Association of beta blockers and mortality in adults with septic shock: systematic review and meta-analysis of randomized clinical trial.

Introduction: Septic shock still entails significant morbidity and mortality, with the heart being affected due to catecholamine overexpression and direct injury from sepsis. Therefore, the effect of ß-blocking the receptors to improve performance is promising when attempting to reverse tachycardia and reduce mortality. Methods: We conducted a comprehensive search across five databases for studies published up to 28 January 2024, using a PICO strategy. Ten studies were identified for quantitative analysis and included in our meta-analysis. Results: Our meta-analysis evaluated 28-day in-hospital mortality risk across nine randomized controlled trials (RCTs) involving a total of 1,121 adults with septic shock. We found an association between ß-blocker use and reduced overall mortality (OR 0.57; 95% CI 0.34-0.98; I 2: 56%). This effect was significant in the esmolol subgroup (OR 0.47; 95% CI 0.26-0.82; I 2: 32%), but not in the landiolol subgroup (OR 0.98; 95% CI 0.0-1,284.5; I 2: 72%). Additionally, the intervention group shows a significant reduction in HR and lactate levels, as well as an increase in stroke volume index (SVI). Conclusion: In adults with septic shock, ß-blockers are associated with a reduction in 28-day in-hospital mortality, a benefit primarily observed with esmolol rather than landiolol. Furthermore, improvements in heart rate (HR) control, lactate levels, and SVI were noted. However, these findings should be interpreted with caution, and further high-quality RCTs comparing different ß-blockers are necessary to better elucidate these effects. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024513610.

Beta-Blocker Usage in Patients With Heart Failure With Reduced Ejection Fraction During Acute Decompensated Heart Failure Hospitalizations.

Background: Acute decompensated heart failure accounts for more than 1 million hospitalizations in the United States every year. Beta-blockers are a first-line agent for patients experiencing heart failure with reduced ejection fraction, but beta-blocker use in patients hospitalized for acute decompensated heart failure remains low. We conducted an analysis of the existing evidence and guidelines to determine the conditions for prescribing beta-blockers to patients with acute decompensated heart failure. Methods: We searched the PubMed database for studies from 2004 to 2024 that included the search terms "beta blockers" and "acute decompensated heart failure." We included studies in which beta-blockers were used in patients with heart failure with reduced ejection fraction and excluded studies that did not study beta-blockers directly. We compiled recommendations from professional societies regarding beta-blocker usage-both for outpatients with heart failure with reduced ejection fraction and for patients hospitalized with acute decompensated heart failure. Results: Studies consistently demonstrated lower rates of mortality and rehospitalization when beta-blocker therapy was maintained for patients with heart failure with reduced ejection fraction who were already on beta-blocker therapy. Conversely, withdrawal of beta-blocker therapy was associated with increased in-hospital and short-term mortality. We summarized our findings in a guideline-based flowchart to help physicians make informed decisions regarding beta-blocker therapy in patients with acute decompensated heart failure. Based on the evidence, beta-blockers should be initiated at a low dose in patients with heart failure with reduced ejection fraction who have never been on beta-blockers, provided the patient is hemodynamically stable. Conclusion: Our research and our guideline-based flowchart promote guideline-directed use of beta-blockers to improve the outcomes of patients with heart failure with reduced ejection fraction.

Beta-blockers and breastfeeding: a real-life prospective study.

PURPOSE: At Lille University Hospital, a pregnancy heart team including cardiologists, obstetricians, pediatricians, anesthetists, geneticists, and pharmacologists discusses about treatment compatibility taken during breastfeeding in pregnant women (or those wishing to be pregnant) with complex cardiovascular pathologies. Beta-blockers are among the drug most often used in these patients, and data are missing or suggest a risk to the breastfed child. The aim of this study was to evaluate the proportion of women treated with beta-blockers, identified during the multidisciplinary meeting, who breastfed and to monitor adverse effects (AEs) in newborns. METHODS: A prospective descriptive study was conducted from 1 December 2017 to 1 December 2021. All pregnant patients followed up by the pregnancy heart team in Lille University Hospital, treated with beta-blockers and who gave birth, were contacted as part of the pharmacovigilance follow-up. RESULTS: The proportion of women treated with beta-blockers intending to breastfeed was 69.8%. Among the 53 women interviewed, 49% did not breastfeed, including 10 because of the theoretical incompatibility of their beta-blocker with breastfeeding. Among the 27 women who breastfed, 30% breastfed while treated with a theoretically incompatible beta-blocker; 56% was changed from their initial beta-blocker to allow safe breastfeeding. No serious AE was observed. CONCLUSION: To our knowledge, our study is the largest series of patients treated with beta-blockers during breastfeeding. Taking a treatment can be an obstacle to breastfeeding, but for the particular case of beta-blockers, even if the available data are few and sometimes worrying, the data from this study are reassuring.

