Family Medicine
RCT: Transcatheter Edge-to-edge Repair Improves Outcomes in Severe Tricuspid Regurgitation
29 Nov, 2024 | 12:37h | UTCBackground: 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.
Review: Chronic Hand Eczema
29 Nov, 2024 | 12:28h | UTCIntroduction: 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:
- 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.
- 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.
- 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.
- 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.
- Phototherapy: Consider short-term phototherapy (4–8 weeks) with options like PUVA or narrow-band UVB for patients inadequately controlled with topical treatments.
- 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.
- 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.
Cohort Study: Oral Hormone Therapy and Tibolone Increase Cardiovascular Risk in Menopausal Women
28 Nov, 2024 | 18:42h | UTCBackground: 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.
Review: Management of Degenerative Rotator-Cuff Disorders
28 Nov, 2024 | 12:48h | UTCIntroduction: Degenerative rotator-cuff disorders are a leading cause of shoulder pain, especially in adults over 40 years of age, involving tendon degeneration from tendinopathy to full-thickness tears. Recognizing the need for clear clinical guidance, Jain and Khazzam provide a comprehensive review aimed at informing clinicians on evidence-based strategies for the evaluation and management of degenerative rotator-cuff tears to optimize patient outcomes.
Key Recommendations:
- First-Line Nonoperative Management: Initiate treatment with nonoperative measures, primarily structured physical therapy. The therapy should focus on strengthening periscapular muscles, correcting scapular posture, and improving rotator-cuff muscle strength and endurance. (Evidence Level: Expert consensus)
- Pharmacologic Therapy: Employ topical NSAIDs for pain relief due to their favorable safety profile. Oral NSAIDs may offer modest pain relief but should be used cautiously because of potential adverse effects. Opioids are generally not recommended due to associated risks and lack of superior efficacy. (Evidence Level: Moderate)
- Glucocorticoid Injections: Consider a single subacromial glucocorticoid injection to provide short-term pain relief, which may facilitate participation in physical therapy. (Evidence Level: Limited)
- Selective Imaging Use: Reserve imaging modalities like ultrasonography or MRI for cases with diagnostic uncertainty, potential surgical candidates, or when detailed assessment of tear extent and muscle degeneration is required. Routine imaging is not recommended in primary care settings. (Evidence Level: Consensus)
- Surgical Intervention Criteria: Surgery is not the initial treatment and should be considered for patients not improving with nonoperative measures. Factors favoring surgery include younger age, smaller tear size, and absence of significant psychosocial barriers. The decision should be individualized due to debated surgical indications. (Evidence Level: Observational studies)
- Avoidance of Unproven Therapies: Current evidence does not support the use of orthobiologic therapies, such as platelet-rich plasma or stem cells, in treating rotator-cuff disorders. (Evidence Level: Insufficient)
Conclusion: Implementing these recommendations can enhance patient care by emphasizing effective nonoperative strategies and judicious use of surgery for degenerative rotator-cuff disorders. Early initiation of physical therapy and appropriate pain management can lead to significant improvements in pain and function, potentially reducing the need for surgical intervention and improving patients’ quality of life.
RCT: Twice-Yearly Lenacapavir Reduces HIV Incidence in Men and Gender-Diverse Persons Background
28 Nov, 2024 | 12:38h | UTCBackground: Although preexposure prophylaxis (PrEP) effectively reduces HIV transmission, adherence to daily oral regimens is suboptimal among high-risk populations. Lenacapavir, a long-acting HIV-1 capsid inhibitor administered subcutaneously every six months, has shown efficacy in cisgender women, but its efficacy in men and gender-diverse individuals remains unclear.
Objective: To evaluate the safety and efficacy of twice-yearly subcutaneous lenacapavir compared to background HIV incidence and daily oral emtricitabine–tenofovir disoproxil fumarate (F/TDF) in preventing HIV infection among men and gender-diverse persons.
Methods: In this phase 3, double-blind, randomized trial, 3,271 HIV-negative participants were assigned in a 2:1 ratio to receive subcutaneous lenacapavir every 26 weeks or daily oral F/TDF, with matching placebos. Participants were cisgender men, transgender women and men, and gender-nonbinary persons aged 16 or older who have sex with male-assigned partners. The primary endpoint compared HIV incidence in the lenacapavir group to background incidence; secondary analysis compared lenacapavir to F/TDF.
Results: In the modified intention-to-treat analysis (n=3,265), HIV infections occurred in 2 participants in the lenacapavir group (0.10 per 100 person-years) and 9 in the F/TDF group (0.93 per 100 person-years). The background HIV incidence was 2.37 per 100 person-years. Lenacapavir significantly reduced HIV incidence compared to background (incidence rate ratio [IRR], 0.04; 95% CI, 0.01–0.18; P<0.001) and F/TDF (IRR, 0.11; 95% CI, 0.02–0.51; P=0.002). No significant safety concerns emerged. Injection-site reactions led to discontinuation in 1.2% of lenacapavir recipients and 0.3% of F/TDF recipients.
Conclusions: Twice-yearly subcutaneous lenacapavir significantly reduced HIV incidence compared to both the background incidence and daily oral F/TDF among men and gender-diverse persons. These findings support lenacapavir as an effective PrEP option in this population.
Implications for Practice: The introduction of a long-acting, twice-yearly injectable PrEP option like lenacapavir could improve adherence and uptake among populations challenged by daily oral regimens.
