methods, including sensitivity analysis, which confirmed the robustness of the results. Limitations involve the small number of studies (five RCTs), potential variability in colchicine dosing regimens, and the lack of data on other clinically relevant outcomes.
Future Research: Large-scale, multicenter RCTs are warranted to further assess the effects of colchicine on other important outcomes in CABG patients, such as graft patency, myocardial infarction rates, and long-term mortality. Future studies should also evaluate the risk-benefit profile of colchicine in this patient population to establish its full role in clinical practice.
Reference: Kirov H., Caldonazo T., Runkel A., et al. (2024). Colchicine in Patients with Coronary Disease Undergoing Coronary Artery Bypass Surgery – A Meta-Analysis of Randomized Controlled Trials. The American Journal of Cardiology. DOI: http://doi.org/10.1016/j.amjcard.2024.09.003
RCT: Twice-Yearly Depemokimab Reduced Exacerbations in Severe Eosinophilic Asthma
17 Sep, 2024 | 22:39h | UTCBackground: Severe asthma with an eosinophilic phenotype often leads to frequent exacerbations despite treatment with medium- or high-dose inhaled glucocorticoids and additional controllers. Interleukin-5 is pivotal in eosinophil growth and survival, contributing to airway inflammation. Existing biologic therapies targeting interleukin-5 require frequent dosing intervals. Depemokimab is an ultra-long-acting anti–interleukin-5 biologic with enhanced binding affinity, potentially allowing effective dosing every six months.
Objective: To evaluate the efficacy and safety of twice-yearly depemokimab in reducing exacerbations in patients with severe eosinophilic asthma.
Methods: Two multicenter, randomized, double-blind, placebo-controlled phase 3A trials (SWIFT-1 and SWIFT-2) were conducted. Patients aged ≥12 years with severe asthma and an eosinophilic phenotype (blood eosinophil count ≥300 cells/μL in the previous 12 months or ≥150 cells/μL at screening) and at least two exacerbations in the prior year despite medium- or high-dose inhaled glucocorticoids plus another controller were enrolled. Participants were randomized 2:1 to receive depemokimab 100 mg or placebo subcutaneously at weeks 0 and 26, alongside standard care. The primary endpoint was the annualized rate of exacerbations over 52 weeks. Secondary endpoints included changes from baseline in the St. George’s Respiratory Questionnaire (SGRQ) score, prebronchodilator FEV₁, and asthma symptom scores at 52 weeks.
Results: A total of 792 patients were randomized, with 762 included in the full analysis set (502 depemokimab, 260 placebo). In SWIFT-1, depemokimab significantly reduced the annualized exacerbation rate compared to placebo (0.46 vs 1.11; rate ratio 0.42; 95% CI, 0.30–0.59; P < .001). Similar results were observed in SWIFT-2 (0.56 vs 1.08; rate ratio 0.52; 95% CI, 0.36–0.73; P < .001). No significant between-group differences were found in change from baseline in SGRQ scores. The incidence of adverse events was similar between groups in both trials.
Conclusions: Twice-yearly administration of depemokimab significantly reduced the annualized rate of exacerbations in patients with severe eosinophilic asthma.
Implications for Practice: Depemokimab administered every six months may offer an effective treatment option for reducing exacerbations in severe eosinophilic asthma, potentially enhancing patient adherence and reducing treatment burden associated with more frequent dosing schedules.
Study Strengths and Limitations: Strengths include large, multicenter, randomized, placebo-controlled design and replicate trials confirming efficacy. Limitations involve the lack of significant improvement in quality-of-life measures, low exacerbation rates in the placebo group, potential impact of the COVID-19 pandemic on trial conduct and outcomes, and limited data on certain subpopulations.
Future Research: Further studies are needed to assess long-term safety and efficacy, effects on quality-of-life measures, and the role of depemokimab in broader asthma populations, including those with varying eosinophil counts and biomarker profiles.
Systematic Review: Antidepressants Offer Limited Pain Relief with Potential Harms in Older Adults
17 Sep, 2024 | 11:34h | UTCBackground: Chronic pain is prevalent among older adults and significantly affects their quality of life. Antidepressants are commonly prescribed for pain management in this population across various countries. While several systematic reviews have evaluated the efficacy and safety of antidepressants for pain in adults, none have specifically focused on individuals aged 65 years and older. The efficacy and safety profile of antidepressants for pain relief in older adults remains unclear.
Objective: To assess the efficacy and safety of antidepressant medications compared to all alternatives for the management of non-cancer pain in older adults aged 65 years and above.