Improving oxygenation in severe ARDS treated with VV-ECMO: comparative efficacy of moderate hypothermia and landiolol in a swine ARDS model.

BACKGROUND: Acute respiratory distress syndrome (ARDS) remains a significant challenge in critical care, with high mortality rates despite advancements in treatment. Venovenous extracorporeal membrane oxygenation (VV-ECMO) is employed as salvage therapy for refractory cases. However, some patients may continue to experience persistent severe hypoxemia despite being treated with VV-ECMO. To achieve this, moderate hypothermia and short-acting selective ß1-blockers have been proposed. METHODS: Using a swine model of severe ARDS treated with VV-ECMO, this study investigated the efficacy of moderate hypothermia or ß-blockade in improving arterial oxygen saturation (SaO2) three hours after VV-ECMO initiation. Primary endpoints included the ratio of VV-ECMO flow to cardiac output and arterial oxygen saturation before VV-ECMO start (H0) and three hours after ECMO start (H3). Secondary safety criteria encompassed hemodynamics and oxygenation parameters. RESULTS: Twenty-two male pigs were randomized into three groups: control (n = 6), hypothermia (n = 9) and ß-blockade (n = 7). At H0, all groups demonstrated similar hemodynamic and respiratory parameters. Both moderate hypothermia and ß-blockade groups exhibited a significant increase in the ratio of VV-ECMO flow to cardiac output at H3, resulting in improved SaO2. At H3, despite a decrease in oxygen delivery and consumption in the intervention groups compared to the control group, oxygen extraction ratios across groups remained unchanged and lactate levels were normal. CONCLUSIONS: In a swine model of severe ARDS treated with VV-ECMO, both moderate hypothermia and ß-blockade led to an increase in the ratio of VV-ECMO flow to cardiac output resulting in improved arterial oxygen saturation without any impact on tissue perfusion.

Early Intravenous Beta-Blockade with Esmolol in Adults with Severe Traumatic Brain Injury: A Phase 2a Intervention Design Study.

BACKGROUND: Targeted beta-blockade after severe traumatic brain injury may reduce secondary brain injury by attenuating the sympathoadrenal response. The potential role and optimal dosage for esmolol, a selective, short-acting, titratable beta-1 beta-blocker, as a safe, putative early therapy after major traumatic brain injury has not been assessed. METHODS: We conducted a single-center, open-label dose-finding study using an adaptive model-based design. Adults (18 years or older) with severe traumatic brain injury and intracranial pressure monitoring received esmolol within 24 h of injury to reduce their heart rate by 15% from baseline of the preceding 4 h while ensuring cerebral perfusion pressure was maintained above 60 mm Hg. In cohorts of three, the starting dosage and dosage increments were escalated according to a prespecified plan in the absence of dose-limiting toxicity. Dose-limiting toxicity was defined as failure to maintain cerebral perfusion pressure, triggering cessation of esmolol infusion. The primary outcome was the maximum tolerated dosage schedule of esmolol, defined as that associated with less than 10% probability of dose-limiting toxicity. Secondary outcomes include 6-month mortality and 6-month extended Glasgow Outcome Scale score. RESULTS: Sixteen patients (6 [37.5%] female patients; mean age 36 years [standard deviation 13 years]) with a median Glasgow Coma Scale score of 6.5 (interquartile range 5-7) received esmolol. The optimal starting dosage of esmolol was 10 µg/kg/min, with increments every 30 min of 5 µg/kg/min, as it was the highest dosage with less than 10% estimated probability of dose-limiting toxicity (7%). All-cause mortality was 12.5% at 6 months (corresponding to a standardized mortality ratio of 0.63). One dose-limiting toxicity event and no serious adverse hemodynamic effects were seen. CONCLUSIONS: Esmolol administration, titrated to a heart rate reduction of 15%, is feasible within 24 h of severe traumatic brain injury. The probability of dose-limiting toxicity requiring withdrawal of esmolol when using the optimized schedule is low. Trial registrationI SRCTN, ISRCTN11038397, registered retrospectively January 7, 2021 ( https://www.isrctn.com/ISRCTN11038397 ).