Study Strengths and Limitations: Strengths include a large, diverse participant population with significant representation of transgender and gender-nonbinary persons, and the use of an active comparator. The novel counterfactual design estimating background HIV incidence avoided ethical issues of placebo controls but may have limitations in accuracy. Limitations include a relatively short follow-up and potential impact of injection-site reactions on adherence. The emergence of resistance mutations in participants who acquired HIV while on lenacapavir is a concern needing further investigation.
Future Research: Further studies should assess the long-term safety, efficacy, and resistance patterns associated with lenacapavir use. Research into optimizing injection techniques to minimize injection-site reactions and exploring lenacapavir’s applicability in other at-risk populations is recommended.
Cohort Study: Metformin Linked to Fewer Asthma Attacks in Patients with Asthma and Type 2 Diabetes
24 Nov, 2024 | 20:36h | UTCBackground: 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.
Consensus Guideline: Low-Dose Oral Minoxidil for Hair Loss Management
24 Nov, 2024 | 20:27h | UTCIntroduction: 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:
- 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.
- 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.
- Adults:
- 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.
- 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.
- 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.
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 | UTCBackground: 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.
RCT: Fezolinetant Reduces Vasomotor Symptoms in Menopausal Individuals Unfit for Hormone Therapy
24 Nov, 2024 | 19:29h | UTCBackground: 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.
News Release: Anticoagulation Does Not Prevent Cognitive Decline in Younger Low-Risk AFib Patients
20 Nov, 2024 | 20:17h | UTCIntroduction: 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
News Release: Edoxaban Comparable to Warfarin for Stroke Prevention After Bioprosthetic Valve Surgery
20 Nov, 2024 | 20:05h | UTCIntroduction: 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
Review: Comparative Analysis of ESC and ESH Hypertension Guidelines
20 Nov, 2024 | 15:03h | UTCIntroduction: 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:
- Diagnosis Criteria: Both guidelines recommend diagnosing hypertension based on office systolic and diastolic blood pressures of ≥140/90 mmHg.
- 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.
- Out-of-Office Measurements: Emphasis is placed on home blood pressure monitoring and ambulatory measurements to confirm diagnoses and tailor treatments.
- Comprehensive Assessment: Both recommend thorough initial evaluations, including screening for orthostatic hypotension, comorbidities, and hypertension-mediated organ damage (HMOD).
- Early Treatment Initiation: Both suggest starting antihypertensive therapy promptly, preferably using a single-pill combination of two agents after lifestyle interventions.
- Treatment Goals and Follow-Up: Both aim for patients to reach blood pressure targets within three months, underscoring the importance of close monitoring.
- 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:
- Blood Pressure Classification: The ESC introduces a new category of “elevated blood pressure,” altering patient classification but with minimal impact on practical management.
- Screening for Secondary Hypertension: The ESC strongly encourages screening for secondary hypertension, particularly primary aldosteronism; the ESH does not emphasize this as strongly.
- 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.
- 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.
- 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.
RCT: Catheter Ablation Superior to Antiarrhythmic Drugs in Ischemic Cardiomyopathy with Ventricular Tachycardia
20 Nov, 2024 | 14:32h | UTCBackground: Patients with ventricular tachycardia and ischemic cardiomyopathy face high risks of adverse outcomes, including death and recurrent arrhythmias. While catheter ablation is commonly used when antiarrhythmic drugs fail to suppress ventricular tachycardia, its effectiveness as a first-line therapy compared to antiarrhythmic drugs remains uncertain.
Objective: To compare the efficacy of catheter ablation versus antiarrhythmic drug therapy as a first-line treatment in patients with ischemic cardiomyopathy and ventricular tachycardia who have an implantable cardioverter–defibrillator (ICD).
Methods: In this multicenter, randomized controlled trial (VANISH2), 416 patients with previous myocardial infarction, clinically significant ventricular tachycardia, and an ICD were randomly assigned to receive catheter ablation within 14 days or antiarrhythmic drug therapy with sotalol or amiodarone based on prespecified criteria. The primary endpoint was a composite of death from any cause during follow-up or, more than 14 days after randomization, ventricular tachycardia storm, appropriate ICD shock, or sustained ventricular tachycardia treated by medical intervention.
Results: Over a median follow-up of 4.3 years, the primary endpoint occurred in 50.7% of patients in the catheter ablation group and 60.6% in the drug therapy group (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.58–0.97; P=0.03). Adverse events within 30 days post-ablation included death in 1.0% and nonfatal events in 11.3% of patients. In the drug therapy group, adverse events attributed to antiarrhythmic drugs included death from pulmonary toxicity in 0.5% and nonfatal events in 21.6% of patients.
Conclusions: Catheter ablation as an initial therapy significantly reduced the risk of the composite primary endpoint compared to antiarrhythmic drug therapy in patients with ischemic cardiomyopathy and ventricular tachycardia.
Implications for Practice: These findings support considering catheter ablation as a first-line treatment option for patients with ischemic cardiomyopathy and ventricular tachycardia, potentially leading to improved clinical outcomes over initial antiarrhythmic drug therapy.
Study Strengths and Limitations: Strengths include the randomized, multicenter design and long-term follow-up. Limitations involve the inability to assess effects on individual components of the primary endpoint, such as mortality. Operator experience with catheter ablation may affect outcomes, potentially influencing the generalizability of the results.