Methods: A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted. Thirteen databases were searched from inception to February 1, 2024, to identify relevant studies. Trials included compared any antidepressant medication to any alternative (e.g., placebo, other medications, or non-drug therapies) for the treatment of non-cancer pain in older adults. Data extracted included study and participant characteristics, primary efficacy outcomes (pain scores converted to a 0–100 scale), and harms. Estimates for efficacy were pooled using a random-effects model and reported as mean differences with 95% confidence intervals (CIs). The quality of included trials was assessed using the Cochrane risk of bias tool.
Results: Fifteen studies encompassing 1,369 participants met the inclusion criteria. The most frequently studied antidepressants were duloxetine and amitriptyline (six studies each). Pain related to knee osteoarthritis was the most commonly studied condition (six studies). For knee osteoarthritis:
- Immediate Term (0–2 weeks): Antidepressants did not provide a statistically significant reduction in pain compared to alternatives (mean difference [MD], –5.6; 95% CI, –11.5 to 0.3).
- Intermediate Term (≥6 weeks and <12 months): Duloxetine provided a statistically significant, albeit very small, reduction in pain (MD, –9.1; 95% CI, –11.8 to –6.4).
Nearly half of the studies (7 out of 15) reported increased withdrawal of participants in the antidepressant treatment group compared to the comparator group due to adverse events.
Conclusions: For most chronic painful conditions in older adults, the benefits and harms of antidepressant medications are unclear. The available evidence predominantly comes from trials with small sample sizes (less than 100 participants), disclosed industry ties, and trials classified as having unclear or high risk of bias.
Implications for Practice:
- Minimal Benefit: Antidepressants, particularly duloxetine, may offer a very small benefit for pain relief in older adults with knee osteoarthritis over the intermediate term.
- Risk of Harms: The potential harms, including increased adverse events leading to higher withdrawal rates, may outweigh these minimal benefits.
- Clinical Decision-Making: Clinicians should carefully weigh the benefits against the risks when considering prescribing antidepressants for pain in older adults.
- Alternative Strategies: Non-pharmacological interventions and alternative pain management strategies should be prioritized in this population.
Study Strengths and Limitations: Strengths include the comprehensive search strategy across multiple databases and the focus on older adults, a population often underrepresented in clinical trials. Limitations involve the generally low quality of the included trials, small sample sizes, high risk of bias, and inconsistent reporting of pain outcomes and adverse events among studies.
Future Research: Further large-scale, high-quality randomized controlled trials are needed to investigate the efficacy and safety of antidepressants for pain management in older adults. Future studies should also compare antidepressants to non-pharmacological interventions and explore long-term outcomes and optimal dosing regimens in this population.
RCT: Cabozantinib Improves Progression-Free Survival in Advanced Neuroendocrine Tumors
17 Sep, 2024 | 11:03h | UTCBackground: Advanced neuroendocrine tumors (NETs) present limited treatment options, with many patients experiencing disease progression despite existing therapies. Angiogenesis is pivotal in NET pathogenesis. Cabozantinib, an oral tyrosine kinase inhibitor targeting VEGF receptors, MET, AXL, and RET, has demonstrated clinical activity in phase 2 studies involving NETs. The efficacy of cabozantinib in patients with progressive, advanced extrapancreatic or pancreatic NETs after prior treatments remains uncertain.
Objective: To assess the efficacy and safety of cabozantinib compared with placebo in patients with previously treated, progressive advanced extrapancreatic or pancreatic NETs.
Methods: A multicenter, double-blind, randomized, placebo-controlled phase 3 trial (CABINET) was conducted at 62 sites in the United States from October 2018 to August 2023. Eligible patients were adults aged ≥18 years with histologically confirmed, locally advanced or metastatic well- or moderately differentiated extrapancreatic or pancreatic NETs (WHO grades 1–3) and documented disease progression within 12 months prior to enrollment. Patients were randomized 2:1 to receive cabozantinib (60 mg orally once daily) or placebo. Randomization was stratified by concurrent somatostatin analogue use and primary tumor site. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review according to RECIST 1.1 criteria. Key secondary endpoints included objective response rate (ORR), overall survival (OS), and safety.
Results: A total of 203 patients with extrapancreatic NETs and 95 patients with pancreatic NETs were randomized.
- Extrapancreatic NET Cohort:
- Median PFS was 8.4 months with cabozantinib vs. 3.9 months with placebo (stratified hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.25–0.59; P<0.001).
- Partial responses were observed in 5% of patients receiving cabozantinib vs. 0% with placebo.
- Pancreatic NET Cohort:
- Median PFS was 13.8 months with cabozantinib vs. 4.4 months with placebo (stratified HR, 0.23; 95% CI, 0.12–0.42; P<0.001).
