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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.
Phase 2 RCT: Zerlasiran Lowers Lipoprotein(a) Levels by Over 80% in Patients With ASCVD
24 Nov, 2024 | 20:18h | UTCBackground: Elevated lipoprotein(a) [Lp(a)] is a genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. Traditional lipid-lowering therapies, including statins and lifestyle modifications, do not effectively reduce Lp(a) levels. Small-interfering RNA (siRNA) therapies targeting hepatic production of apolipoprotein(a) offer a potential approach to lowering Lp(a) concentrations.
Objective: To evaluate the efficacy and safety of zerlasiran, an siRNA targeting apolipoprotein(a) synthesis, in reducing serum Lp(a) concentrations in patients with ASCVD.
Methods: In this randomized, double-blind, placebo-controlled phase 2 trial, 178 adults with stable ASCVD and elevated Lp(a) levels (≥125 nmol/L) were enrolled across 26 sites in Europe and South Africa. Participants were randomized to receive subcutaneous zerlasiran at doses of 450 mg every 24 weeks (n=45), 300 mg every 16 weeks (n=42), or 300 mg every 24 weeks (n=44), or matching placebo every 16 weeks (n=23) or every 24 weeks (n=24). The primary outcome was the time-averaged percent change in Lp(a) concentration from baseline to week 36.
Results: Zerlasiran significantly reduced Lp(a) levels compared to placebo. The placebo-adjusted time-averaged percent reductions were −85.6% (95% CI, −90.9% to −80.3%) for 450 mg every 24 weeks, −82.8% (95% CI, −88.2% to −77.4%) for 300 mg every 16 weeks, and −81.3% (95% CI, −86.7% to −76.0%) for 300 mg every 24 weeks. Median percent reductions at week 36 exceeded 90% in all zerlasiran groups. The most common adverse events were mild injection site reactions, occurring in up to 7.1% of participants. No serious adverse events were attributed to the study drug.
Conclusions: Zerlasiran was well-tolerated and produced substantial reductions in Lp(a) levels over 36 weeks in patients with ASCVD.
Implications for Practice: If validated in larger, long-term studies that assess cardiovascular outcomes, zerlasiran may offer a novel treatment for patients with elevated Lp(a), addressing a significant unmet need in cardiovascular risk management. Clinicians should, however, exercise caution until the impact on hard endpoints such as myocardial infarction and stroke, as well as long-term safety, are confirmed.
Study Strengths and Limitations: Strengths include the randomized, double-blind design and significant Lp(a) reductions observed. Limitations involve the predominantly White, male study population, limiting generalizability. The study did not assess clinical endpoints like cardiovascular events, so the impact on actual cardiovascular risk remains unknown. Additionally, the moderate sample size and duration may not detect rare adverse events or long-term effects, necessitating further investigation.
Future Research: Larger, long-term phase 3 trials are needed to confirm these findings, assess the impact on cardiovascular events, and evaluate efficacy and safety in more diverse populations.
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.
Review: Candida auris Infections
24 Nov, 2024 | 19:50h | UTCIntroduction: 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:
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Review: Target Trial Emulation in Observational Studies
24 Nov, 2024 | 19:43h | UTCIntroduction:
Randomized controlled trials (RCTs) are the gold standard for evaluating medical interventions but are often resource-intensive. Observational studies using real-world data (RWD) from electronic health records (EHRs) or claims data offer advantages like larger sample sizes and timely availability. However, they are prone to biases. “Target trial emulation” aligns observational studies with hypothetical RCTs to improve validity and causal inference.
Key Recommendations:
- Design Alignment with RCTs: Observational studies should replicate key trial design elements like eligibility, treatment strategies, follow-up, and outcome measures. This reduces biases and clarifies treatment-effect definitions.
- Specification of “Time Zero”: Clearly define the start of eligibility, treatment assignment, and follow-up to prevent immortal time and selection bias. Proper alignment ensures comparable treatment groups.
- Addressing Bias and Confounding: Observational studies remain vulnerable to confounding from unmeasured variables. Researchers must use matching, sensitivity analyses, and robust methods to assess findings’ reliability.
- Data Quality Challenges: Using RWD requires careful validation of completeness, consistency, and accuracy. Missing or inconsistent data can affect results. Clear descriptions of data sources and quality metrics are essential.
- Best Practices:
- Protocols and SAPs: Pre-specify protocols and statistical plans (SAPs) to enhance transparency and mitigate bias.
- Clear Reporting: State the observational nature of the study to avoid confusion with RCTs. Use tables to outline target trial elements.
- Sensitivity Analyses: Explore unmeasured confounding and perform negative control outcomes to ensure robustness.
Limitations:
Despite emulating RCTs, observational studies cannot fully eliminate biases inherent in nonrandomized designs. Confounding, selection bias, and data quality issues remain risks. Careful design, pre-specification, and transparency are essential for credible results.