Future Research: Further studies are needed to evaluate the long-term benefits and risks of catheter ablation, particularly with advancements in ablation technology. Research into new antiarrhythmic drugs and alternative ICD programming strategies may also provide additional insights.
Phase 2 RCT: Oral Muvalaplin Significantly Reduces Lipoprotein(a) Levels in High-Risk Patients
20 Nov, 2024 | 14:22h | UTCBackground: Elevated lipoprotein(a) [Lp(a)] levels are an independent risk factor for atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Current therapeutic options to lower Lp(a) are limited, and no approved pharmacotherapies specifically target Lp(a) reduction.
Objective: To evaluate the efficacy and safety of muvalaplin, an oral small-molecule inhibitor of Lp(a) formation, in reducing Lp(a) levels in patients at high risk of cardiovascular events.
Methods: In this phase 2, randomized, double-blind, placebo-controlled trial, 233 adults aged 40 years or older with Lp(a) concentrations of 175 nmol/L or greater and high cardiovascular risk (due to atherosclerotic cardiovascular disease, diabetes, or familial hypercholesterolemia) were enrolled across 43 sites worldwide. Participants were randomized to receive muvalaplin at doses of 10 mg/d (n = 34), 60 mg/d (n = 64), or 240 mg/d (n = 68), or placebo (n = 67) for 12 weeks. The primary endpoint was the placebo-adjusted percentage change from baseline in Lp(a) levels at week 12, measured using both an intact Lp(a) assay and a traditional apolipoprotein(a)-based assay.
Results
At week 12, muvalaplin achieved significant, dose-dependent reductions in Lp(a) levels compared with placebo. Using the intact Lp(a) assay, placebo-adjusted reductions were:
- 47.6% (95% CI, 35.1%-57.7%) for 10 mg/d
- 81.7% (95% CI, 78.1%-84.6%) for 60 mg/d
- 85.8% (95% CI, 83.1%-88.0%) for 240 mg/d
Using the apolipoprotein(a)-based assay, reductions were:
- 40.4% (95% CI, 28.3%-50.5%) for 10 mg/d
- 70.0% (95% CI, 65.0%-74.2%) for 60 mg/d
- 68.9% (95% CI, 63.8%-73.3%) for 240 mg/d
Dose-dependent decreases in apolipoprotein B levels were also observed, with placebo-adjusted reductions ranging from 8.9% to 16.1%. Muvalaplin was well tolerated across all doses, with no significant safety or tolerability concerns reported.
Conclusions: Muvalaplin significantly reduced Lp(a) levels in high-risk patients over a 12-week period and was well tolerated. These findings suggest that muvalaplin could be an effective oral therapy for lowering Lp(a) levels.
Implications for Practice: Muvalaplin may offer a convenient oral option to reduce elevated Lp(a) levels, potentially lowering cardiovascular risk in high-risk patient populations.
Study Strengths and Limitations: Strengths of the study include its randomized, double-blind, placebo-controlled design and the use of both traditional and novel assays to accurately measure Lp(a) levels. Limitations involve the short duration of the trial, the relatively small sample size for each dosage group, and the lack of assessment of long-term cardiovascular outcomes and safety.
Future Research: Long-term studies are necessary to determine whether the reduction in Lp(a) levels with muvalaplin translates into decreased cardiovascular events. Future research should also explore optimal dosing strategies and assess the long-term safety profile of muvalaplin.
RCT: Intensive Systolic Blood Pressure Target Reduces Cardiovascular Events in Type 2 Diabetes
16 Nov, 2024 | 16:49h | UTCBackground: Patients with type 2 diabetes frequently have elevated systolic blood pressure, heightening their risk for cardiovascular disease. Optimal systolic blood-pressure targets in this population remain unclear due to inconclusive results from previous trials.
Objective: To determine whether intensive treatment targeting a systolic blood pressure of less than 120 mm Hg reduces major cardiovascular events compared to standard treatment targeting less than 140 mm Hg in patients with type 2 diabetes.
Methods: In this randomized controlled trial conducted at 145 sites in China, 12,821 patients aged 50 or older with type 2 diabetes, elevated systolic blood pressure, and increased cardiovascular risk were assigned to intensive treatment (target <120 mm Hg) or standard treatment (target <140 mm Hg). The primary outcome was a composite of nonfatal stroke, nonfatal myocardial infarction, treatment or hospitalization for heart failure, or death from cardiovascular causes.
Results: Over a median follow-up of 4.2 years, the intensive-treatment group achieved a mean systolic blood pressure of 121.6 mm Hg versus 133.2 mm Hg in the standard-treatment group at 1 year. Primary outcome events occurred in 393 patients in the intensive group (1.65 events per 100 person-years) versus 492 patients in the standard group (2.09 events per 100 person-years) (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.69 to 0.90; P<0.001). Serious adverse events were similar between groups, but symptomatic hypotension and hyperkalemia were more frequent in the intensive-treatment group.
Conclusions: Intensive systolic blood-pressure control to less than 120 mm Hg significantly reduced major cardiovascular events in patients with type 2 diabetes compared to standard treatment.
Implications for Practice: These findings support adopting more aggressive systolic blood-pressure targets in patients with type 2 diabetes to prevent cardiovascular events. Clinicians should balance the benefits with potential risks, monitoring for hypotension and hyperkalemia.
