Internal Medicine

Prospective Cohort: Combined CRP, LDL Cholesterol, and Lipoprotein(a) Levels Predict 30-Year Cardiovascular Risk in Women

8 Dec, 2024 | 20:58h | UTC

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RCT: Transcatheter Edge-to-edge Repair Improves Outcomes in Severe Tricuspid Regurgitation

29 Nov, 2024 | 12:37h | UTC

Background: Severe tricuspid regurgitation (TR) is linked to poor quality of life and increased mortality. Traditional medical therapy offers limited symptom relief, and surgical options carry high risks. Transcatheter tricuspid valve therapies like transcatheter edge-to-edge repair (T-TEER) have emerged as less invasive alternatives, but their impact on patient outcomes needs further exploration.

Objective: To determine if T-TEER combined with optimized medical therapy (OMT) enhances patient-reported outcomes and clinical events compared to OMT alone in patients with severe, symptomatic TR.

Methods: In this multicenter, prospective, randomized (1:1) trial, 300 adults with severe, symptomatic TR despite stable OMT were enrolled from 24 centers in France and Belgium between March 2021 and March 2023. Participants were randomized to receive either T-TEER plus OMT or OMT alone. The primary outcome was a composite clinical endpoint at 1 year, including changes in New York Heart Association (NYHA) class, patient global assessment (PGA), or occurrence of major cardiovascular events. Secondary outcomes encompassed TR severity, Kansas City Cardiomyopathy Questionnaire (KCCQ) score, and a composite of death, tricuspid valve surgery, KCCQ improvement, or hospitalization for heart failure.

Results: At 1 year, 74.1% of patients in the T-TEER plus OMT group improved in the composite endpoint versus 40.6% in the OMT-alone group (P < .001). Massive or torrential TR persisted in 6.8% of the T-TEER group compared to 53.5% of the OMT group (P < .001). The mean KCCQ score was higher in the T-TEER group (69.9 vs 55.4; P < .001). The win ratio for the composite secondary outcome was 2.06 (95% CI, 1.38-3.08; P < .001). No significant differences were observed in major cardiovascular events or cardiovascular death between groups.

Conclusions: Adding T-TEER to OMT significantly reduces TR severity and improves patient-reported outcomes at 1 year in patients with severe, symptomatic TR, without increasing adverse events.

Implications for Practice: T-TEER may offer a valuable addition to OMT for selected patients with severe TR, enhancing symptoms and quality of life. However, the absence of significant differences in hard clinical endpoints and the open-label design suggest cautious interpretation. Clinicians should weigh the benefits against potential biases in patient-reported outcomes.

Study Strengths and Limitations: Strengths include the randomized design and multicenter participation, enhancing the study’s validity. Limitations involve the open-label design without a sham control, potentially introducing bias in subjective outcomes. The short follow-up period and selective patient population based on anatomical suitability for T-TEER may limit generalizability.

Future Research: Longer-term studies are necessary to assess T-TEER’s impact on survival and heart failure hospitalization. Comparative studies of different transcatheter devices and investigations into optimal patient selection criteria are also recommended.

Reference: Donal E, Dreyfus J, Leurent G, et al. Transcatheter Edge-to-Edge Repair for Severe Isolated Tricuspid Regurgitation: The Tri.Fr Randomized Clinical Trial. JAMA. Published online November 27, 2024. DOI: http://doi.org/10.1001/jama.2024.21189

 

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Management of Adult Sepsis in Resource-Limited Settings: A Global Delphi-Based Consensus

24 Dec, 2024 | 13:35h | UTC

Introduction: This summary presents key points from a recent expert consensus on managing adult sepsis under limited-resource conditions, where patients may lack access to an ICU bed, advanced monitoring technologies, or sufficient staffing. The statements were developed through a Delphi process involving an international panel of clinicians, aiming to complement existing sepsis guidelines by focusing on pragmatic approaches and context-specific adaptations. These consensus statements address unique challenges such as limited diagnostic tests, alternative strategies for hemodynamic monitoring, and management of sepsis in areas with tropical infections.

Key Recommendations:

1. Location of Care and Transfer
   • When an ICU bed is unavailable, care can be provided in a non-ICU setting if minimum monitoring (neurological status, blood pressure, peripheral perfusion) is ensured.
   • Before transferring a patient, ensure airway patency, initiate intravenous fluids and antimicrobials, and maintain safe transport conditions.
   • Incorporate telemedicine or phone consultation with critical care specialists whenever feasible.
2. Diagnostic Considerations
   • Employ screening tools (e.g., qSOFA) in areas with limited resources, acknowledging its diagnostic constraints.
   • Use clinical parameters like altered mental state, capillary refill time (CRT), and urine output to gauge tissue perfusion when lactate measurement is unavailable.
   • Insert an indwelling urinary catheter in septic shock to monitor urine output accurately, balancing infection risks against close monitoring needs.
3. Hemodynamic Management
   • Rely on clinical indicators (CRT, urine output) to guide fluid resuscitation when serum lactate is not accessible.
   • Use fluid responsiveness tests (e.g., passive leg raising, pulse pressure variation) if advanced hemodynamic monitoring is impractical.
   • Consider balanced solutions such as Ringer’s lactate or Hartmann’s solution for fluid resuscitation.
   • Recognize that patients with tropical infections (e.g., malaria, dengue) may require cautious fluid volumes to avoid overload.
   • Initiate epinephrine if norepinephrine or vasopressin is unavailable, and use vasopressors through peripheral lines if central access cannot be established.
4. Antimicrobial Therapy
   • Administer antibiotics without delay (ideally within one hour) in suspected sepsis or septic shock.
   • In severe infections of parasitic origin (e.g., malaria), start antiparasitic agents promptly.
   • In settings where laboratory investigations are limited, begin broad-spectrum antimicrobial coverage when infection cannot be ruled out.
   • De-escalate or discontinue therapy based on clinical improvement, declining white blood cell counts, and adequate source control.
5. Respiratory Support
   • For acute hypoxemic respiratory failure in septic patients, noninvasive ventilation (NIV) can be used if high-flow nasal oxygen is not available, provided close monitoring for potential failure is ensured.

Conclusion: These consensus-based statements offer practical guidance for clinicians treating sepsis in resource-limited environments. By adapting globally accepted recommendations and incorporating alternative strategies—such as clinical markers of perfusion, use of peripheral vasopressors, and prioritizing immediate antimicrobial therapy—these principles aim to improve patient outcomes where healthcare resources are scarce. Further research and context-specific adaptations will be essential to address remaining uncertainties and refine these expert recommendations.

Reference:
Thwaites, L., Nasa, P., Abbenbroek, B. et al. Management of adult sepsis in resource-limited settings: global expert consensus statements using a Delphi method. Intensive Care Medicine (2024). https://doi.org/10.1007/s00134-024-07735-7

 

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Review: Chronic Hand Eczema

29 Nov, 2024 | 12:28h | UTC

Introduction: Hand eczema is a highly prevalent inflammatory skin condition and one of the most common work-related disorders, with a lifetime prevalence of approximately 15%. In up to two-thirds of affected individuals, the disease becomes chronic—persisting for more than three months or recurring multiple times within a year—leading to substantial personal and occupational disability. This review by Weidinger and Novak synthesizes current knowledge on the epidemiology, risk factors, clinical features, diagnosis, mechanisms, and management of chronic hand eczema, highlighting the need for further research to enhance prevention and treatment strategies.

Key Recommendations:

1. Risk Factor Identification: Recognize major risk factors, including current or past atopic dermatitis, dry skin, and occupational exposure to irritants and allergens. Occupational history is crucial, as hand eczema is prevalent in high-risk professions such as health care, hairdressing, and cleaning.
2. Diagnosis and Assessment: Diagnose chronic hand eczema based on history and clinical features, considering differential diagnoses like psoriasis and tinea manus. Patch testing is recommended to identify contact allergens, especially in cases unresponsive to initial therapy.
3. Patient Education and Prevention: Implement structured education on skin care, avoidance of trigger factors, and use of protective measures. Emphasize primary to tertiary prevention strategies, including workplace interventions and rehabilitation programs.
4. Topical Therapies: Initiate treatment with topical glucocorticosteroids for anti-inflammatory effect. Use calcineurin inhibitors as second-line therapy, particularly for patients refractory to steroids or requiring long-term treatment. The topical pan-Janus kinase inhibitor delgocitinib is approved for moderate to severe chronic hand eczema unresponsive to corticosteroids.
5. Phototherapy: Consider short-term phototherapy (4–8 weeks) with options like PUVA or narrow-band UVB for patients inadequately controlled with topical treatments.
6. Systemic Therapies: For severe cases unresponsive to topical treatments, systemic retinoids such as alitretinoin are first-line therapy. Off-label use of immunosuppressants like ciclosporine, methotrexate, and azathioprine may be considered. Systemic immunomodulatory therapies approved for atopic dermatitis, including dupilumab and Janus kinase inhibitors, show promise, especially in atopic hand eczema.
7. Adjunctive Measures: Encourage the use of emollients for skin barrier repair and recommend avoidance of harmful exposures. Patient self-management is crucial, including appropriate hand hygiene and use of protective gloves.