Stroke Risk Reduction in Migraine Patients Using Propranolol: Evidence from Two Large-Scale Real-World Data Analyses.

Background: Propranolol, a non-selective beta-blocker, is commonly used for migraine prevention, but its impact on stroke risk among migraine patients remains controversial. Using two large electronic health records-based datasets, we examined stroke risk differences between migraine patients with- and without- documented use of propranolol. Methods: This retrospective case-control study utilized EHR data from the Vanderbilt University Medical Center (VUMC) and the All of Us Research Program. Migraine patients were first identified based on the International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria using diagnosis codes. Among these patients, cases were defined as those with a primary diagnosis of stroke following the first diagnosis of migraine, while controls had no stroke after their first migraine diagnosis. Logistic regression models, adjusted for potential factors associated with stroke risk, assessed the association between propranolol use and stroke risk, stratified by sex and migraine subtype. A Cox proportional hazards regression model was used to estimate the hazard ratio (HR) for stroke risk at 1, 2, 5, and 10 years from baseline. Results: In the VUMC database, 378 cases and 15,209 controls were identified, while the All of Us database included 267 cases and 6,579 controls. Propranolol significantly reduced stroke risk in female migraine patients (VUMC: OR=0.52, p=0.006; All of Us: OR=0.39, p=0.007), but not in males. The effect was more pronounced for ischemic stroke and in females with migraines without aura (MO) (VUMC: OR=0.60, p=0.014; All of Us: OR=0.28, p=0.006). The Cox model showed lower stroke rates in propranolol-treated female migraine patients at 1, 2, 5, and 10 years (VUMC: HR=0.06-0.55, p=0.0018-0.085; All of Us: HR=0.23, p=0.045 at 10 years). Conclusions: Propranolol is associated with a significant reduction in stroke risk, particularly ischemic stroke, among female migraine without aura patients. These findings suggest that propranolol may benefit stroke prevention in high-risk populations.

An Unusual Case of Paroxysmal Third-Degree Atrioventricular Block: Thinking Outside the Box.

During the assessment of a third-degree atrioventricular (AV) block in a patient with syncope, different etiologies should be considered and evaluated. Extrinsic vagal paroxysmal AV block, extrinsic idiopathic AV block and intrinsic paroxysmal AV block are among the types of third-degree AV block in the differential diagnoses. Extrinsic vagal paroxysmal third-degree atrioventricular block (EV-AVB) is linked to parasympathetic influence on cardiac conduction and can be observed in bladder distention and urinary retention. Topical and ophthalmic beta-blockers have shown systemic effects such as bradycardia with and without syncope. We present the case of an 80-year-old male with symptomatic EV-AVB likely precipitated by bladder outlet obstruction and chronic use of an ophthalmic beta-blocker, often overlooked causes of third-degree AV block.

G Protein-Coupled Receptors: A Century of Research and Discovery.