Study Strengths and Limitations: Strengths include a large sample size, multicenter design, and sufficient power to detect differences in cardiovascular outcomes. Limitations involve unblinded treatment assignment, which may introduce bias, and reliance on self-reported home blood-pressure measurements during the COVID-19 pandemic, potentially affecting data accuracy. The exclusive enrollment of Chinese patients may limit generalizability to other populations. The increased incidence of hypotension and hyperkalemia raises concerns about the safety of intensive blood-pressure lowering in broader practice.
Future Research: Further studies should assess the long-term safety and efficacy of intensive blood-pressure control in diverse populations and explore strategies to minimize adverse events. Investigations into personalized blood-pressure targets based on patient characteristics may enhance clinical outcomes.
RCT: Tirzepatide Reduces Heart Failure Events and Improves Health Status in Obese HFpEF Patients
16 Nov, 2024 | 16:42h | UTCBackground: Obesity significantly increases the risk of heart failure with preserved ejection fraction (HFpEF) due to visceral adiposity-induced systemic inflammation affecting the myocardium. Tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, induces substantial weight loss. However, its effects on cardiovascular outcomes in obese HFpEF patients were previously unknown.
Objective: To assess the impact of tirzepatide on cardiovascular events and health status in patients with HFpEF and obesity.
Methods: In this international, double-blind, randomized, placebo-controlled trial, 731 patients with HFpEF (ejection fraction ≥50%), a body-mass index (BMI) of at least 30, and New York Heart Association class II–IV symptoms were assigned to receive tirzepatide (up to 15 mg subcutaneously once weekly) or placebo for at least 52 weeks. The two primary endpoints were the composite of adjudicated death from cardiovascular causes or worsening heart-failure events, and the change from baseline to 52 weeks in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS).
Results: Over a median follow-up of 104 weeks, death from cardiovascular causes or worsening heart-failure events occurred in 9.9% of patients in the tirzepatide group versus 15.3% in the placebo group (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.41 to 0.95; P=0.026). Worsening heart-failure events occurred in 8.0% with tirzepatide versus 14.2% with placebo (HR, 0.54; 95% CI, 0.34 to 0.85). At 52 weeks, the mean increase in KCCQ-CSS was 19.5 points in the tirzepatide group compared to 12.7 points in the placebo group (between-group difference, 6.9; 95% CI, 3.3 to 10.6; P<0.001). Adverse events leading to discontinuation occurred in 6.3% of tirzepatide patients versus 1.4% of placebo patients, mainly due to gastrointestinal symptoms.
Conclusions: Tirzepatide significantly reduced the risk of cardiovascular death or worsening heart failure and improved health status in patients with HFpEF and obesity.
Implications for Practice: These findings suggest that tirzepatide may be an effective therapeutic option for reducing heart failure events and enhancing quality of life in obese patients with HFpEF. Its benefits may be attributed to significant weight loss and anti-inflammatory effects, offering a potential new approach in managing this patient population.
Study Strengths and Limitations: Strengths include the randomized, double-blind design and a long median follow-up of 104 weeks. Limitations involve the exclusion of patients with BMI less than 30, which may limit applicability to non-obese HFpEF patients with increased visceral adiposity. Additionally, the higher rate of gastrointestinal adverse events leading to discontinuation in the tirzepatide group warrants cautious consideration.
Future Research: Further studies are needed to evaluate tirzepatide’s effects in HFpEF patients with lower BMI but increased visceral adiposity and to elucidate the mechanisms underlying its cardiovascular benefits.
Test-Negative Study: RSV Vaccine May Reduce Hospitalizations and ED Visits in Adults Aged ≥60
16 Nov, 2024 | 14:18h | UTCBackground: Respiratory syncytial virus (RSV) is a significant cause of morbidity and mortality among older adults in the USA, with an estimated 100,000–160,000 RSV-associated hospitalizations annually in those aged 60 years and older. In 2023, RSV vaccines were recommended for this population, showing efficacy in clinical trials. However, real-world effectiveness data, particularly against severe outcomes like hospitalizations in high-risk groups, are limited.
Objective: To assess the real-world effectiveness of RSV vaccination against RSV-associated hospitalizations and emergency department (ED) encounters among adults aged 60 years and older during the 2023–24 RSV season in the USA.
Methods: A test-negative design analysis was conducted using data from the Virtual SARS-CoV-2, Influenza, and Other Respiratory Viruses Network (VISION), encompassing eight states. Adults aged ≥60 presenting with RSV-like illness and tested for RSV from Oct 1, 2023, to Mar 31, 2024, were included. Vaccination status was determined through electronic health records, immunization registries, and medical claims. Vaccine effectiveness (VE) was estimated by comparing the odds of vaccination among RSV-positive cases and RSV-negative controls, adjusting for age, sex, race and ethnicity, comorbidities, and geographic region.
Results: Among 28,271 hospitalizations for RSV-like illness in immunocompetent adults aged ≥60, VE against RSV-associated hospitalization was 80% (95% CI 71–85). VE against RSV-associated critical illness (ICU admission or death) was 81% (95% CI 52–92). In 8,435 hospitalizations among immunocompromised adults, VE was 73% (95% CI 48–85) against RSV-associated hospitalization. Among 36,521 ED encounters in immunocompetent adults, VE against RSV-associated ED visits was 77% (95% CI 70–83). VE estimates were consistent across age groups and vaccine products.
Conclusions: RSV vaccination effectively prevented RSV-associated hospitalizations and ED visits among adults aged ≥60 during the first season post-approval, including those at highest risk due to advanced age or immunocompromise.