Conclusion: By adopting these evidence-based management strategies, clinicians can improve patient care by reducing symptoms, preventing disease progression, and enhancing quality of life for individuals with chronic hand eczema. Early identification of risk factors, comprehensive patient education, and individualized treatment plans are essential to mitigate the substantial personal and socioeconomic burden of this condition.

Reference: Weidinger S, Novak N. Hand eczema. The Lancet. 2024. DOI: http://doi.org/10.1016/S0140-6736(24)01810-5

 

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RCT: Adjunctive Middle Meningeal Artery Embolization Reduces Reoperation in Subdural Hematoma

24 Nov, 2024 | 13:53h | UTC

Background: Subacute and chronic subdural hematomas are common neurosurgical conditions with a high recurrence rate after surgical evacuation, affecting 8% to 20% of patients. Middle meningeal artery embolization (MMAE) is a minimally invasive procedure targeting the blood supply to these membranes. Preliminary studies suggest that adjunctive MMAE may reduce hematoma recurrence, but its impact on reoperation risk remains unclear.

Objective: To determine whether adjunctive MMAE reduces the risk of hematoma recurrence or progression leading to repeat surgery within 90 days compared to surgery alone in patients with symptomatic subacute or chronic subdural hematoma.

Methods: In this prospective, multicenter, randomized controlled trial, 400 patients aged 18 to 90 years with symptomatic subacute or chronic subdural hematoma requiring surgical evacuation were randomly assigned to receive either MMAE plus surgery (n=197) or surgery alone (n=203). The primary endpoint was hematoma recurrence or progression leading to repeat surgery within 90 days after the index treatment. The secondary endpoint was deterioration of neurologic function at 90 days, assessed using the modified Rankin Scale.

Results: Hematoma recurrence or progression requiring repeat surgery occurred in 8 patients (4.1%) in the MMAE plus surgery group versus 23 patients (11.3%) in the surgery-alone group (relative risk, 0.36; 95% CI, 0.11 to 0.80; P=0.008). Functional deterioration at 90 days was similar between groups (11.9% vs. 9.8%; risk difference, 2.1 percentage points; 95% CI, −4.8 to 8.9). Mortality at 90 days was 5.1% in the MMAE group and 3.0% in the control group. Serious adverse events related to the embolization occurred in 4 patients (2.0%), including disabling stroke in 2 patients.

Conclusions: Adjunctive MMAE combined with surgery significantly reduced the risk of hematoma recurrence or progression requiring reoperation within 90 days compared to surgery alone. However, there was no significant difference in neurologic functional deterioration, and the procedure was associated with procedural risks.

Implications for Practice: MMAE may be considered as an adjunct to surgical evacuation in patients with subacute or chronic subdural hematoma to reduce reoperation risk. Clinicians should carefully weigh the potential benefits against the risks of procedural complications, including stroke.

Study Strengths and Limitations: Strengths include the randomized controlled design and multicenter approach, enhancing generalizability. Limitations involve the open-label design, introducing potential bias since the primary endpoint was based on surgeon judgment. A substantial loss to follow-up (13.2%) could affect results, and the study was not powered to detect differences in mortality or serious adverse events.

Future Research: Further studies with larger sample sizes are needed to fully evaluate the safety and efficacy of MMAE, including long-term outcomes. Research should focus on optimizing patient selection and assessing the procedure’s impact on mortality and serious adverse events.

Reference: Davies JM, et al. Adjunctive Middle Meningeal Artery Embolization for Subdural Hematoma. New England Journal of Medicine. 2024; DOI: http://doi.org/10.1056/NEJMoa2313472

 

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Cohort Study: Oral Hormone Therapy and Tibolone Increase Cardiovascular Risk in Menopausal Women

28 Nov, 2024 | 18:42h | UTC

Background: Cardiovascular disease is the leading cause of mortality worldwide, with incidence in women increasing notably during the menopausal transition. Menopausal hormone therapy (MHT) effectively alleviates menopausal symptoms but has been associated with cardiovascular risks in previous studies. The impact of contemporary MHT formulations and administration routes on cardiovascular disease risk in women aged 50–58 remains unclear.

Objective: To assess the effect of different types of contemporary MHT on the risk of cardiovascular disease, focusing on various hormone combinations and administration methods.

Methods: This nationwide register-based emulated target trial included 919,614 Swedish women aged 50–58 years between 2007 and 2020 who had not used MHT in the previous two years. Participants were assigned to one of eight treatment groups—including oral and transdermal therapies—or to a non-initiator group. The primary outcomes were hazard ratios (HRs) for venous thromboembolism (VTE), ischemic heart disease (IHD), cerebral infarction, and myocardial infarction, analyzed separately and as a composite cardiovascular disease outcome.

Results: Among the participants, 77,512 were MHT initiators and 842,102 were non-initiators. During follow-up, 24,089 cardiovascular events occurred. In intention-to-treat analyses, tibolone was associated with an increased risk of cardiovascular disease (HR 1.52, 95% CI 1.11 to 2.08) compared with non-initiators. Initiation of tibolone or oral estrogen-progestin therapy was linked to a higher risk of IHD (HRs 1.46 and 1.21, respectively). A higher risk of VTE was observed with oral continuous estrogen-progestin therapy (HR 1.61), sequential therapy (HR 2.00), and estrogen-only therapy (HR 1.57). Per protocol analyses showed that tibolone use was associated with increased risks of cerebral infarction (HR 1.97) and myocardial infarction (HR 1.94).

Conclusions: Use of oral estrogen-progestin therapy was associated with increased risks of IHD and VTE, while tibolone was linked to higher risks of IHD, cerebral infarction, and myocardial infarction but not VTE. These findings underscore the varying cardiovascular risks associated with different MHT types and administration methods.

Implications for Practice: Clinicians should exercise caution when prescribing oral estrogen-progestin therapy or tibolone for menopausal symptom relief, considering the elevated cardiovascular risks. Alternative MHT options, such as transdermal therapies, may offer a safer profile and should be considered.

Study Strengths and Limitations: Strengths include the large, nationwide cohort and the emulated target trial design, which reduces selection bias and confounding. Limitations involve the lack of data on menopausal status, smoking, and body mass index, which may affect cardiovascular risk. Potential misclassification of exposure and adherence could also impact results.

Future Research: Further studies should investigate the cardiovascular effects of specific progestins within MHT formulations and explore the impact of different doses and durations of therapy.

Reference: Johansson T, Karlsson T, Bliuc D, et al. Contemporary menopausal hormone therapy and risk of cardiovascular disease: Swedish nationwide register based emulated target trial. BMJ. 2024;387:e078784. DOI: http://doi.org/10.1136/bmj-2023-078784

 

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Review: Acute Respiratory Distress Syndrome

28 Nov, 2024 | 13:06h | UTC

Introduction: Acute respiratory distress syndrome (ARDS) is a severe inflammatory lung condition characterized by diffuse alveolar damage, leading to hypoxemia and respiratory failure. Since its initial description in 1967, the understanding and definition of ARDS have significantly evolved, integrating advances in basic science and clinical practice. A newly recommended global definition expands diagnostic criteria to enhance early recognition and management, especially in resource-limited settings. This review summarizes current insights into the epidemiology, pathophysiology, and evidence-based management of ARDS, highlighting key updates and future research priorities.

Key Recommendations:

1. New Global Definition of ARDS: Adoption of an expanded definition that includes patients receiving high-flow nasal oxygen (HFNO) support and allows diagnosis using pulse oximetry and thoracic ultrasonography. This makes ARDS identification feasible in diverse clinical environments, including those with limited resources.
2. Established Critical Care Interventions: Emphasis on early implementation of proven strategies such as low tidal volume ventilation (6 mL/kg predicted body weight) with plateau pressures ≤30 cm H₂O, prone positioning for patients with PaO₂/FiO₂ <150 mm Hg, and conservative fluid management after initial resuscitation. These interventions have consistently reduced mortality and are recommended as standard care.
3. Personalized Approaches and Phenotyping: Recognition of the heterogeneity in ARDS pathophysiology underscores the need for personalized treatment strategies. Identification of hyper-inflammatory and hypo-inflammatory phenotypes may guide targeted therapies and improve outcomes, although prospective validation is required.
4. Impact of COVID-19 on ARDS: Acknowledgment of the significant increase in ARDS incidence due to the COVID-19 pandemic. While COVID-19 ARDS shares similarities with traditional ARDS, notable differences in endothelial dysfunction and immune response highlight the necessity for tailored management approaches in these patients.
5. Pharmacologic Interventions: Updated guidelines provide conditional recommendations for the use of corticosteroids in ARDS, particularly in early moderate to severe cases. Ongoing research into pharmacologic agents such as statins, mesenchymal stromal cells, and other cell-based therapies shows potential but requires further clinical trials to establish efficacy.
6. Future Research Priorities: Identification of key areas for investigation, including the long-term sequelae of ARDS, optimization of non-invasive and invasive ventilation strategies, exploration of genetic and environmental risk factors, and development of rapid biomarker assays for real-time phenotyping and targeted therapy.