- Partial responses were observed in 19% of patients receiving cabozantinib vs. 0% with placebo.
Grade ≥3 treatment-related adverse events occurred in 62–65% of patients receiving cabozantinib and 23–27% receiving placebo. Common grade ≥3 adverse events included hypertension (21–22%), fatigue (11–13%), diarrhea (11%), and thromboembolic events (11%).
Conclusions: Cabozantinib significantly improved progression-free survival compared to placebo in patients with previously treated, progressive advanced extrapancreatic or pancreatic NETs. The safety profile was consistent with known adverse events associated with cabozantinib.
Implications for Practice:
- New Treatment Option: Cabozantinib offers a new therapeutic avenue for patients with advanced NETs who have progressed after prior therapies.
- Broad Applicability: The findings support the use of cabozantinib in both extrapancreatic and pancreatic NETs.
- Adverse Event Management: Clinicians should closely monitor and manage treatment-related adverse events to optimize patient outcomes.
Study Strengths and Limitations: Strengths include a large sample size, randomized controlled design, and inclusion of patients who had progressed after standard therapies, enhancing the applicability of the findings to clinical practice. Limitations involve early trial termination based on interim analysis, which may overestimate the treatment effect, the use of placebo rather than an active comparator, and the high rate of dose modifications due to adverse events.
Future Research: Further studies should explore the optimal sequencing of cabozantinib with other therapies in NETs and investigate combination treatments. Long-term studies assessing overall survival benefits and quality of life are warranted.
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.
Polled Analysis: Semaglutide Reduces Heart Failure Events in Obese Patients with HFpEF
12 Sep, 2024 | 13:39h | UTCStudy Design and Population: This post-hoc pooled analysis combined data from four randomized, placebo-controlled trials (SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM) involving 3,743 participants with heart failure and preserved or mildly reduced ejection fraction (HFpEF). The participants had various comorbidities including obesity, diabetes, and atherosclerotic cardiovascular disease. They were randomized to receive either semaglutide or placebo.
Main Findings: Semaglutide significantly reduced the risk of the composite endpoint of cardiovascular death or worsening heart failure events compared to placebo (HR 0.69, 95% CI 0.53–0.89, p=0.0045). It also reduced worsening heart failure events alone (HR 0.59, 95% CI 0.41–0.82, p=0.0019). However, no significant reduction in cardiovascular death alone was observed (HR 0.82, 95% CI 0.57–1.16, p=0.25). Semaglutide was generally well tolerated, with fewer serious adverse events compared to placebo.
Implications for Practice: These findings suggest semaglutide may be an effective therapy to reduce heart failure-related events in obese patients with HFpEF. Although semaglutide did not reduce cardiovascular death, its ability to lower the risk of heart failure hospitalizations makes it a potential therapeutic option for managing HFpEF in this population, a condition with limited treatment choices.
RCT: Once-Weekly Insulin Efsitora Non-Inferior to Insulin Degludec for HbA1c Control but Increases Hypoglycemia in Adults with Type 1 Diabetes
12 Sep, 2024 | 13:06h | UTCStudy Design and Population: This 52-week, randomized, open-label non-inferiority trial included 692 adults with type 1 diabetes from 82 global sites. Participants were randomly assigned to receive once-weekly insulin efsitora (n=343) or once-daily insulin degludec (n=349), both in combination with insulin lispro. The primary objective was to assess the change in HbA1c from baseline to week 26, with a non-inferiority margin of 0.4%.
Main Findings: HbA1c reduction was similar between the groups at 26 weeks (–0.51% for efsitora vs. –0.56% for degludec; p=0.43). However, participants on efsitora experienced higher rates of level 2 or 3 hypoglycemia (14.03 vs. 11.59 events per patient year, p=0.016) and a greater incidence of severe hypoglycemia (10% for efsitora vs. 3% for degludec). Overall, the safety profile was similar, with no treatment-related deaths.
Implications for Practice: Once-weekly insulin efsitora offers comparable glycemic control to daily degludec, but its association with increased hypoglycemia, especially during dose titration, indicates that closer monitoring and optimization are necessary. This treatment could reduce the burden of daily injections, but its hypoglycemia risks must be managed carefully.
Cohort Study: Lower Risk of Cardiovascular Complications in Post–COVID-19 Vaccine Myocarditis Compared to Conventional Etiologies
7 Sep, 2024 | 20:36h | UTCStudy Design and Population: This French nationwide cohort study included 4,635 individuals aged 12-49 hospitalized for myocarditis between December 2020 and June 2022. The cohort was divided into three groups: 558 patients with post–COVID-19 mRNA vaccine myocarditis, 298 with post–COVID-19 infection myocarditis, and 3,779 with conventional myocarditis.