Implications for Practice: These findings support recommending RSV vaccination for adults aged ≥60 to reduce severe RSV-related morbidity and mortality. Clinicians should consider advising eligible patients to receive the RSV vaccine to prevent hospitalizations and critical illness.
Study Strengths and Limitations: Strengths include a large, geographically diverse cohort and integrated medical, laboratory, and vaccination data, allowing robust VE estimates across subgroups. Limitations involve potential misclassification of vaccination status, residual confounding, and reliance on clinician-directed RSV testing, which may introduce bias.
Future Research: Further studies are needed to evaluate the duration of vaccine protection over multiple RSV seasons and to assess VE in other high-risk populations and settings.
Phase 3 RCT: Resmetirom Significantly Improves NASH Resolution and Liver Fibrosis
16 Nov, 2024 | 13:56h | UTCBackground: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatments. It significantly increases the risk of liver-related complications, especially in patients with type 2 diabetes. Resmetirom, a thyroid hormone receptor beta-selective agonist, is being investigated for its potential to treat NASH and liver fibrosis.
Objective: To evaluate the efficacy and safety of resmetirom in resolving NASH and improving fibrosis in adults with biopsy-confirmed NASH and fibrosis stages F1B to F3.
Methods: This double-blind, placebo-controlled phase 3 trial randomized 966 adults with NASH to receive once-daily resmetirom (80 mg or 100 mg) or placebo for 52 weeks. Primary endpoints included (1) NASH resolution with no fibrosis worsening and (2) fibrosis improvement by at least one stage without NAFLD activity score worsening. Secondary outcomes included changes in lipid profiles and liver biomarkers.
Results: At 52 weeks, NASH resolution occurred in 25.9% of patients receiving 80 mg and 29.9% receiving 100 mg of resmetirom, compared with 9.7% in the placebo group (P<0.001 for both doses vs. placebo). Fibrosis improved by at least one stage in 24.2% (80 mg) and 25.9% (100 mg) of resmetirom-treated patients versus 14.2% for placebo (P<0.001). LDL cholesterol reductions were −13.6% (80 mg) and −16.3% (100 mg) at 24 weeks versus 0.1% for placebo (P<0.001). Improvements were also noted in triglycerides, liver enzymes, and imaging biomarkers. Adverse events, primarily mild gastrointestinal symptoms, were more frequent with resmetirom. Serious adverse events were similar across groups (10.9%–12.7%).
Conclusions: Resmetirom significantly improved NASH resolution and fibrosis compared to placebo, demonstrating its potential as a treatment for NASH with liver fibrosis.
Implications for Practice: Resmetirom offers a promising treatment option for NASH, potentially altering the disease course and improving outcomes. Clinicians should monitor for regulatory approval and long-term safety data.
Study Strengths and Limitations: Strengths include robust biopsy-confirmed endpoints and a large sample size. Limitations include short follow-up and lack of clinical-outcome data.
Future Research: Long-term studies are needed to assess durability, safety, and effects on clinical outcomes like cirrhosis and liver-related mortality.
RCT: Once-Weekly Semaglutide Reduces Weight and Knee Osteoarthritis Pain in Obese Patients
16 Nov, 2024 | 13:41h | UTCBackground: Obesity is a major risk factor for the development and progression of knee osteoarthritis, leading to chronic pain and reduced mobility. Weight reduction has been shown to alleviate symptoms, but sustained, non-surgical interventions are limited. Glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide, have demonstrated efficacy in weight management; however, their impact on knee osteoarthritis pain is not well established.
Objective: To assess the efficacy of once-weekly subcutaneous semaglutide (2.4 mg) versus placebo, alongside lifestyle interventions, on body weight reduction and pain related to knee osteoarthritis in adults with obesity.
Methods: In this 68-week, double-blind, randomized, placebo-controlled trial conducted at 61 sites across 11 countries, 407 adults with obesity (BMI ≥30) and moderate knee osteoarthritis with at least moderate pain were enrolled. Participants were randomized in a 2:1 ratio to receive semaglutide or placebo, in addition to counseling on a reduced-calorie diet and increased physical activity. The primary endpoints were the percentage change in body weight and the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score from baseline to week 68.
Results: Semaglutide treatment resulted in a mean weight reduction of −13.7% compared to −3.2% with placebo (P<0.001). The mean change in WOMAC pain score was −41.7 points with semaglutide versus −27.5 points with placebo (P<0.001), indicating a significant reduction in pain. Additionally, semaglutide led to greater improvements in physical function scores and a decrease in the use of nonsteroidal anti-inflammatory drugs. Serious adverse events were similar between groups; however, gastrointestinal disorders led to more discontinuations in the semaglutide group (6.7% vs. 3.0%).
Conclusions: Once-weekly subcutaneous semaglutide significantly reduces body weight and alleviates pain related to knee osteoarthritis in obese adults, compared to placebo, when combined with lifestyle modifications. These findings support semaglutide as an effective non-surgical intervention for weight management and symptom relief in this population.
Implications for Practice: Semaglutide may be considered as part of a comprehensive treatment strategy for obese patients with knee osteoarthritis, potentially improving pain, physical function, and reducing reliance on analgesics. Clinicians should weigh the benefits against potential gastrointestinal side effects.
Study Strengths and Limitations: Strengths include the randomized, double-blind design and a sizable, diverse cohort. Limitations involve the absence of imaging follow-up, lack of metabolic and inflammatory marker assessments, and no post-treatment outcome data to evaluate the sustainability of benefits after discontinuation.