Conclusion: The evolving definition and understanding of ARDS aim to improve early detection and standardization of care across various clinical settings. Reinforcing established critical care interventions while advancing personalized and novel therapeutic approaches holds promise for reducing mortality and enhancing long-term patient outcomes. Continuous research into the pathophysiology and management of ARDS, enriched by insights from the COVID-19 pandemic, is essential to address ongoing challenges and improve patient care.

Reference: Wick KD, Ware LB, Matthay MA. Acute respiratory distress syndrome. BMJ. 2024;387:e076612. DOI: http://doi.org/10.1136/bmj-2023-076612

 

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Review: Management of Degenerative Rotator-Cuff Disorders

28 Nov, 2024 | 12:48h | UTC

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RCT: Twice-Yearly Lenacapavir Reduces HIV Incidence in Men and Gender-Diverse Persons Background

28 Nov, 2024 | 12:38h | UTC

Background: Although preexposure prophylaxis (PrEP) effectively reduces HIV transmission, adherence to daily oral regimens is suboptimal among high-risk populations. Lenacapavir, a long-acting HIV-1 capsid inhibitor administered subcutaneously every six months, has shown efficacy in cisgender women, but its efficacy in men and gender-diverse individuals remains unclear.

Objective: To evaluate the safety and efficacy of twice-yearly subcutaneous lenacapavir compared to background HIV incidence and daily oral emtricitabine–tenofovir disoproxil fumarate (F/TDF) in preventing HIV infection among men and gender-diverse persons.

Methods: In this phase 3, double-blind, randomized trial, 3,271 HIV-negative participants were assigned in a 2:1 ratio to receive subcutaneous lenacapavir every 26 weeks or daily oral F/TDF, with matching placebos. Participants were cisgender men, transgender women and men, and gender-nonbinary persons aged 16 or older who have sex with male-assigned partners. The primary endpoint compared HIV incidence in the lenacapavir group to background incidence; secondary analysis compared lenacapavir to F/TDF.

Results: In the modified intention-to-treat analysis (n=3,265), HIV infections occurred in 2 participants in the lenacapavir group (0.10 per 100 person-years) and 9 in the F/TDF group (0.93 per 100 person-years). The background HIV incidence was 2.37 per 100 person-years. Lenacapavir significantly reduced HIV incidence compared to background (incidence rate ratio [IRR], 0.04; 95% CI, 0.01–0.18; P<0.001) and F/TDF (IRR, 0.11; 95% CI, 0.02–0.51; P=0.002). No significant safety concerns emerged. Injection-site reactions led to discontinuation in 1.2% of lenacapavir recipients and 0.3% of F/TDF recipients.

Conclusions: Twice-yearly subcutaneous lenacapavir significantly reduced HIV incidence compared to both the background incidence and daily oral F/TDF among men and gender-diverse persons. These findings support lenacapavir as an effective PrEP option in this population.

Implications for Practice: The introduction of a long-acting, twice-yearly injectable PrEP option like lenacapavir could improve adherence and uptake among populations challenged by daily oral regimens.

Study Strengths and Limitations: Strengths include a large, diverse participant population with significant representation of transgender and gender-nonbinary persons, and the use of an active comparator. The novel counterfactual design estimating background HIV incidence avoided ethical issues of placebo controls but may have limitations in accuracy. Limitations include a relatively short follow-up and potential impact of injection-site reactions on adherence. The emergence of resistance mutations in participants who acquired HIV while on lenacapavir is a concern needing further investigation.

Future Research: Further studies should assess the long-term safety, efficacy, and resistance patterns associated with lenacapavir use. Research into optimizing injection techniques to minimize injection-site reactions and exploring lenacapavir’s applicability in other at-risk populations is recommended.

Reference: Kelley CF, et al. Twice-Yearly Lenacapavir for HIV Prevention in Men and Gender-Diverse Persons. New England Journal of Medicine. Published November 27, 2024. DOI: http://doi.org/10.1056/NEJMoa2411858

 

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Cohort Study: Metformin Linked to Fewer Asthma Attacks in Patients with Asthma and Type 2 Diabetes

24 Nov, 2024 | 20:36h | UTC

Background: Patients with asthma frequently have comorbid obesity and type 2 diabetes (T2D), conditions associated with an increased risk of asthma attacks. Experimental studies suggest that metformin and glucagon-like peptide-1 receptor agonists (GLP-1RAs) can reduce airway inflammation and hyperresponsiveness. However, epidemiological evidence supporting these effects is limited.

Objective: To evaluate the association between metformin use, with or without add-on antidiabetic medications, and the risk of asthma attacks in patients with asthma and T2D.

Methods: This study utilized data from the UK Clinical Practice Research Datalink Aurum from 2004 to 2020, employing two analytical approaches: a self-controlled case series (SCCS) of 4,278 new metformin users with asthma who experienced asthma attacks, and a population-based cohort study using inverse probability of treatment weighting (IPTW) including 8,424 patients. The primary exposure was initiation of metformin; secondary exposures included add-on antidiabetic medications. The primary outcome was the first asthma exacerbation—defined as a short course of oral corticosteroids, unscheduled asthma-related hospital attendance, or death—during 12 months of follow-up.

Results: Metformin use was associated with a significant reduction in asthma attacks in both analyses. In the SCCS, metformin initiation was linked to a 32% reduction in risk (incidence rate ratio [IRR], 0.68; 95% CI, 0.62-0.75). In the IPTW cohort, metformin use was associated with a 24% reduction (hazard ratio [HR], 0.76; 95% CI, 0.67-0.85). Addition of GLP-1RAs led to a further reduction in asthma attacks (IRR, 0.60; 95% CI, 0.49-0.73). Associations were consistent regardless of glycemic control, body mass index, asthma severity, or blood eosinophil counts.

Conclusions: The findings suggest that metformin use is associated with a lower rate of asthma attacks among patients with asthma and T2D, with additional benefits when GLP-1RAs are added. These effects appear independent of glycemic control or weight loss and occur across different asthma phenotypes.

Implications for Practice: These results indicate potential for repurposing metformin as an adjunct therapy to reduce asthma attacks in patients with asthma and T2D. However, as observational studies cannot establish causality, clinicians should interpret these findings cautiously. The higher cost and side-effect profile of GLP-1RAs warrant careful consideration before widespread adoption.

Study Strengths and Limitations: Strengths include a large, nationally representative sample and the use of two distinct analytical methods to enhance robustness. Limitations involve the observational design, which cannot confirm causality, and potential residual confounding factors such as medication adherence and dosage. Additionally, possible misclassification of asthma diagnosis and lack of data on changes in weight may affect the findings.

Future Research: Randomized controlled trials are necessary to confirm these findings and elucidate the mechanisms by which metformin and GLP-1RAs may reduce asthma attacks. Further studies should explore the benefits of early pharmacological intervention with antidiabetic medications in patients with asthma and metabolic dysfunction.

Reference: Lee B, et al. Antidiabetic Medication and Asthma Attacks. JAMA Internal Medicine. 2024. DOI: http://doi.org/10.1001/jamainternmed.2024.5982

 

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Consensus Guideline: Low-Dose Oral Minoxidil for Hair Loss Management

24 Nov, 2024 | 20:27h | UTC

Introduction: Hair loss significantly affects patients’ quality of life, encompassing conditions like androgenetic alopecia, alopecia areata, and telogen effluvium. While topical minoxidil is FDA-approved for certain hair loss types, limitations have led to increased off-label use of low-dose oral minoxidil (LDOM). Recognizing the need for standardized guidance, an international panel of 43 dermatologists from 12 countries developed a consensus statement using a modified Delphi process to inform best practices for prescribing LDOM until more robust evidence emerges.