GPCRs (G protein-coupled receptors), also known as 7 transmembrane domain receptors, are the largest receptor family in the human genome, with ≈800 members. GPCRs regulate nearly every aspect of human physiology and disease, thus serving as important drug targets in cardiovascular disease. Sharing a conserved structure comprised of 7 transmembrane α-helices, GPCRs couple to heterotrimeric G-proteins, GPCR kinases, and ß-arrestins, promoting downstream signaling through second messengers and other intracellular signaling pathways. GPCR drug development has led to important cardiovascular therapies, such as antagonists of ß-adrenergic and angiotensin II receptors for heart failure and hypertension, and agonists of the glucagon-like peptide-1 receptor for reducing adverse cardiovascular events and other emerging indications. There continues to be a major interest in GPCR drug development in cardiovascular and cardiometabolic disease, driven by advances in GPCR mechanistic studies and structure-based drug design. This review recounts the rich history of GPCR research, including the current state of clinically used GPCR drugs, and highlights newly discovered aspects of GPCR biology and promising directions for future investigation. As additional mechanisms for regulating GPCR signaling are uncovered, new strategies for targeting these ubiquitous receptors hold tremendous promise for the field of cardiovascular medicine.

Early postoperative beta-blockers are associated with improved cardiac output after late complete repair of tetralogy of Fallot: a retrospective cohort study.

Tetralogy of Fallot is the most common cyanotic congenital heart disease. For decades, our institution has cared for humanitarian patients with late presentation of tetralogy of Fallot. They are characterized by severe right ventricular hypertrophy with consecutive diastolic dysfunction, increasing the risk of postoperative low cardiac output syndrome (LCOS). By right ventricular restrictive physiology, we hypothesized that patients receiving early postoperative beta-blockers (within 48 h after cardiopulmonary bypass) may have better diastolic function and cardiac output. This is a retrospective cohort study in a single-center tertiary pediatric intensive care unit. We included > 1-year-old humanitarian patients with a confirmed diagnosis of tetralogy of Fallot undergoing a complete surgical repair between 2005 and 2019. We measured demographic data, preoperative echocardiographic and cardiac catheterization measures, postoperative mean heart rate, vasoactive-inotropic scores, LCOS scores, length of stay, and mechanical ventilation duration. One hundred sixty-five patients met the inclusion criteria. Fifty-nine patients (36%) received early postoperative beta-blockers, associated with a lower mean heart rate, higher vasoactive-inotropic scores, and lower LCOS scores during the first 48 h following cardiopulmonary bypass. There was no significant difference in lengths of stay and ventilation. Conclusion: Early postoperative beta-blockers lower the prevalence of postoperative LCOS at the expense of a higher need for vasoactive drugs without any consequence on length of stay and ventilation duration. This approach may benefit the specific population of children undergoing a late complete repair of tetralogy of Fallot. What is Known: • Prevalence of low cardiac output syndrome is high following a late complete surgical repair of tetralogy of Fallot. What is New: • Early postoperative beta-blockade is associated with lower heart rate, prolonged relaxation time, and lower prevalence of low cardiac output syndrome. • Negative chronotropic agents like beta-blockers may benefit selected patients undergoing a late complete repair of tetralogy of Fallot, who are numerous in low-income countries.

Do beta-blockers reduce negative intrusive thoughts and anxiety in cancer survivors? - An emulated trial.

BACKGROUND: High rates of negative intrusive thoughts have been reported among cancer patients. Prevalent users of beta-blocker therapy have reported lower levels of cancer related intrusive thoughts than non-user. The aim of this study is to investigate if initiation of beta-blocker therapy reduces the prevalence and severity of intrusive thoughts (co-primary endpoints) and the prevalence of anxiety, depressed mood, and low quality of life (secondary endpoints) in cancer survivors. METHODS: Data on patient-reported outcomes from three cohort studies of Swedish patients diagnosed with colon, prostate or rectal cancer were combined with data on beta-blocker prescriptions retrieved from the Swedish Prescribed Drug Register. Two randomized controlled trials were emulated. Trial 1 had follow-up 1 year after diagnosis, trial 2 had follow-up 2 years after diagnosis, baseline in both trials was 12 months before follow-up. Those who initiated beta-blocker therapy between baseline and follow-up was assigned Active group, those who did not was assigned Control group. All endpoints were analysed using Bayesian ordered logistic regression. RESULTS: Trial 1 consisted of Active group, n = 59, and Control group, n = 3936. Trial 2 consisted of Active group, n = 87, and Control group, n = 3132. The majority of participants were men, 83% in trial 1 and 94% in trial 2. The prevalence and severity of intrusive thoughts were lower in the Active group in trial 1, but no significant differences between groups were found in either trial. The prevalence of depressed mood, worse quality of life and periods of anxiety were higher in the Active group in both trials with significant differences for quality of life in trial 1 and anxiety in trial 2. CONCLUSIONS: The emulated trials demonstrated no evidence of a protective effect of beta-blocker therapy against intrusive thoughts. The Active group had reduced quality of life and elevated anxiety compared to the Control group. TRIAL REGISTRATION: The three cohort studies were registered at isrctn.com/clinicaltrials.gov (ISRCTN06393679, NCT02530593 and NCT01477229).