Future Research: Further studies are warranted to explore the long-term effects of semaglutide on knee osteoarthritis progression, its mechanisms of action on joint pathology, and its effectiveness in broader patient populations.
Meta-Analysis: Spinal Cord Stimulation May Be Effective for Chronic Back and Leg Pain
15 Nov, 2024 | 13:43h | UTCBackground: Chronic back and leg pain causes significant disability worldwide. Spinal cord stimulation (SCS) offers treatment for patients unresponsive to conventional medical management (CMM). The comparative efficacy of conventional and novel SCS forms versus CMM is debated, requiring thorough evaluation.
Objective: To evaluate the efficacy of conventional and novel SCS therapies compared with CMM in adults with chronic back or leg pain who had not previously used SCS.
Methods: A systematic review and Bayesian network meta-analysis per PRISMA guidelines were performed. MEDLINE, Embase, and Cochrane Library were searched up to September 2, 2022. Thirteen RCTs with 1,561 patients were included. Interventions were conventional SCS, novel SCS modalities (e.g., high-frequency, burst stimulation), and CMM. Primary outcomes were pain intensity (visual analog scale) and responder rates (≥50% pain relief) in back or leg. Secondary outcomes were quality of life (EQ-5D index) and functional disability (Oswestry Disability Index).
Results: At 6 months, both conventional and novel SCS were superior to CMM in five of six outcomes. For back pain responder rates, conventional SCS had an OR of 3.00 (95% CrI, 1.49–6.72) and novel SCS had an OR of 8.76 (95% CrI, 3.84–22.31) versus CMM. Pain intensity in the back decreased significantly with conventional SCS (MD, –1.17; 95% CrI, –1.64 to –0.70) and novel SCS (MD, –2.34; 95% CrI, –2.96 to –1.73). Leg pain intensity also decreased significantly with conventional SCS (MD, –2.89; 95% CrI, –4.03 to –1.81) and novel SCS (MD, –4.01; 95% CrI, –5.31 to –2.75) compared to CMM. Quality of life improved with both SCS therapies (conventional SCS MD, 0.15; 95% CrI, 0.09–0.21; novel SCS MD, 0.17; 95% CrI, 0.13–0.21). Functional disability improved significantly with conventional SCS (MD, –7.10; 95% CrI, –10.91 to –3.36).
Conclusions: Both conventional and novel SCS therapies are associated with significant improvements in pain relief, quality of life, and functional ability compared with CMM in patients with chronic back and leg pain at 6 months.
Implications for Practice: The results support integrating SCS therapies into clinical practice for patients with chronic back and leg pain unresponsive to CMM.
Study Strengths and Limitations: Strengths include inclusion of recent RCTs and use of Bayesian network meta-analysis, allowing comprehensive evidence synthesis with both direct and indirect comparisons, enhancing reliability. Limitations involve potential biases due to challenges in blinding participants and assessors, as patients can perceive whether a device is active. Heterogeneity among studies in patient populations and interventions may affect generalizability. Inability to include long-term efficacy data due to crossover in many trials limits understanding of sustained outcomes.
Future Research: Long-term RCTs are needed to assess sustained efficacy and safety of SCS therapies. Future studies should compare different SCS modalities directly and identify patient subgroups most likely to benefit.
RCT: Tirzepatide Significantly Reduces Weight and Diabetes Risk in Obese Adults with Prediabetes
15 Nov, 2024 | 13:29h | UTCBackground: Obesity is a chronic disease that significantly increases the risk of type 2 diabetes, particularly in individuals with prediabetes. Weight reduction has been shown to improve insulin sensitivity and beta-cell function, potentially delaying or preventing the onset of type 2 diabetes. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated significant weight loss and glycemic control in short-term studies.
Objective: To evaluate the long-term efficacy and safety of tirzepatide in reducing body weight and delaying progression to type 2 diabetes in obese adults with prediabetes over a period of three years.
Methods: In this phase 3, double-blind, randomized, controlled trial (SURMOUNT-1), 1032 obese adults with prediabetes were randomized 1:1:1:1 to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo, alongside lifestyle intervention, for 176 weeks, followed by a 17-week off-treatment period. The primary endpoints included percent change in body weight and onset of type 2 diabetes during the treatment and follow-up periods.
Results: At week 176, participants receiving tirzepatide achieved significant mean weight reductions of –12.3% (5 mg), –18.7% (10 mg), and –19.7% (15 mg), compared to –1.3% with placebo (P<0.001 for all comparisons). Progression to type 2 diabetes was significantly lower in the tirzepatide groups (1.3%) compared to placebo (13.3%), with a hazard ratio of 0.07 (95% CI, 0.0 to 0.1; P<0.001). After the 17-week off-treatment period, 2.4% of tirzepatide-treated participants and 13.7% of placebo-treated participants had developed type 2 diabetes (hazard ratio, 0.12; 95% CI, 0.1 to 0.2; P<0.001). Common adverse events were gastrointestinal and generally mild to moderate.
Conclusions: Three years of tirzepatide treatment in obese adults with prediabetes resulted in substantial and sustained weight loss and significantly reduced the risk of progression to type 2 diabetes compared to placebo, with an acceptable safety profile.
Implications for Practice: Tirzepatide may be an effective long-term therapeutic option for weight management and diabetes prevention in obese patients with prediabetes, potentially altering clinical approaches to obesity and metabolic disease management.