Key Recommendations:

1. Patient Selection:
   • Indications: LDOM may benefit adults and adolescents with androgenetic alopecia, age-related thinning, alopecia areata, telogen effluvium, traction alopecia, persistent chemotherapy-induced alopecia, and endocrine therapy–induced alopecia.
   • Contraindications: LDOM is contraindicated in patients with hypersensitivity to minoxidil, significant drug interactions, history of pericardial effusion or tamponade, pericarditis, congestive heart failure, pulmonary hypertension with mitral stenosis, pheochromocytoma, and during pregnancy or breastfeeding.
   • Precautions: Use cautiously in patients with tachycardia, arrhythmias, hypotension (blood pressure <90/60 mm Hg), impaired kidney function, or those undergoing dialysis.
2. Dosing Guidelines:
   • Adults:
     • Females: Starting dose of 1.25 mg daily; dosing range 0.625 mg to 5 mg daily.
     • Males: Starting dose of 2.5 mg daily; dosing range 1.25 mg to 5 mg daily.
   • Adolescents (12–17 years):
     • Females: Starting dose of 0.625 mg daily; dosing range 0.625 mg to 2.5 mg daily.
     • Males: Starting dose of 1.25 mg daily; dosing range 1.25 mg to 5 mg daily.
   • Considerations: Dosing influenced by sex, age, risk of systemic adverse effects, and desire to minimize hypertrichosis.
3. Monitoring and Evaluation:
   • Baseline Assessments: Routine labs and ECGs are not required unless precautions are present; consult specialists if needed.
   • Adverse Effects Monitoring: Counsel patients on potential side effects like hypertrichosis, dizziness, tachycardia, and fluid retention; monitor for signs such as swelling or weight gain.
   • Efficacy Expectations: Initial effects may be observed at three months; efficacy may take up to six months if transient shedding occurs.
4. Adjunctive Therapies:
   • Spironolactone: May be co-administered in female patients with hirsutism, acne, or polycystic ovary syndrome to enhance treatment efficacy and manage fluid retention.
   • Beta-Blockers: Consider in consultation with specialists, especially for managing tachycardia.
5. Preference Over Topical Minoxidil:
   • LDOM may be preferred when topical minoxidil causes scalp irritation, is cosmetically unacceptable, ineffective, or when enhanced hypertrichosis is desired.

Conclusion: This consensus provides a structured approach for clinicians considering LDOM as an off-label treatment for hair loss. By outlining patient selection, dosing, monitoring, and when to seek specialist input, these recommendations aim to optimize patient outcomes and safety.

Reference: Akiska YM, et al. Low-Dose Oral Minoxidil Initiation for Patients With Hair Loss: An International Modified Delphi Consensus Statement. JAMA Dermatology. 2024. DOI: http://doi.org/10.1001/jamadermatol.2024.4593

 

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Phase 2 RCT: Zerlasiran Lowers Lipoprotein(a) Levels by Over 80% in Patients With ASCVD

24 Nov, 2024 | 20:18h | UTC

Background: Elevated lipoprotein(a) [Lp(a)] is a genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. Traditional lipid-lowering therapies, including statins and lifestyle modifications, do not effectively reduce Lp(a) levels. Small-interfering RNA (siRNA) therapies targeting hepatic production of apolipoprotein(a) offer a potential approach to lowering Lp(a) concentrations.

Objective: To evaluate the efficacy and safety of zerlasiran, an siRNA targeting apolipoprotein(a) synthesis, in reducing serum Lp(a) concentrations in patients with ASCVD.

Methods: In this randomized, double-blind, placebo-controlled phase 2 trial, 178 adults with stable ASCVD and elevated Lp(a) levels (≥125 nmol/L) were enrolled across 26 sites in Europe and South Africa. Participants were randomized to receive subcutaneous zerlasiran at doses of 450 mg every 24 weeks (n=45), 300 mg every 16 weeks (n=42), or 300 mg every 24 weeks (n=44), or matching placebo every 16 weeks (n=23) or every 24 weeks (n=24). The primary outcome was the time-averaged percent change in Lp(a) concentration from baseline to week 36.

Results: Zerlasiran significantly reduced Lp(a) levels compared to placebo. The placebo-adjusted time-averaged percent reductions were −85.6% (95% CI, −90.9% to −80.3%) for 450 mg every 24 weeks, −82.8% (95% CI, −88.2% to −77.4%) for 300 mg every 16 weeks, and −81.3% (95% CI, −86.7% to −76.0%) for 300 mg every 24 weeks. Median percent reductions at week 36 exceeded 90% in all zerlasiran groups. The most common adverse events were mild injection site reactions, occurring in up to 7.1% of participants. No serious adverse events were attributed to the study drug.

Conclusions: Zerlasiran was well-tolerated and produced substantial reductions in Lp(a) levels over 36 weeks in patients with ASCVD.

Implications for Practice: If validated in larger, long-term studies that assess cardiovascular outcomes, zerlasiran may offer a novel treatment for patients with elevated Lp(a), addressing a significant unmet need in cardiovascular risk management. Clinicians should, however, exercise caution until the impact on hard endpoints such as myocardial infarction and stroke, as well as long-term safety, are confirmed.

Study Strengths and Limitations: Strengths include the randomized, double-blind design and significant Lp(a) reductions observed. Limitations involve the predominantly White, male study population, limiting generalizability. The study did not assess clinical endpoints like cardiovascular events, so the impact on actual cardiovascular risk remains unknown. Additionally, the moderate sample size and duration may not detect rare adverse events or long-term effects, necessitating further investigation.

Future Research: Larger, long-term phase 3 trials are needed to confirm these findings, assess the impact on cardiovascular events, and evaluate efficacy and safety in more diverse populations.

Reference: Nissen SE, Wang Q, Nicholls SJ, et al. Zerlasiran—A Small-Interfering RNA Targeting Lipoprotein(a): A Phase 2 Randomized Clinical Trial. Journal of the American Medical Association. Published online November 18, 2024. DOI: http://doi.org/10.1001/jama.2024.21957

 

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Meta-analysis: Low/Moderate-Intensity Statins with Ezetimibe May Offer Better LDL-C Reduction and Safety over High-Intensity Statins

24 Nov, 2024 | 20:01h | UTC

Background: Despite widespread use of high-intensity statin therapy, achieving target LDL-C levels and reducing cardiovascular events remain challenging in patients with or at high risk of atherosclerotic cardiovascular disease (ASCVD). High-intensity statins can have dose-dependent adverse effects, limiting their tolerability. Combining low/moderate-intensity statins with ezetimibe, a cholesterol absorption inhibitor, may enhance lipid-lowering efficacy with fewer side effects.

Objective: To compare the clinical effectiveness and safety of low/moderate-intensity statins combined with ezetimibe versus high-intensity statin monotherapy in reducing major adverse cardiovascular events (MACEs) and lowering LDL-C levels.

Methods: A systematic review and meta-analysis were conducted according to PRISMA guidelines. Fifteen studies (6 randomized controlled trials [RCTs] and 9 observational studies) encompassing 251,450 participants were included. The primary outcome was a composite of cardiovascular death or major cardiovascular events. Secondary outcomes included lipid-lowering efficacy and safety measures such as muscle-related adverse events and liver enzyme elevations.

Results: Observational studies indicated that combination therapy was associated with lower rates of the primary composite outcome (HR = 0.76; 95% CI [0.73, 0.80]), cardiovascular death (HR = 0.80; 95% CI [0.74, 0.88]), all-cause death (HR = 0.84; 95% CI [0.78, 0.91]), and non-fatal stroke (HR = 0.81; 95% CI [0.75, 0.87]). RCTs showed that combination therapy resulted in a greater number of patients achieving LDL-C levels < 70 mg/dL (RR = 1.27; 95% CI [1.21, 1.34]) and significant reductions in LDL-C (MD = –7.95 mg/dL; 95% CI [–10.02, –5.89]) and total cholesterol (MD = –26.77 mg/dL; 95% CI [–27.64, –25.89]). Combination therapy also reduced muscle-related adverse events (RR = 0.52; 95% CI [0.32, 0.85]) and liver enzyme elevations (RR = 0.51; 95% CI [0.29, 0.89]) in RCTs.

Conclusions: Combining low/moderate-intensity statins with ezetimibe may offer superior lipid-lowering effects and better safety profiles compared to high-intensity statin monotherapy. While observational studies suggest improved clinical outcomes, these findings need confirmation from large-scale, long-term RCTs.

Implications for Practice: The combination therapy could be a viable option for patients intolerant to high-intensity statins or those requiring additional LDL-C lowering to reach target levels. However, clinicians should interpret these potential benefits cautiously due to reliance on observational data for clinical outcomes and the lack of robust RCT evidence.

Study Strengths and Limitations: Strengths include a comprehensive search strategy and a large patient population. Limitations involve heavy reliance on observational studies for clinical outcomes.

Future Research: Large, well-designed RCTs with longer follow-up periods are needed to confirm the clinical benefits and safety of the combination therapy over high-intensity statin monotherapy across diverse populations.

Reference: Sydhom P, et al. The clinical effectiveness and safety of low/moderate-intensity statins & ezetimibe combination therapy vs. high-intensity statin monotherapy: a systematic review and meta-analysis. BMC Cardiovascular Disorders. 2024; DOI: https://doi.org/10.1186/s12872-024-04144-y

 

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Review: Candida auris Infections

24 Nov, 2024 | 19:50h | UTC

Introduction: Candida auris, first identified in Japan in 2009, has rapidly emerged as a global public health threat due to its multidrug resistance and propensity to cause difficult-to-control outbreaks in healthcare settings. This review by Lionakis and Chowdhary aims to provide clinicians with an in-depth understanding of the mycologic features, immune responses, epidemiology, risk factors, clinical manifestations, diagnosis, antifungal resistance, treatment, and prevention strategies associated with C. auris infections to inform effective patient care and containment measures.