The effect of the four pharmacological pillars of heart failure on haemoglobin level.

Anaemia, a condition characterized by low levels of haemoglobin, is frequently observed in patients with heart failure (HF). Guideline-directed medical therapy improves HF outcomes by using medications like beta blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, along with mineralocorticoid receptor antagonists and sodium-glucose cotransporter 2 inhibitors. In this study, we aimed to review the pathophysiology of anaemia in patients with HF and present the current evidence regarding the relationship between the main recommended medications for these patients and haemoglobin levels. The authors conducted a comprehensive search in the medical literature for relevant original clinical articles in which the four pharmacological pillars of HF were given to the patients; we, then, assessed whether the association of use of these medications and haemoglobin level or development of anaemia was provided. These common medications have been shown in the literature that may exacerbate or ameliorate anaemia. Besides, it has been shown that even in the case that they result in the development of anaemia, their use is associated with positive effects that outweigh this potential harm. The literature also suggests that among patients receiving medications with negative effects on the level of haemoglobin, there was no difference in the rate of mortality between anaemic and non-anaemic patients when both were on treatment for anaemia; this point highlights the importance of the detection and treatment of anaemia in these patients. Further research is needed to explore these relationships and identify additional strategies to mitigate the risk of anaemia in this population.

Mental Health of School-Aged Children Treated with Propranolol or Atenolol for Infantile Hemangioma and Their Parents.

BACKGROUND: Infants with infantile hemangioma (IH) have been effectively treated with propranolol or atenolol. Concerns were raised about the mental health of these children at school age, due to central nervous system effects of propranolol and visible nature of IH. OBJECTIVE: This study aimed to compare the mental health at school age of children treated with propranolol to children treated with atenolol for IHs and their parents. METHODS: This two-centered cross-sectional study included children aged ≥6 years and treated with either propranolol or atenolol for IH during infancy. Children's outcomes were performance-based affect recognition (Dutch version of the Developmental Neuropsychological Assessment-II [NEPSY-II-NL]), parent-reported emotional and behavioral functioning (Child Behavioral Checklist [CBCL]), and health-related quality of life (KIDSCREEN-27). Parents' outcome was parenting stress (Parenting Stress Questionnaire [OBVL]). RESULTS: Data of 105 children (36 propranolol, 69 atenolol; 6.0-11.8 years) were analyzed. Mental health outcomes did not differ between both ß-blocker groups. Although overall functioning was in line with norms, children presented specific problems concerning affect recognition, parent-reported attention, and social quality of life. Parents showed increased physical symptoms, depressive symptoms, and parent-child relationship problems. CONCLUSION: No difference in mental health at school age was found between children treated with propranolol or atenolol for IH. Although few overall mental health problems were found, specific problems require follow-up. Follow-up of children should be directed toward affect recognition, attention, and social functioning in daily life. Problems reported by parents could be ameliorated by mental health support during and after their infant's ß-blocker treatment.

Beta-blocker therapy in heart failure with preserved ejection fraction (B-HFpEF): A systematic review and meta-analysis.