Study Strengths and Limitations: Strengths include the long duration of the trial and large sample size, providing robust data on long-term efficacy and safety. Limitations involve participant attrition and higher withdrawal rates, especially in the placebo group, which may affect the generalizability of the findings.
Future Research: Further studies are needed to explore the mechanisms of tirzepatide’s effects on beta-cell function and insulin sensitivity, as well as its impact on cardiovascular outcomes and quality of life in diverse populations.
Target Trial Emulation: SGLT-2 Inhibitors May Reduce Recurrent Nephrolithiasis in Patients with Type 2 Diabetes and Pre-existing Nephrolithiasis
10 Nov, 2024 | 18:17h | UTCBackground: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors, initially approved for glycemic control in type 2 diabetes, have demonstrated multiple cardiometabolic and renal benefits, including reducing serum urate levels and lowering gout flare-ups. However, data on the effectiveness of SGLT-2 inhibitors in preventing recurrent nephrolithiasis, especially among patients with concomitant gout, are limited.
Objective: To evaluate the comparative effectiveness of SGLT-2 inhibitors versus glucagon-like peptide-1 (GLP-1) receptor agonists in reducing the recurrence of nephrolithiasis among patients with type 2 diabetes and pre-existing nephrolithiasis, including those with concomitant gout.
Methods: A target trial emulation study was conducted using a population-based cohort from British Columbia, Canada, between January 2014 and June 2022. Adults with type 2 diabetes and pre-existing nephrolithiasis who initiated an SGLT-2 inhibitor or a GLP-1 receptor agonist were included. The primary outcome was recurrent nephrolithiasis events identified from emergency department visits, hospital admissions, or outpatient diagnoses. Inverse probability of treatment weighting was applied to adjust for baseline differences.
Results: After weighting, 14,456 patients initiating SGLT-2 inhibitors and 5,877 initiating GLP-1 receptor agonists were analyzed. The incidence of recurrent nephrolithiasis was significantly lower among SGLT-2 inhibitor users (105.3 per 1000 person-years) compared to GLP-1 receptor agonist users (156.4 per 1000 person-years), with an adjusted rate ratio of 0.67 (95% CI 0.57 to 0.79) and a rate difference of –51 per 1000 person-years (number needed to treat [NNT] = 20).
Conclusions: SGLT-2 inhibitor use is associated with a significant reduction in recurrent nephrolithiasis among patients with type 2 diabetes and pre-existing nephrolithiasis, including those with concomitant gout. These findings suggest that SGLT-2 inhibitors may offer dual benefits in managing nephrolithiasis recurrence and gout comorbidities.
Implications for Practice: In patients with type 2 diabetes and a history of nephrolithiasis, particularly those with concomitant gout, SGLT-2 inhibitors may be a valuable addition to current treatment strategies to reduce the recurrence of kidney stones and manage comorbid conditions.
Study Strengths and Limitations: Strengths include the use of a large, population-based cohort and rigorous statistical methods to emulate a target trial, enhancing causal inference. Limitations involve potential residual confounding due to unmeasured factors such as body mass index and laboratory measures, and the inability to capture nephrolithiasis events not requiring medical attention.
Future Research: Further studies are warranted to explore the mechanisms underlying the nephrolithiasis protective effects of SGLT-2 inhibitors, assess their impact in patients without diabetes, and investigate the effects on different types of kidney stones.
Review: Frailty in Older Adults
10 Nov, 2024 | 18:03h | UTCIntroduction: Frailty is a state of decreased physiological reserve and increased vulnerability to adverse health outcomes, becoming more prevalent with age. This review by Kim and Rockwood outlines definitions, biological mechanisms, measurement, and management of frailty in older adults, aiming to guide clinical practice.
Key Recommendations:
- Definitions of Frailty: Clinicians should recognize two predominant concepts: the Fried frailty phenotype, defining frailty as a clinical syndrome with features like exhaustion, weakness, slowness, inactivity, and weight loss; and the deficit-accumulation model, quantifying frailty based on accumulated health deficits.
- Biology of Frailty: Understanding biological mechanisms—such as chronic inflammation, cellular senescence, mitochondrial dysfunction, deregulated nutrient sensing, and hormonal changes—is essential for identifying modifiable risk factors and developing targeted interventions.
- Measurement of Frailty: Utilize validated assessment tools appropriate to the clinical context. The Fried frailty phenotype and the deficit-accumulation frailty index are widely used; brief screening tools and performance measures like gait speed can be practical, especially in acute care settings.
- Management and Interventions for Frailty: Management should focus on increasing physiological reserve through multicomponent interventions. Exercise (aerobic and resistance training), combined with nutritional support, comprehensive geriatric assessment, and medication optimization, has been shown to ameliorate frailty and improve mobility, strength, and daily functioning.
- Frailty Screening Before Stressful Treatments: In high-risk clinical contexts such as oncology and surgery, pre-treatment frailty assessment can guide decision-making, personalize care plans, and improve outcomes by reducing treatment-related adverse effects.
- Evidence Gaps and Future Directions: More research is needed on effective strategies for frailty identification, interventions to prevent or reverse frailty, and the cost-effectiveness of frailty-guided care models, particularly in primary care settings.