Key Points:

1. Mycologic Features: C. auris is a budding yeast that thrives in high-salt and high-temperature environments. It is divided into five clades (I–V) with distinct geographic distributions and varying virulence and resistance profiles.
2. Immune Response: The interleukin-17 pathway is crucial in reducing skin colonization by C. auris, while phagocytes like monocytes, macrophages, and neutrophils are essential for clearing bloodstream and organ infections.
3. Epidemiology: Reported in over 45 countries, C. auris is known for causing outbreaks in healthcare facilities due to its persistence on skin and surfaces and challenges in accurate identification. The CDC classifies it as an urgent threat, and the WHO places it in the “critical” group of human fungal pathogens.
4. Risk Factors: Key risk factors include advanced age, indwelling medical devices, immunocompromised states, diabetes, recent surgery, use of broad-spectrum antibiotics or antifungals, prolonged hospitalization, and severe COVID-19.
5. Clinical Manifestations: Primarily causing invasive infections like candidemia, C. auris is associated with high morbidity and mortality rates (30–60%). Up to 25% of critically ill colonized patients may develop invasive infections.
6. Diagnosis: Accurate identification is challenging due to misidentification with other Candida species on conventional tests. Reliable methods include MALDI-TOF mass spectrometry, sequencing of rDNA regions, and molecular assays like PCR.
7. Antifungal Resistance: C. auris exhibits clade-specific multidrug resistance, with most strains resistant to fluconazole and some resistant to echinocandins and amphotericin B. Resistance mechanisms involve mutations in the ERG11 and FKS1 genes.
8. Treatment: Echinocandins are recommended as first-line treatment for invasive C. auris infections. Close monitoring is essential due to potential treatment failure and emergence of resistance. Amphotericin B formulations may be used in neonates or if echinocandin resistance is present.
9. Prevention: Strict infection control measures are critical, including contact precautions, environmental cleaning with EPA-registered disinfectants effective against C. auris, surveillance screening, and cohorting of patients to prevent nosocomial transmission.

Conclusion: The rapid global spread of multidrug-resistant C. auris presents significant challenges for clinical management and infection control. Early and accurate diagnosis, appropriate antifungal therapy, and stringent prevention strategies are essential to improve patient outcomes and prevent further dissemination of this pathogen.

Reference: Lionakis MS, Chowdhary A. Candida auris Infections. New England Journal of Medicine. 2024; DOI: http://doi.org/10.1056/NEJMra2402635

 

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RCT: Fezolinetant Reduces Vasomotor Symptoms in Menopausal Individuals Unfit for Hormone Therapy

24 Nov, 2024 | 19:29h | UTC

Background: Vasomotor symptoms (VMS), including hot flushes and night sweats, are prevalent and often debilitating during menopause. Hormone therapy (HT) is effective but contraindicated or unsuitable for many due to medical conditions or personal choice, creating a need for safe, non-hormonal treatments.

Objective: To evaluate the efficacy and safety of fezolinetant, a non-hormonal neurokinin 3 receptor antagonist, in treating moderate to severe VMS in menopausal individuals unsuitable for HT.

Methods: This phase 3b, randomized, double-blind, placebo-controlled trial was conducted across 16 countries. A total of 453 individuals aged 40-65 years with moderate to severe VMS unsuitable for HT were randomized 1:1 to receive fezolinetant 45 mg once daily or placebo for 24 weeks. The primary endpoint was the mean change in daily frequency of moderate to severe VMS from baseline to week 24. Secondary endpoints included changes in VMS severity, sleep disturbance, and safety evaluations.

Results: Of the 452 participants who received at least one dose of the study drug (fezolinetant n=226, placebo n=226), 370 (81.7%) completed the study. The mean age was 54.5 years, and most participants were white (96.7%) and categorized as either HT averse or requiring caution with HT. At week 24, fezolinetant significantly reduced the frequency of VMS compared with placebo (least squares mean difference [LSMD] –1.93 episodes/day; 95% CI –2.64 to –1.22; P<0.001). It also significantly reduced VMS severity (LSMD –0.39; 95% CI –0.57 to –0.21; P<0.001) and improved sleep disturbance scores (LSMD –2.5; 95% CI –3.9 to –1.1; P<0.001). Improvements were observed as early as week 1 and sustained throughout the study. The incidence of treatment-emergent adverse events (TEAEs) was similar between the fezolinetant and placebo groups (65.0% vs. 61.1%, respectively). No significant safety concerns, including liver toxicity, were identified.

Conclusions: Fezolinetant was effective and well-tolerated over 24 weeks in reducing moderate to severe VMS in menopausal individuals unsuitable for HT.

Implications for Practice: Fezolinetant offers a promising alternative for managing VMS in individuals who cannot or choose not to use HT. Clinicians should consider this option but remain cautious due to limited long-term safety data. Individual patient preferences, risk factors, and the novelty of the medication should be weighed in clinical decision-making.

Study Strengths and Limitations: Strengths include the large sample size and extended placebo-controlled duration. Limitations involve the predominantly white study population, potentially limiting generalizability to more diverse groups. The exclusion of individuals over 65 years old and the lack of direct comparison with other non-hormonal treatments also constrain the applicability of the findings.

Future Research: Further studies are needed to assess the long-term safety and efficacy of fezolinetant, particularly in diverse populations and older individuals.

Reference: Schaudig K, et al. Efficacy and safety of fezolinetant for moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy: phase 3b randomised controlled trial. BMJ. 2024; DOI: http://doi.org/10.1136/bmj-2024-079525

 

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News Release: Anticoagulation Does Not Prevent Cognitive Decline in Younger Low-Risk AFib Patients

20 Nov, 2024 | 20:17h | UTC

Introduction: A recent large-scale trial has found that anticoagulation therapy does not reduce the risk of cognitive decline, stroke, or transient ischemic attack (TIA) in adults under 65 years old with atrial fibrillation (AFib) who have no additional stroke risk factors. AFib is the most common type of irregular heart rhythm and is known to increase the risk of stroke, especially in older individuals or those with comorbidities. This study aimed to determine if blood thinners could offer neurocognitive and cerebrovascular protection in younger, low-risk AFib patients.

Highlights: The Blinded Randomized Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive Impairment in Atrial Fibrillation (BRAIN-AF) enrolled over 1,200 participants with an average age of 53 years, none of whom had standard indications for anticoagulation therapy. Participants were randomly assigned to receive either rivaroxaban (15 mg daily) or a placebo and were followed for an average of 3.7 years.

Key findings from the trial include:

• No Significant Difference in Primary Outcomes: There was no significant difference between the rivaroxaban and placebo groups in the combined outcome of cognitive decline (a decrease of two or more points on the Montreal Cognitive Assessment), stroke, or TIA. The annual rates were 7% for rivaroxaban and 6.4% for placebo.
• High Rate of Cognitive Decline: Approximately 1 in 5 participants experienced cognitive decline, accounting for 91% of the primary outcome events. Despite this high rate, anticoagulation did not mitigate the risk.
• Low Incidence of Stroke: The incidence of stroke was low in this population, at less than 1 in 100 participants per year.
• Early Termination of the Trial: The study was terminated early due to futility, as continuing was unlikely to demonstrate a benefit from anticoagulation in preventing cognitive decline or stroke in this group.
• Safety Profile: Major bleeding events were rare and did not differ significantly between the rivaroxaban and placebo groups.

These results confirm that younger AFib patients without additional stroke risk factors have a low incidence of stroke and that anticoagulation does not reduce the risk of cognitive decline or cerebrovascular events in this population.

Conclusion: The BRAIN-AF trial supports current clinical guidelines that do not recommend anticoagulation therapy for AFib patients under 65 years old without other stroke risk factors. The findings suggest that anticoagulation is not effective in preventing cognitive decline or stroke in this low-risk group. Clinicians should continue to focus on standard recommendations for maintaining cognitive health, such as promoting a healthy lifestyle, engaging in brain-stimulating activities, and encouraging regular physical activity, rather than prescribing anticoagulation therapy for neurocognitive protection in these patients.

Source: This study was conducted by researchers at the Montreal Heart Institute and Université de Montréal and was presented at the American Heart Association’s Scientific Sessions 2024.

• American Heart Association News Release: https://newsroom.heart.org/news/blood-thinners-didnt-reduce-cognitive-decline-in-adults-65-and-younger-with-afib

Additional commentaries:

• TCTMD: https://www.tctmd.com/news/rivaroxaban-doesnt-cut-cognitive-decline-stroke-or-tia-younger-af-patients
• American College of Cardiology: https://www.acc.org/latest-in-cardiology/clinical-trials/2024/11/15/15/17/brain-af

 

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News Release: Edoxaban Comparable to Warfarin for Stroke Prevention After Bioprosthetic Valve Surgery

20 Nov, 2024 | 20:05h | UTC

Introduction: A recent multicenter trial from Japan, presented at the American Heart Association’s Scientific Sessions 2024, has found that edoxaban, a direct oral anticoagulant, is as effective as warfarin in preventing stroke and systemic embolism in patients following bioprosthetic heart valve replacement surgery. This addresses the ongoing need for alternative anticoagulant therapies that simplify post-surgical management and enhance patient quality of life.