INTRODUCTION: While beta-blockers are considered the cornerstone of treatment for heart failure with reduced ejection fraction, the same may not apply to patients with heart failure with preserved ejection fraction (HFpEF). To date, the benefit of beta-blockers remains uncertain, and there is no current consensus on their effectiveness. This study sought to evaluate the efficacy of beta-blockers on mortality and rehospitalization among patients with HFpEF. METHODS: A systematic review and meta-analysis of randomized or observational cohort studies examined the efficacy of beta-blocker therapy in comparison with placebo, control, or standard medical care in patients with HFpEF, defined as left ventricular ejection fraction ≥50 %. The main endpoints were mortality (i.e., all-cause and cardiovascular), rehospitalization (i.e., all-cause and for heart failure) and a composite of the two. RESULTS: Out of the 13,189 records initially identified, 16 full-text records met the inclusion criteria and were analyzed recruiting a total of 27,188 patients. The mean age range was 62-84 years old, predominantly female, with HFpEF in which 63.4 % of patients received a beta-blocker and 36.6 % did not. The pooled analysis of included cohort studies, of variable follow-up durations, showed a significant reduction in all-cause mortality by 19 % (odds ratio (OR) 0.81; 95 % confidence interval (CI): 0.65-0.99, p = 0.044) whereas rehospitalization for heart failure (OR 1.13; 95 % CI: 0.91-1.41, p = 0.27) or its composite with all-cause mortality (OR 1.01; 95 % CI: 0.78-1.32, p = 0.92) were similar between the beta-blocker and control groups. CONCLUSION: This meta-analysis showed that beta-blocker therapy has the potential to reduce all-cause mortality in patients with HFpEF based on observational studies. Nevertheless, it did not affect rehospitalization for heart failure or its composite with all-cause mortality. Large scale randomized trials are needed to clarify this uncertainty.

Early Intravenous Beta-Blockade with Esmolol in Adults with Severe Traumatic Brain Injury (EBB-TBI): Protocol for a Phase 2a Intervention Design Study.

Traumatic brain injury is a leading cause of death and disability worldwide. Interventions that mitigate secondary brain injury have the potential to improve outcomes for patients and reduce the impact on communities and society. Increased circulating catecholamines are associated with worse outcomes and there are supportive animal data and indications in human studies of benefit from beta-blockade after severe traumatic brain injury. Here, we present the protocol for a dose-finding study using esmolol in adults commenced within 24 h of severe traumatic brain injury. Esmolol has practical advantages and theoretical benefits as a neuroprotective agent in this setting, but these must be balanced against the known risk of secondary injury from hypotension. The aim of this study is to determine a dose schedule for esmolol, using the continual reassessment method, that combines a clinically significant reduction in heart rate as a surrogate for catecholamine drive with maintenance of cerebral perfusion pressure. The maximum tolerated dosing schedule for esmolol can then be tested for patient benefit in subsequent randomized controlled trials.Trial registration ISRCTN, ISRCTN11038397, registered retrospectively 07/01/2021 https://www.isrctn.com/ISRCTN11038397.

The role of plasma concentrations and drug characteristics of beta-blockers in fall risk of older persons.

Beta-blocker usage is inconsistently associated with increased fall risk in the literature. However, due to age-related changes and interindividual heterogeneity in pharmacokinetics and dynamics, it is difficult to predict which older adults are more at risk for falls. Therefore, we wanted to explore whether elevated plasma concentrations of selective and nonselective beta-blockers are associated with an increased risk of falls in older beta-blocker users. To answer our research question, we analyzed samples of selective (metoprolol, n = 316) and nonselective beta-blockers (sotalol, timolol, propranolol, and carvedilol, n = 179) users from the B-PROOF cohort. The associations between the beta-blocker concentration and time to first fall were assessed using Cox proportional hazard models. Change of concentration over time in relation to fall risk was assessed with logistic regression models. Models were adjusted for potential confounders. Our results showed that above the median concentration of metoprolol was associated with an increased fall risk (HR 1.55 [1.11-2.16], p = .01). No association was found for nonselective beta-blocker concentrations. Also, changes in concentration over time were not associated with increased fall risk. To conclude, metoprolol plasma concentrations were associated with an increased risk of falls in metoprolol users while no associations were found for nonselective beta-blockers users. This might be caused by a decreased ß1-selectivity in high plasma concentrations. In the future, beta-blocker concentrations could potentially help clinicians estimate fall risk in older beta-blockers users and personalize treatment.

Multicenter, Prospective, Randomized Controlled Trial of High-Sensitivity Cardiac Troponin I-Guided Combination Angiotensin Receptor Blockade and Beta-Blocker Therapy to Prevent Anthracycline Cardiotoxicity: The Cardiac CARE Trial.