Main Findings: At 18 months of follow-up, the frequency of cardiovascular events was significantly lower in the postvaccine myocarditis group (5.7%) compared to conventional myocarditis (13.2%) with a weighted hazard ratio (wHR) of 0.55 (95% CI, 0.36-0.86). Hospital readmission for myopericarditis occurred in 3.2% of postvaccine cases, 4.0% of post–COVID-19 cases, and 5.8% of conventional cases. The all-cause mortality rate was 0.2% for postvaccine myocarditis, 1.3% for post–COVID-19 myocarditis, and 1.3% for conventional myocarditis.
Implications for Practice: Postvaccine myocarditis patients, primarily young males, experience fewer complications compared to conventional myocarditis, but long-term follow-up is still needed. These findings should guide future mRNA vaccine recommendations and clinical management for myocarditis patients.
Reference: Semenzato L. et al. (2024). Long-term Prognosis of Myocarditis Attributed to COVID-19 mRNA Vaccination, SARS-CoV-2, or Conventional Etiologies. JAMA, Online. DOI: http://doi.org/10.1001/jama.2024.16380
Link: https://jamanetwork.com/journals/jama/fullarticle/2822933
RCT: Olanzapine Improves Nausea and Vomiting Control in Moderately Emetogenic Chemotherapy but Increases Somnolence
7 Sep, 2024 | 19:28h | UTCStudy Design and Population: This phase 3, multicenter, open-label randomized clinical trial involved 560 chemotherapy-naive patients aged 18 years or older with solid malignant tumors. The trial, conducted at three institutes in India, compared the efficacy of adding olanzapine to standard antiemetic therapy in patients receiving moderately emetogenic chemotherapy (MEC) based on oxaliplatin, carboplatin, or irinotecan.
Main Findings: The group receiving olanzapine in addition to standard antiemetic therapy showed significantly higher complete response (CR) rates (91% vs 82%, P = .005) compared to the observation group. The olanzapine group also demonstrated superior control of nausea (96% vs 87%, P < .001) and chemotherapy-induced nausea and vomiting (CINV) (96% vs 91%, P = .02). The use of rescue medications was significantly lower in the olanzapine group. Grade 1 somnolence occurred in 10% of patients receiving olanzapine but was absent in the observation group.
Implications for Practice: The results support the inclusion of olanzapine in antiemetic regimens for MEC to improve CINV outcomes. However, mild somnolence should be considered when prescribing olanzapine as part of antiemetic prophylaxis. Further research could explore dose optimization to minimize adverse effects.
Reference: Ostwal, V. et al. (2024). Olanzapine as antiemetic prophylaxis in moderately emetogenic chemotherapy: a phase 3 randomized clinical trial. JAMA Network Open. DOI: http://doi.org/10.1001/jamanetworkopen.2024.26076
Link: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2822027
Meta-Analysis: Ticagrelor Monotherapy Reduces Bleeding Without Increasing Ischemic Risk in Coronary Stent Patients
7 Sep, 2024 | 15:06h | UTCStudy Design and Population: This systematic review and individual patient-level meta-analysis pooled data from six randomized trials, comparing ticagrelor monotherapy after short-term dual antiplatelet therapy (DAPT) with standard 12-month DAPT in patients who underwent percutaneous coronary intervention with drug-eluting stents. The analysis included 23,256 patients in the per-protocol population and 24,407 in the intention-to-treat population, excluding those requiring long-term anticoagulants.
Main Findings: Ticagrelor monotherapy was found to be noninferior to 12-month DAPT for major adverse cardiovascular or cerebrovascular events (MACCE), with a hazard ratio (HR) of 0.91 (95% CI 0.78-1.07). It also reduced the risk of major bleeding (HR 0.43, p<0.0001) and all-cause mortality (HR 0.76, p=0.034). Subgroup analyses suggested possible benefits in women for mortality and in patients with acute coronary syndrome (ACS) for bleeding reduction.
Implications for Practice: Ticagrelor monotherapy may offer a safer alternative to prolonged DAPT by reducing bleeding risks without increasing ischemic events, particularly in ACS patients. Further research is needed to fully explore potential survival benefits, especially in women.
Reference: Valgimigli M, Hong S-J, Gragnano F, et al. (2024). De-escalation to ticagrelor monotherapy versus 12 months of dual antiplatelet therapy in patients with and without acute coronary syndromes: a systematic review and individual patient-level meta-analysis of randomised trials. Lancet. http://doi.org/10.1016/S0140-6736(24)01616-7
Link: https://www.sciencedirect.com/science/article/pii/S0140673624016167