Highlights: The ENBALV trial enrolled approximately 400 adults aged 41 to 84 who underwent bioprosthetic valve replacement at the aortic and/or mitral position. Participants were randomly assigned to receive either edoxaban (60 mg or 30 mg once daily) or warfarin for 12 weeks post-surgery. Unlike warfarin, edoxaban does not require regular blood tests to monitor clotting activity and has fewer interactions with food and other medications.

Key findings include:

• Efficacy: Stroke or systemic embolism occurred in 0.5% of patients receiving edoxaban compared to 1.5% in the warfarin group, indicating comparable effectiveness.
• Thrombus Formation: No intracardiac thrombus was observed in the edoxaban group, whereas it occurred in 1% of patients on warfarin.
• Bleeding Risks: Major bleeding events were higher in the edoxaban group (4.1% vs. 1% with warfarin). While no fatal bleeding or intracranial hemorrhage occurred with edoxaban, one fatal cerebral hemorrhage was reported in the warfarin group. Gastrointestinal bleeding was more common with edoxaban (2.1% vs. 0% with warfarin).

Lead author Dr. Chisato Izumi noted that edoxaban’s fixed dosing and minimal dietary interactions reduce the treatment burden, potentially improving patient adherence during the critical post-operative period.

Conclusion: The findings suggest that edoxaban is a viable alternative to warfarin for anticoagulation after bioprosthetic valve surgery, offering similar protection against stroke and blood clots with the convenience of simplified management. However, the increased incidence of bleeding events with edoxaban underscores the need for careful patient selection and further research to identify individuals at higher risk. These results may inform future clinical guidelines and improve patient care by providing more flexible anticoagulant options.

Source: This study was conducted by the National Cerebral and Cardiovascular Center in Suita, Japan, and presented at the American Heart Association’s Scientific Sessions 2024. The full news release is available at: http://newsroom.heart.org/news/patients-taking-edoxoban-after-heart-valve-surgery-had-lower-risk-of-stroke-blood-clots

Additional commentaries can be found at:

• American College of Cardiology: https://www.acc.org/latest-in-cardiology/articles/2024/11/13/21/17/sun-935am-enbalv-aha-2024
• TCTMD: https://www.tctmd.com/news/enbalv-edoxaban-matches-warfarin-after-bioprosthetic-valve-surgery

 

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News Release: Sacubitril/Valsartan May Reduce Chemotherapy-Induced Cardiotoxicity in High-Risk Cancer Patients

20 Nov, 2024 | 18:38h | UTC

Introduction: A recent study presented at the American Heart Association’s Scientific Sessions 2024 introduces sacubitril/valsartan, a widely used heart failure medication, as a potential protective agent against heart damage in high-risk cancer patients undergoing anthracycline chemotherapy. Anthracyclines, while effective for treating various cancers such as breast cancer, leukemia, and lymphoma, carry a significant risk of cardiotoxicity, leading to cardiomyopathy and heart failure. The SARAH trial aimed to evaluate whether sacubitril/valsartan could mitigate this risk and preserve cardiac function during chemotherapy.

Highlights: The SARAH trial was a randomized, double-blind, placebo-controlled study involving 114 high-risk cancer patients at Erasto Gaertner Hospital in Curitiba, Brazil. High risk was defined by elevated high-sensitivity troponin I levels post-anthracycline infusion, indicating early signs of cardiac injury. Participants, predominantly women with breast cancer (81%), were randomized to receive sacubitril/valsartan or a placebo over 24 weeks.

Key findings include:

• Significant Reduction in Cardiotoxicity: Sacubitril/valsartan was associated with a 77% reduction in the relative risk of cardiotoxicity compared to placebo. Cardiotoxicity was measured as a ≥15% reduction in global longitudinal strain (GLS), a sensitive marker of left ventricular function.
• Improvement in Cardiac Function: Patients in the sacubitril/valsartan group experienced an average improvement in GLS by 2.55%, whereas those in the placebo group showed an average decline of 6.65%.
• Dose Titration and Tolerance: The medication was initiated at a dose of 24/26 mg twice daily and titrated every two weeks to a target of 97/103 mg twice daily or the highest tolerated dose without side effects. It was generally well tolerated, with hypotension being more common in the treatment group (14% vs. 1.8%) but no significant differences in other adverse events.
• Independent of Other Factors: The protective effect of sacubitril/valsartan was consistent regardless of cumulative anthracycline dose, HER2 status, presence of hypertension, or patient age.

Conclusion: The findings from the SARAH trial suggest that sacubitril/valsartan may offer a promising strategy to prevent chemotherapy-induced cardiotoxicity in high-risk cancer patients. By preserving cardiac function during anthracycline treatment, this medication has the potential to improve patient outcomes, enhance quality of life, and reduce the long-term burden of heart failure among cancer survivors. Further research with larger, more diverse populations and extended follow-up is warranted to confirm these results and assess the impact on long-term clinical outcomes.

Source: This research was conducted by the Heart Institute at the University of São Paulo, Brazil, and presented at the American Heart Association Scientific Sessions 2024.

Primary Source: American Heart Association News Release
https://newsroom.heart.org/news/a-common-heart-failure-medication-may-help-prevent-heart-damage-related-to-chemotherapy-6906417

Secondary Sources:

• American College of Cardiology Summary of the SARAH Trial
  https://www.acc.org/Latest-in-Cardiology/Articles/2024/11/13/21/17/mon-915am-sarah-aha-2024
• TCTMD Article: “ARNI Lessens Anthracycline Cardiotoxicity in High-Risk Patients: SARAH”
  https://www.tctmd.com/news/arni-lessens-anthracycline-cardiotoxicity-high-risk-patients-sarah

 

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RCT: 7-Day Antibiotic Therapy Noninferior to 14-Day for Bloodstream Infections

20 Nov, 2024 | 18:19h | UTC

Background: Bloodstream infections are a significant cause of morbidity and mortality worldwide. Early and appropriate antibiotic therapy is essential, but the optimal duration remains uncertain. Prolonged antibiotic use can lead to adverse events, Clostridioides difficile infection, antimicrobial resistance, and increased healthcare costs.

Objective: To determine whether a 7-day course of antibiotic treatment is noninferior to a 14-day course in hospitalized patients with bloodstream infections regarding 90-day all-cause mortality.

Methods: In this multicenter, noninferiority randomized controlled trial, 3,608 hospitalized patients from 74 hospitals in seven countries were enrolled. Eligible patients had bloodstream infections but were excluded if they had severe immunosuppression, infections requiring prolonged therapy, possible contaminants, or Staphylococcus aureus bacteremia. Participants were randomized to receive either 7 days (n=1,814) or 14 days (n=1,794) of adequate antibiotic therapy, with antibiotic selection at the clinicians’ discretion. The primary outcome was death from any cause by 90 days post-diagnosis, with a noninferiority margin of 4 percentage points.

Results: At 90 days, mortality was 14.5% in the 7-day group and 16.1% in the 14-day group (difference: –1.6 percentage points; 95.7% CI, –4.0 to 0.8), demonstrating noninferiority of the shorter duration. Noninferiority was confirmed in per-protocol and modified intention-to-treat analyses. Secondary outcomes, including relapse rates, adverse events, and hospital length of stay, were similar between groups. Findings were consistent across subgroups based on infection source, pathogen type, and patient characteristics.

Conclusions: A 7-day antibiotic regimen is noninferior to a 14-day regimen for treating hospitalized patients with bloodstream infections, without increasing mortality or relapse rates.

Implications for Practice: Implementing a 7-day antibiotic course could reduce antibiotic exposure, minimize adverse events, and potentially limit antimicrobial resistance development. Clinicians should consider individual patient factors, such as infection severity and comorbidities, before universally adopting shorter treatment durations.

Study Strengths and Limitations: Strengths include a large, diverse patient population and inclusion of critically ill patients, enhancing generalizability. Limitations involve the open-label design and nonadherence to assigned durations in some cases (23.1% in the 7-day group continued antibiotics longer). Exclusion of S. aureus bacteremia limits applicability to that subgroup. The study may not have been powered to detect differences in rare adverse outcomes like C. difficile infection or antimicrobial resistance emergence.

Future Research: Further studies should explore the efficacy of even shorter antibiotic durations, individualized treatment strategies based on patient response, and the long-term impact on antimicrobial resistance and healthcare costs.

Reference: The BALANCE Investigators, for the Canadian Critical Care Trials Group and others. Antibiotic Treatment for 7 versus 14 Days in Patients with Bloodstream Infections. New England Journal of Medicine. Published November 20, 2024. DOI: http://doi.org/10.1056/NEJMoa2404991

 

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RCT: Colchicine Does Not Reduce Cardiovascular Events After Myocardial Infarction

20 Nov, 2024 | 18:12h | UTC

Background: Inflammation is a key contributor to atherosclerosis and adverse cardiovascular events. Previous trials have suggested that anti-inflammatory agents like colchicine may reduce cardiovascular risks in patients with coronary artery disease.