BACKGROUND: Anthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by elevations in cardiac troponin concentrations. Beta-adrenergic receptor blocker and renin-angiotensin system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients receiving anthracycline chemotherapy. METHODS: In a multicenter, prospective, randomized, open-label, blinded end-point trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent serial high-sensitivity cardiac troponin testing and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Patients at high risk of cardiotoxicity (cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomized to standard care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary outcome was adjusted change in left ventricular ejection fraction at 6 months. In low-risk nonrandomized patients with cardiac troponin I concentrations in the lower 2 tertiles, we hypothesized the absence of a 6-month change in left ventricular ejection fraction and tested for equivalence of ±2%. RESULTS: Between October 2017 and June 2021, 175 patients (mean age, 53 years; 87% female; 71% with breast cancer) were recruited. Patients randomized to cardioprotection (n=29) or standard care (n=28) had left ventricular ejection fractions of 69.4±7.4% and 69.1±6.1% at baseline and 65.7±6.6% and 64.9±5.9% 6 months after completion of chemotherapy, respectively. After adjustment for age, pretreatment left ventricular ejection fraction, and planned anthracycline dose, the estimated mean difference in 6-month left ventricular ejection fraction between the cardioprotection and standard care groups was -0.37% (95% CI, -3.59% to 2.85%; P=0.82). In low-risk nonrandomized patients, baseline and 6-month left ventricular ejection fractions were 69.3±5.7% and 66.4±6.3%, respectively: estimated mean difference, 2.87% (95% CI, 1.63%-4.10%; P=0.92, not equivalent). CONCLUSIONS: Combination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment cardiac troponin I concentrations. Low-risk nonrandomized patients had similar declines in left ventricular ejection fraction, bringing into question the utility of routine cardiac troponin monitoring. Furthermore, the modest declines in left ventricular ejection fraction suggest that the value and clinical impact of early cardioprotection therapy need to be better defined in patients receiving high-dose anthracycline. REGISTRATION: URL: https://doi.org; Unique identifier: 10.1186/ISRCTN24439460. URL: https://www.clinicaltrialsregister.eu/ctr-search/search; Unique identifier: 2017-000896-99.

Association between antihypertensive medicine use and risk of ovarian cancer in women aged 50 years and older.

BACKGROUND: Epithelial ovarian cancer (EOC) has few modifiable risk factors. There is evidence that some antihypertensive medicines may have cancer preventive and/or therapeutic actions; therefore, we assessed the associations between use of different antihypertensive medicines and risk of specific EOC histotypes. METHODS: Our nested case-control study of linked administrative health data included 6070 Australian women aged over 50 years diagnosed with EOC from 2004 to 2013, and 30,337 matched controls. We used multivariable conditional logistic regression to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for the association between ever use of each antihypertensive medicine group, including beta-adrenergic blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, diuretics, and alpha blockers, and the risk of EOC overall and separately for the serous, endometrioid, mucinous, clear cell and other histotypes. RESULTS: We found that most antihypertensive medicines were not associated with risk of EOC. However, women who used calcium channel blockers had a reduced risk of serous EOC (OR= 0.89, 95 % CI:0.81,0.98) and use of combination thiazide and potassium-sparing diuretics was associated with an increased risk of endometroid EOC (OR= 2.09, 95 % CI:1.15,3.82). CONCLUSION: Our results provide little support for a chemo-preventive role for most antihypertensives, however, the histotype-specific associations we found warrant further investigation.

Non-selective beta-blockers and the incidence of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis.