Conclusion: Incorporating frailty assessment into clinical practice enables personalized, holistic care that aligns with older patients’ health goals and needs. Interventions targeting frailty can enhance physiological reserve, reduce vulnerability to stressors, and improve clinical outcomes. Further research is essential to optimize frailty management strategies and fully realize the benefits of frailty-guided care in our aging society.
News Release: Seven-Day Antibiotic Regimen Effective for Bloodstream Infections
10 Nov, 2024 | 17:54h | UTCIntroduction: A recent large-scale, multicenter randomized clinical trial has shown that a seven-day course of antibiotics is as effective as the traditional 14-day regimen for treating hospitalized patients with bloodstream infections (BSIs). This finding addresses a critical need in medical practice to optimize antibiotic use amid rising concerns about antimicrobial resistance and healthcare costs.
Highlights: The Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) trial evaluated 3,608 patients with BSIs across 74 hospitals in seven countries, including the United States, Canada, and Australia. Patients were randomized to receive either a seven-day or a 14-day antibiotic course, with the choice of antibiotic, dosage, and administration route determined by their healthcare team.
- Efficacy Results: The 90-day mortality rates were similar between the two groups—14.5% in the seven-day group versus 16.1% in the 14-day group—demonstrating the non-inferiority of the shorter regimen.
- Secondary Outcomes: Rates of relapse, ICU mortality, hospital mortality, and other clinical markers showed no significant differences between the two groups.
- Patient Demographics: The study included a diverse patient population, with 55% in intensive care units at enrollment. Infections originated from various sources, most commonly the urinary tract (42.2%), abdomen (18.8%), and lungs (13.0%).
- Applicability: Exclusion criteria were minimal, enhancing the generalizability of the findings to everyday clinical practice. Patients with extreme immunosuppression or undrained abscesses were excluded, but those with conditions like renal failure were included.
Lead investigator Dr. Nick Daneman emphasized, “These findings underscore the effectiveness of a shorter antibiotic regimen in patients with bloodstream infections, which is welcomed as we look to identify evidence-based prescribing guidelines for serious bacterial infections.”
Conclusion: The BALANCE trial provides robust evidence that a seven-day antibiotic course is sufficient for treating BSIs, potentially transforming current clinical practice. Adopting shorter antibiotic regimens can reduce healthcare costs, minimize adverse effects, and combat antimicrobial resistance without compromising patient outcomes. This aligns with antimicrobial stewardship goals and promotes more efficient use of healthcare resources.
Source: This study was presented at IDWeek 2024, the joint annual meeting of the Infectious Diseases Society of America and other related organizations. The research was conducted by a team from Sunnybrook Health Sciences Centre and the University of Toronto, led by Dr. Nick Daneman and Dr. Robert Fowler. More information can be found at: http://www.idsociety.org/news–publications-new/articles/2024/antibiotic-treatment-regimen-for-bloodstream-infections-can-safely-be-cut-by-half
RCT: Preemptive TAVR Does Not Improve Composite Outcomes but May Improve Quality of Life in HFrEF Patients with Moderate Aortic Stenosis
10 Nov, 2024 | 14:18h | UTCBackground: Heart failure with reduced ejection fraction (HFrEF) management emphasizes neurohormonal modulation and afterload reduction. Moderate aortic stenosis (AS) increases afterload, potentially worsening outcomes in HFrEF patients. While transcatheter aortic valve replacement (TAVR) is established for severe AS, its benefit in moderate AS remains uncertain.
Objective: To determine whether TAVR provides clinical benefits over guideline-directed medical therapy (GDMT) in patients with HFrEF and moderate AS.
Methods: In the TAVR UNLOAD randomized controlled trial, 178 symptomatic HFrEF patients (left ventricular ejection fraction 20%-50%) on GDMT with moderate AS were randomized 1:1 to receive TAVR with a balloon-expandable valve or clinical AS surveillance (CASS) with aortic valve replacement upon progression to severe AS. The primary endpoint was the hierarchical occurrence of: (1) all-cause death; (2) disabling stroke; (3) disease-related hospitalizations and heart failure equivalents; and (4) change from baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS).
Results: The mean age was 77 years, 20.8% were female, and 55.6% were in NYHA class III or IV. Median follow-up was 23 months. In the CASS group, 43% underwent TAVR due to progression to severe AS at a median of 12 months. TAVR was not superior to CASS for the primary endpoint (win ratio 1.31; 95% CI: 0.91-1.88; P = 0.14). However, at 1 year, TAVR resulted in a greater improvement in KCCQ-OSS compared with CASS (12.8 ± 21.9 vs 3.2 ± 22.8 points; P = 0.018). There were no significant differences in all-cause mortality or major adverse events between groups.
Conclusions: In HFrEF patients with moderate AS on GDMT, TAVR was not superior to clinical surveillance for the primary composite endpoint but was associated with improved quality of life at 1 year.
Implications for Practice: Preemptive TAVR may offer quality-of-life benefits in select symptomatic HFrEF patients with moderate AS but does not reduce mortality or major cardiovascular events compared to surveillance. Clinicians should weigh patient-specific factors when considering TAVR for moderate AS.
Study Strengths and Limitations: Strengths include being the first randomized trial assessing TAVR in moderate AS with HFrEF. Limitations involve being underpowered due to slow enrollment and protocol changes, and a high crossover rate (43% in the CASS group underwent TAVR), potentially attenuating differences between groups.
Future Research: Larger, adequately powered trials are needed to confirm these findings and identify patients who may benefit most from preemptive TAVR in moderate AS.