Objective: To evaluate whether colchicine reduces the incidence of major cardiovascular events when initiated soon after a myocardial infarction.

Methods: In this multicenter, randomized, placebo-controlled trial with a 2-by-2 factorial design, 7,062 patients who experienced a myocardial infarction were assigned to receive colchicine (0.5 mg daily) or placebo, and spironolactone or placebo. The colchicine results are reported here. The primary outcome was a composite of death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemia-driven coronary revascularization. Median follow-up was 3 years.

Results: A primary outcome event occurred in 9.1% of patients in the colchicine group and 9.3% in the placebo group (hazard ratio, 0.99; 95% CI, 0.85 to 1.16; P=0.93). Individual components of the primary outcome were similar between groups. Colchicine significantly reduced C-reactive protein levels at 3 months (adjusted mean difference of –1.28 mg/L; 95% CI, –1.81 to –0.75). Diarrhea was more frequent with colchicine (10.2% vs. 6.6%; P<0.001), but serious infections did not differ significantly.

Conclusions: Among patients post-myocardial infarction, colchicine did not reduce the incidence of major cardiovascular events over a median of 3 years compared to placebo.

Implications for Practice: These findings suggest that initiating colchicine after myocardial infarction may not provide additional cardiovascular benefits. Clinicians should weigh the lack of efficacy and potential gastrointestinal side effects when considering colchicine for secondary prevention in this population.

Study Strengths and Limitations: Strengths include a large sample size and extended follow-up. Limitations involve a higher-than-expected discontinuation rate and underrepresentation of women and diverse populations. The predominance of STEMI patients may limit applicability to NSTEMI cases.

Future Research: Further studies are needed to identify if specific subgroups might benefit from colchicine or if different dosing strategies could be more effective in reducing cardiovascular events post-myocardial infarction.

Reference: Jolly SS, d’Entremont M-A, Lee SF, et al. Colchicine in Acute Myocardial Infarction. New England Journal of Medicine. Published November 17, 2024. DOI: http://doi.org/10.1056/NEJMoa2405922

 

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RCT: Routine Spironolactone Post-MI Does Not Reduce Cardiovascular Events

20 Nov, 2024 | 18:03h | UTC

Background: Mineralocorticoid receptor antagonists (MRAs), such as spironolactone, have demonstrated mortality benefits in patients with heart failure following myocardial infarction (MI). However, the efficacy of routine spironolactone use in all patients post-MI, regardless of heart failure status, remains uncertain.

Objective: To evaluate whether routine administration of spironolactone reduces cardiovascular events in patients after MI who have undergone percutaneous coronary intervention (PCI).

Methods: In a multicenter, double-blind, placebo-controlled trial with a 2-by-2 factorial design, 7,062 patients with MI undergoing PCI were randomized to receive spironolactone (25 mg daily) or placebo, and colchicine or placebo. The two primary outcomes were: (1) a composite of death from cardiovascular causes or new or worsening heart failure, assessed as the total number of events; and (2) a composite of the first occurrence of MI, stroke, new or worsening heart failure, or death from cardiovascular causes. Median follow-up was 3 years.

Results: No significant differences were observed between the spironolactone and placebo groups in the primary outcomes. For the first primary outcome, there were 183 events (1.7 per 100 patient-years) in the spironolactone group versus 220 events (2.1 per 100 patient-years) in the placebo group (hazard ratio [HR] adjusted for competing risk, 0.91; 95% confidence interval [CI], 0.69–1.21; P=0.51). For the second primary outcome, events occurred in 280 patients (7.9%) in the spironolactone group and 294 patients (8.3%) in the placebo group (HR adjusted for competing risk, 0.96; 95% CI, 0.81–1.13; P=0.60). Serious adverse events were similar between groups.

Conclusions: Routine use of spironolactone after MI did not reduce cardiovascular mortality or new or worsening heart failure compared to placebo.

Implications for Practice: These findings suggest that routine prescription of spironolactone for all patients after MI may not be beneficial and should be reconsidered. Clinicians should carefully evaluate the indication for MRAs post-MI, particularly in patients without heart failure, and remain cautious about routine use without clear evidence of benefit.

Study Strengths and Limitations: Strengths of the study include its large sample size, multicenter international design, and long follow-up period, enhancing the generalizability of the findings. However, limitations include lower-than-expected event rates, potentially reducing statistical power to detect significant differences. The high rate of discontinuation of the trial regimen and underrepresentation of women and certain racial and ethnic groups may also limit the applicability of the results. Additionally, the possibility of a type II error due to reduced power cannot be excluded.

Future Research: Further studies are warranted to identify specific subgroups of patients who may benefit from spironolactone post-MI and to explore alternative therapies that effectively reduce cardiovascular events after MI.

Reference: Jolly SS, d’Entremont M-A, Pitt B, et al. Routine Spironolactone in Acute Myocardial Infarction. New England Journal of Medicine. Published November 17, 2024. DOI: http://doi.org/10.1056/NEJMoa2405923

 

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RCT: Left Atrial Appendage Closure May Reduce Bleeding Without Increasing Stroke Risk After AF Ablation

20 Nov, 2024 | 16:28h | UTC

Background: Catheter ablation is an effective treatment for symptomatic atrial fibrillation (AF), but patients at high risk for stroke require ongoing oral anticoagulation (OAC) due to the potential for asymptomatic AF recurrence. Left atrial appendage closure (LAAC) is a mechanical alternative to OAC, but its efficacy and safety post-AF ablation are not well established.

Objective: To compare the safety and efficacy of LAAC versus continued OAC in patients with AF undergoing catheter ablation.

Methods: In this international, randomized trial, 1,600 patients with AF and elevated CHA₂DS₂-VASc scores (≥2 in men, ≥3 in women) who underwent or were scheduled for catheter ablation were assigned to either LAAC (n=803) or OAC (n=797). The primary safety endpoint was non–procedure-related major bleeding or clinically relevant nonmajor bleeding through 36 months. The primary efficacy endpoint was a composite of death from any cause, stroke, or systemic embolism at 36 months. The secondary endpoint was major bleeding, including procedure-related bleeding.

Results: At 36 months, bleeding events occurred in 8.5% of the LAAC group versus 18.1% of the OAC group (P<0.001 for superiority). The primary efficacy endpoint occurred in 5.3% of the LAAC group and 5.8% of the OAC group (P<0.001 for noninferiority). Major bleeding, including procedure-related bleeding, occurred in 3.9% of the LAAC group and 5.0% of the OAC group (P<0.001 for noninferiority). Device-related complications occurred in 23 patients, and incomplete device closure was noted in up to 20% of patients.

Conclusions: Among patients undergoing AF ablation, LAAC reduced the risk of bleeding compared to OAC without increasing the risk of death, stroke, or systemic embolism over 36 months.

Implications for Practice: LAAC may be considered as an alternative to long-term OAC in patients undergoing AF ablation who are at moderate to high risk of stroke. However, clinicians should exercise caution due to potential device-related complications, such as incomplete closure and peri-device leaks, which may increase stroke risk. The decision to use LAAC should involve a thorough discussion with the patient about the benefits and risks.

Study Strengths and Limitations: Strengths include the randomized design and large sample size. Limitations involve the exclusion of procedure-related bleeding from the primary safety endpoint, potentially underestimating the true bleeding risk of LAAC. The inclusion of all-cause mortality in the primary efficacy endpoint may dilute the ability to detect differences in stroke risk. Additionally, missing data and a significant rate of incomplete device closure raise concerns about the generalizability and safety of LAAC.

Future Research: Further large-scale, randomized trials are needed to address these limitations, especially to assess stroke risk adequately and the impact of procedural complications. Studies should also evaluate long-term outcomes and the cost-effectiveness of LAAC compared to OAC in diverse patient populations.

References:

1. Wazni OM, Saliba WI, Nair DG, et al. Left Atrial Appendage Closure after Ablation for Atrial Fibrillation. New England Journal of Medicine. Published November 16, 2024. DOI: http://doi.org/10.1056/NEJMoa2408308
2. Mandrola J. Electrophysiology is on the brink of a possible disaster. November 19, 2024. Available at: https://johnmandrola.substack.com/p/electrophysiology-is-on-the-brink

 

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Meta-Analysis: Moderately Rapid Sodium Correction Linked to Better Outcomes in Severe Hyponatremia

20 Nov, 2024 | 16:10h | UTC

Background: Severe hyponatremia is a critical condition that can lead to hyponatremic encephalopathy, necessitating prompt treatment to prevent neurological damage or death. Traditional guidelines recommend limiting sodium correction rates to prevent osmotic demyelination syndrome (ODS). However, emerging evidence suggests that slower correction rates may be associated with increased mortality.