Conclusion:
Target trial emulation enhances observational study design by aligning it with RCT principles, mitigating biases, and improving the reliability of findings. However, it is not a substitute for randomization. Rigorous implementation and interpretation are critical for improving patient care and outcomes.
Reference:
Hubbard RA, Gatsonis CA, Hogan JW, et al. “Target Trial Emulation” for Observational Studies — Potential and Pitfalls. New England Journal of Medicine. 2024 Nov 23. DOI: http://doi.org/10.1056/NEJMp2407586
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
News Release: Sacubitril/Valsartan May Reduce Chemotherapy-Induced Cardiotoxicity in High-Risk Cancer Patients
20 Nov, 2024 | 18:38h | UTCIntroduction: 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
RCT: 7-Day Antibiotic Therapy Noninferior to 14-Day for Bloodstream Infections
20 Nov, 2024 | 18:19h | UTCBackground: 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.
RCT: Colchicine Does Not Reduce Cardiovascular Events After Myocardial Infarction
20 Nov, 2024 | 18:12h | UTCBackground: 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.
RCT: Routine Spironolactone Post-MI Does Not Reduce Cardiovascular Events
20 Nov, 2024 | 18:03h | UTCBackground: 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.
RCT: Left Atrial Appendage Closure May Reduce Bleeding Without Increasing Stroke Risk After AF Ablation
20 Nov, 2024 | 16:28h | UTCBackground: 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:
- 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
- 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
Meta-Analysis: Moderately Rapid Sodium Correction Linked to Better Outcomes in Severe Hyponatremia
20 Nov, 2024 | 16:10h | UTCBackground: 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.
RCT: Linear Ablation Plus Ethanol infusion of the vein of Marshall Enhances Rhythm Outcomes in Persistent AF
20 Nov, 2024 | 15:48h | UTCBackground: 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.
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: Low-Dose Ketamine Enhances Pain Relief When Added to Morphine in ED Patients
20 Nov, 2024 | 14:42h | UTCBackground: Acute pain is a prevalent complaint among emergency department (ED) patients, yet effective pain management remains suboptimal, especially in individuals with current opioid use due to opioid tolerance and hyperalgesia. Low-dose ketamine (LDK) has been proposed as an adjunct to opioids to enhance analgesia through synergistic or additive effects, but its efficacy in patients with and without current opioid use in the ED setting is not well established.
Objective: This randomized controlled trial aimed to determine the effectiveness of LDK as an adjunct to morphine versus morphine alone for acute pain management in ED patients with and without current opioid use.
Methods: In this single-center, double-blind study, 116 adult patients presenting to the ED with acute pain (numeric rating scale [NRS] ≥5) requiring intravenous opioids were randomized to receive either 0.1 mg/kg ketamine or isotonic saline (placebo) as an adjunct to morphine. Patients with and without current opioid use were randomized separately. Pain intensity was measured at baseline and at 10, 20, 30, 45, 60, and 120 minutes post-randomization. The primary outcome was pain reduction from baseline to 10 minutes. Secondary outcomes included pain intensity over 120 minutes, need for rescue opioids, side effects, and patient and provider satisfaction.
Results: The study included 116 patients (median age 51 years; 58% male; 36% with current opioid use). Pain reduction from baseline to 10 minutes was significantly greater in the LDK group compared to placebo (median reduction of 4 [IQR 3–6] vs. 1 [IQR 0–2]; p = 0.001). Pain intensity was significantly lower in the LDK group at 10, 20, and 30 minutes post-administration. There was a higher incidence of nausea, vomiting, and dissociation in the LDK group during the first 10 minutes. No significant differences were observed in the need for rescue opioids or in patient and provider satisfaction between groups.
Conclusions: LDK administered as an adjunct to morphine significantly enhances short-term pain relief in ED patients with acute pain, regardless of current opioid use status. However, the increased risk of transient side effects necessitates careful consideration.
Implications for Practice: LDK may be considered as an adjunct to morphine for acute pain management in the ED, particularly when traditional opioid treatments are insufficient. Clinicians should weigh the benefits against the potential for transient side effects, and LDK should not be universally recommended for all patients with moderate to severe pain.
Study Strengths and Limitations: Strengths of the study include its randomized, double-blind design and the inclusion of patients with current opioid use. Limitations include early termination leading to a smaller sample size, potentially underpowering the stratified analysis, and heterogeneity in patient pain conditions. Additionally, assessing the primary outcome at 10 minutes may not capture the peak effect of morphine.
Future Research: Further studies should focus on optimizing LDK administration protocols, such as exploring bolus versus continuous infusion methods, to achieve sustained pain reduction and minimize side effects.
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.
Cohort Study: High Rate of Preventable Adverse Events in Surgical Inpatients
16 Nov, 2024 | 17:29h | UTCBackground: Adverse events during hospital admissions, particularly in surgical settings, remain a significant cause of patient harm despite efforts to improve patient safety since the “To Err is Human” report. Advances in surgical techniques and patient care necessitate an updated assessment of the current state of perioperative safety.