Background: Hepatocellular carcinoma (HCC) is a serious complication of cirrhosis. Currently, non-selective beta-blockers (NSBBs) are commonly used to treat portal hypertension in patients with cirrhosis. The latest research shows that NSBBs can induce apoptosis and S-phase arrest in liver cancer cells and inhibit the development of hepatic vascular endothelial cells, which may be effective in preventing HCC in cirrhosis patients. Aim: To determine the relationship between different NSBBs and HCC incidence in patients with cirrhosis. Methods: We searched the Cochrane database, MEDLINE, EMBASE, PubMed, and Web of Science. Cohort studies, case‒control studies, and randomized controlled trials were included if they involved cirrhosis patients who were divided into an experimental group using NSBBs and a control group with any intervention. Based on heterogeneity, we calculated odds ratio (OR) and 95% confidence interval (CI) using random-effect models. We also conducted subgroup analysis to explore the source of heterogeneity. Sensitivity analysis and publication bias detection were performed. Results: A total of 47 studies included 38 reporting HCC incidence, 26 reporting HCC-related mortality, and 39 reporting overall mortality. The HCC incidence between the experimental group and the control group was OR = 0.87 (0.69 and 1.10), p = 0.000, and I2 = 81.8%. There was no significant association between propranolol (OR = 0.94 and 95%CI 0.62-1.44) or timolol (OR = 1.32 and 95%CI 0.44-3.95) and HCC incidence, while the risk of HCC decreased by 26% and 38% with nadolol (OR = 0.74 and 95%CI 0.64-0.86) and carvedilol (OR = 0.62 and 95%CI 0.52-0.74), respectively. Conclusion: Different types of NSBB have different effects on the incidence of patients with cirrhosis of the liver, where nadolol and carvedilol can reduce the risk. Also, the effect of NSBBs may vary in ethnicity. Propranolol can reduce HCC incidence in Europe and America. Systematic Review Registration: identifier https://CRD42023434175, https://www.crd.york.ac.uk/PROSPERO/.

A Rare Case of Angiolymphoid Hyperplasia With Eosinophilia With a New Effective Treatment.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a benign locally proliferating lesion of unknown etiology, composed of vascular channels lined by endothelial cells, surrounded by lymphocytes and eosinophils. It presents clinically as a cluster of skin to violaceous-colored nodules on the head and neck, particularly in and around the ear. We present the case of a 50-year-old, Pakistani woman with unilateral multiple nodular lesions for eight years in the left ear concha and postauricular area causing complete obliteration of the external auditory meatus with conductive hearing loss of the left ear for seven years. Biopsy showed lymphoid follicles and dilated blood vessels with mixed infiltrate predominantly eosinophils corresponding to the diagnosis of angiolymphoid hyperplasia with eosinophilia. Surgical excision was not feasible, and there was no response to topical steroids. The patient was started on beta blockers. After three months, postauricular lesions completely resolved, and the size of the rest of the nodules decreased markedly; then hearing loss also recovered. Our objective in this study is to emphasize the importance of considering beta blockers for the treatment of ALHE.

Beta-blocker exposure and survival outcomes in patients with advanced pancreatic ductal adenocarcinoma: a retrospective cohort study (BETAPANC).

Introduction: Preclinical studies have demonstrated the possible role of beta-adrenergic receptors in pancreatic ductal adenocarcinoma (PDAC) tumor invasion and migration. The current study aimed to explore the possible association between survival outcomes and beta-blocker (BB) exposure in patients with advanced PDAC. Methods: This retrospective single-center study included 182 patients with advanced PDAC. Clinical [age, sex, BMI, cardiovascular condition, presence (SBB) or absence (NSBB) of beta-1 selectivity of BB, exposure duration, and multimorbidity], oncological (stage and anticancer treatment regimen), and biological (renal and liver function) data were collected. The endpoints were overall survival (OS) and progression-free survival (PFS). Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for survival outcomes associated with BB exposure were estimated using Cox regression model and propensity score (PS) methods. Results: Forty-one patients (22.5%) were exposed to BB. A total of 104 patients progressed (57.1%) to PDAC and 139 (76.4%) patients died at the end of follow-up (median, 320 days; IQR, 438.75 days). When compared to the non-exposed group, there was no increase in survival outcomes associated with BB use (OS: HR = 1.38, 95% CI = 0.80-2.39, p = 0.25; PFS: adjusted HR = 0.95, 95% CI = 0.48-1.88, p = 0.88). Similar results were obtained using the PS method. Compared to no BB usage, SBB use was associated with a significant decrease in OS (HR = 1.80, 95% CI = 1.16-2.80, p < 10-2). Conclusion: BB exposure was not associated with improved PDAC survival outcomes. Beta-1-selectivity was not independently associated with any differences.