Objective: To evaluate the association between sodium correction rates and mortality among hospitalized adults with severe hyponatremia.

Methods: This systematic review and meta-analysis included 16 cohort studies published between January 2013 and October 2023, involving 11,811 hospitalized adults with severe hyponatremia (serum sodium <120 mEq/L or <125 mEq/L with severe symptoms). Patients were categorized based on sodium correction rates: rapid (≥8-10 mEq/L per 24 hours), slow (<8 or 6-10 mEq/L per 24 hours), and very slow (<4-6 mEq/L per 24 hours). Primary outcomes were in-hospital and 30-day mortality; secondary outcomes included hospital length of stay (LOS) and incidence of ODS.

Results: Rapid correction was associated with significantly lower in-hospital mortality compared to slow correction (odds ratio [OR], 0.67; 95% CI, 0.55-0.82) and very slow correction (OR, 0.29; 95% CI, 0.11-0.79), corresponding to 32 and 221 fewer deaths per 1,000 patients, respectively. At 30 days, rapid correction was associated with 61 and 134 fewer deaths per 1,000 patients compared to slow and very slow correction, respectively. Rapid correction also resulted in shorter hospital LOS by 1.20 days (95% CI, 0.51-1.89) compared to slow correction and 3.09 days (95% CI, 1.21-4.94) compared to very slow correction. There was no statistically significant increase in ODS risk with rapid correction.

Conclusions: In hospitalized adults with severe hyponatremia, rapid sodium correction was associated with reduced mortality and shorter hospital stays without a significant increase in ODS risk.

Implications for Practice: These findings suggest that more aggressive sodium correction may benefit patients with severe hyponatremia, challenging current guidelines that recommend slower correction rates to prevent ODS. Clinicians should weigh the potential benefits of rapid correction against the traditionally emphasized risks, although caution is still warranted given the seriousness of ODS.

Study Strengths and Limitations: Strengths include a large sample size and inclusion of recent studies reflecting current practices. Limitations involve the observational nature of included studies, potential confounding factors, heterogeneity in correction rate definitions, and possible underreporting of ODS due to its rarity and diagnostic challenges.

Future Research: Randomized controlled trials are needed to establish causality and optimal correction rates, as well as to identify patient subgroups that may benefit most from rapid correction while minimizing ODS risk.

Reference: Ayus JC, Moritz ML, Fuentes NA, et al. Correction Rates and Clinical Outcomes in Hospitalized Adults With Severe Hyponatremia: A Systematic Review and Meta-Analysis. JAMA Internal Medicine. Published online November 18, 2024. DOI: http://doi.org/10.1001/jamainternmed.2024.5981

 

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RCT: Linear Ablation Plus Ethanol infusion of the vein of Marshall Enhances Rhythm Outcomes in Persistent AF

20 Nov, 2024 | 15:48h | UTC

Background: Pulmonary vein isolation (PVI) is the cornerstone of catheter ablation for atrial fibrillation (AF) but has modest efficacy in persistent AF. Previous randomized trials have not demonstrated additional benefit from adding linear ablation to PVI, possibly due to challenges in achieving durable lesions. Ethanol infusion of the vein of Marshall (EIVOM) may facilitate linear ablation, especially at the mitral isthmus, potentially improving outcomes.

Objective: To determine whether adding linear ablation combined with EIVOM to PVI improves maintenance of sinus rhythm compared with PVI alone in patients with persistent AF.

Methods: PROMPT-AF was an investigator-initiated, multicenter, open-label randomized trial involving 12 hospitals in China. The study included 498 patients aged 18–80 years with persistent AF lasting >3 months undergoing first-time ablation. Participants were randomized to either PVI alone or PVI plus EIVOM and linear ablation targeting the left atrial roof, mitral isthmus, and cavotricuspid isthmus. Primary outcomes included freedom from atrial arrhythmias lasting >30 seconds without antiarrhythmic drugs over 12 months. Patients were monitored weekly with wearable ECG patches and periodic Holter monitoring.

Results: Among 495 patients analyzed (mean age, 61.1 years; 72.9% male), the intervention group demonstrated significantly higher freedom from atrial arrhythmias without antiarrhythmic drugs (70.7% vs 61.5%; HR, 0.73; 95% CI, 0.54–0.99; P = .045). Secondary outcomes showed no significant differences in quality of life or arrhythmia recurrence with antiarrhythmic drugs. Linear ablation increased procedural time (188.0 vs 140.8 minutes, P < .001) and fluoroscopy exposure. Serious adverse events were comparable between groups, though pericarditis or pericardial effusion occurred in 7 intervention patients versus none in the control.

Conclusions: Adding linear ablation and EIVOM to PVI significantly improves freedom from atrial arrhythmias in patients with persistent AF compared with PVI alone.

Implications for Practice: The combination of linear ablation and EIVOM addresses limitations of PVI alone by enhancing lesion durability and targeting challenging areas such as the mitral isthmus. However, the increased procedural complexity and longer operative times highlight the need for skilled operators. Adoption should be balanced against risks and resource demands.

Study Strengths and Limitations: Strengths include the randomized, multicenter design and high procedural adherence. Limitations involve the open-label design and potential underestimation of arrhythmia recurrence due to intermittent rhythm monitoring rather than continuous monitoring. The increased procedural time and fluoroscopy exposure are concerns, and the findings may not be generalizable to all persistent AF patients, especially those with episodes lasting less than 3 months.

Future Research: Further studies are needed to optimize ablation strategies, assess long-term outcomes, and evaluate the safety, efficacy, and cost-effectiveness of incorporating EIVOM and linear ablation in diverse patient populations.

Reference: Sang C, Liu Q, Lai Y, et al. Pulmonary Vein Isolation With Optimized Linear Ablation vs Pulmonary Vein Isolation Alone for Persistent AF: The PROMPT-AF Randomized Clinical Trial. JAMA. Published online November 18, 2024. DOI: http://doi.org/10.1001/jama.2024.24438

 

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Review: Comparative Analysis of ESC and ESH Hypertension Guidelines

20 Nov, 2024 | 15:03h | UTC

Introduction: Hypertension remains a significant global health challenge with increasing prevalence and substantial morbidity and mortality rates. To address this, the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH) have independently published updated guidelines on hypertension management. This review provides a pragmatic comparison of these guidelines, highlighting their major similarities and differences to assist clinicians in optimizing patient care.

Key Recommendations:

Shared Recommendations:

1. Diagnosis Criteria: Both guidelines recommend diagnosing hypertension based on office systolic and diastolic blood pressures of ≥140/90 mmHg.
2. Blood Pressure Targets: Both advocate aiming for an optimal blood pressure of <130/80 mmHg. The ESH emphasizes personalized targets for specific populations like the elderly, while the ESC adopts the ALARA (as low as reasonably achievable) principle.
3. Out-of-Office Measurements: Emphasis is placed on home blood pressure monitoring and ambulatory measurements to confirm diagnoses and tailor treatments.
4. Comprehensive Assessment: Both recommend thorough initial evaluations, including screening for orthostatic hypotension, comorbidities, and hypertension-mediated organ damage (HMOD).
5. Early Treatment Initiation: Both suggest starting antihypertensive therapy promptly, preferably using a single-pill combination of two agents after lifestyle interventions.
6. Treatment Goals and Follow-Up: Both aim for patients to reach blood pressure targets within three months, underscoring the importance of close monitoring.
7. Adjunctive Therapies: The use of SGLT-2 inhibitors is recommended for patients with chronic kidney disease and/or heart failure. Renal denervation is considered for true resistant hypertension.

Differences:

1. Blood Pressure Classification: The ESC introduces a new category of “elevated blood pressure,” altering patient classification but with minimal impact on practical management.
2. Screening for Secondary Hypertension: The ESC strongly encourages screening for secondary hypertension, particularly primary aldosteronism; the ESH does not emphasize this as strongly.
3. Age Stratification: Different age thresholds for the very elderly are used (ESH: ≥80 years; ESC: ≥85 years), with the ESH providing more detailed treatment personalization for this group.
4. Treatment Targets Philosophy: The ESC supports the ALARA principle for blood pressure targets, aiming for the lowest achievable levels without adverse effects, while the ESH provides specific target ranges.
5. Beta-Blocker Use: The ESH includes beta-blockers as first-line therapy options, whereas the ESC positions them as third-line agents.

Conclusion: Despite minor discrepancies, the ESC and ESH hypertension guidelines are largely concordant and based on the same evidence base. Both sets provide clear, pragmatic recommendations emphasizing early diagnosis, personalized treatment, and close follow-up. Clinicians can confidently use either guideline to inform practice, as both aim to improve patient outcomes by effectively managing hypertension in the primary care setting.

Reference: Virdis A, et al. Juxtaposing Hypertension Guidelines: Are They Different? A Pragmatic Look to ESC and ESH Guidelines on (Arterial) Hypertension. High Blood Pressure & Cardiovascular Prevention. 2024; DOI: https://doi.org/10.1007/s40292-024-00693-7

 

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