Objective: To estimate the frequency, severity, and preventability of adverse events associated with perioperative care in surgical inpatients and to identify the settings and healthcare professionals involved.
Methods: A multicenter retrospective cohort study was conducted across 11 US hospitals in Massachusetts. A weighted random sample of 1,009 patients was selected from 64,121 adults admitted for surgery in 2018. Trained nurses reviewed electronic health records to identify adverse events, which were then adjudicated by physicians. Adverse events were classified by type, severity, preventability, setting, and professions involved.
Results: Adverse events occurred in 38.0% of patients (95% CI, 32.6–43.4%), with major adverse events in 15.9% (12.7–19.0%). Among 593 adverse events identified, 59.5% were potentially preventable, and 20.7% were definitely or probably preventable. The most common events were surgery-related (49.3%), adverse drug events (26.6%), healthcare-associated infections (12.4%), and patient care events (11.2%). Adverse events most frequently occurred in general care units (48.8%) and involved attending physicians (89.5%) and nurses (58.9%).
Conclusions: More than one-third of surgical inpatients experienced adverse events, with nearly half classified as major and most potentially preventable. These findings highlight the critical need for ongoing improvement in patient safety throughout perioperative care involving all healthcare professionals.
Implications for Practice: Healthcare providers should enhance patient safety protocols across all perioperative settings, not just in operating rooms. Emphasis should be placed on preventing surgery-related complications, adverse drug events, and healthcare-associated infections by fostering teamwork and continuous monitoring.
Study Strengths and Limitations: Strengths include a comprehensive review of medical records and systematic classification of adverse events by trained professionals. Limitations involve the study’s confinement to Massachusetts hospitals in 2018, potential variability in documentation practices, and limited sample size affecting generalizability and specialty-specific estimates.
Future Research: Further studies are needed to assess adverse event rates in diverse geographic locations and healthcare systems, explore effective interventions to reduce preventable harm, and evaluate long-term trends in surgical patient safety.
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.
Retrospective Cohort Study: Midline Catheters Associated with Lower Major Complications Than PICCs in Outpatient Antimicrobial Therapy
16 Nov, 2024 | 14:35h | UTCBackground: Outpatient parenteral antimicrobial therapy (OPAT) requires reliable vascular access for administering intravenous antibiotics post-hospitalization. Peripherally inserted central catheters (PICCs) are commonly used due to their versatility and ease of placement. Recently, midline catheters have emerged as potential alternatives for OPAT, offering less invasive access. However, limited evidence exists comparing the safety and complication rates of midline catheters versus PICCs in OPAT patients.
Objective: To compare the risk of major and minor device complications associated with midline catheters versus PICCs in patients receiving OPAT.
Methods: This retrospective cohort study analyzed data from 2,824 hospitalized patients across 69 Michigan hospitals who received either a midline catheter (n=1,999) or a PICC (n=825) for OPAT between January 2017 and November 2023. Patients receiving vancomycin were excluded. The primary outcome was major device complications, defined as catheter-related bloodstream infection (CRBSI) or catheter-related venous thromboembolism (CR-VTE). Secondary outcomes included minor device complications (e.g., catheter dislodgement, occlusion) and device failure, defined as catheter removal due to any complication.
Results: Midline catheters were associated with a lower risk of major complications compared to PICCs (0.8% vs 3.4%; adjusted hazard ratio [aHR], 0.46; 95% CI, 0.23-0.91; P < .001). This difference was more pronounced for devices with dwell times of 14 days or fewer (aHR, 0.29; 95% CI, 0.12-0.68). There were no significant differences in minor complications (10.3% vs 13.8%; aHR, 1.07; 95% CI, 0.83-1.38) or device failure rates (9.6% vs 12.1%; aHR, 1.26; 95% CI, 0.96-1.65) between midline catheters and PICCs.
Conclusions: Midline catheters are associated with a lower risk of major complications compared to PICCs in patients receiving OPAT, particularly for treatment durations of 14 days or fewer. These findings suggest that midline catheters are a safe and effective alternative to PICCs for short-term OPAT.
Implications for Practice: Clinicians should consider using midline catheters for OPAT when the anticipated therapy duration is 14 days or less and the infusate is peripherally compatible. This may reduce the risk of major complications such as CRBSI and CR-VTE, potentially improving patient outcomes and reducing healthcare costs.
Study Strengths and Limitations: Strengths of this study include a large, diverse patient population across multiple hospitals and rigorous data collection methods. Limitations include its retrospective design, potential for unmeasured confounding, and exclusion of patients receiving vancomycin, which may limit generalizability. Additionally, complications occurring after 30 days or post-device removal may have been missed.
Future Research: Further studies are needed to evaluate the safety and efficacy of midline catheters for OPAT durations exceeding 14 days and to explore factors influencing long-term device performance and patient outcomes.