Sex Differences in Cardiovascular Management: A Call for Better Acknowledgment-Part 1 Pharmacological Differences in Women and Men; How Relevant Are They?

BACKGROUND: Sex differences (SDs) in pharmacology of cardiovascular (CV) drugs have been described previously; however, paradoxically, there are scarce recommendations in therapy based on these differences. It is of utmost importance to identify whether these SDs determine a modified clinical response and the potential practical implications for this, to provide a base for personalized medicine. AREA OF UNCERTAINTY: The aim of this article was to outline the most important pharmacological drivers of cardiovascular drugs that differ between women and men, along with their implications and challenges in clinical practice. DATA SOURCES: A detailed assessment of English-written resources reflecting SDs impact in CV drug pharmacology was performed using PubMed and Embase databases. RESULTS: Despite large variations in CV drug pharmacokinetics and pharmacodynamics in individuals, correcting for height, weight, surface area, and body composition compensate for most "sex-dependent" differences. In addition, individual, cultural, and social factors significantly impact disease management in women versus men. Gender-biased prescribing patterns and gender-dependent adherence to therapy also influence outcomes. The development of sex-specific guidelines requires that they should reflect the SDs implications for the management of a disease and that the evidence should be carefully evaluated as to whether there is an adequate representation of both sexes and whether sex-disaggregated data are reported. CONCLUSIONS: Pharmacological drivers are under the influence of an impressive number of differences between women and men. However, to establish their significance in clinical practice, an adequate representation of women in studies and the reporting of distinct results is mandatory.

Heart failure pharmacotherapy and cancer: pathways and pre-clinical/clinical evidence.

Heart failure (HF) patients have a significantly higher risk of new-onset cancer and cancer-associated mortality, compared to subjects free of HF. While both the prevention and treatment of new-onset HF in patients with cancer have been investigated extensively, less is known about the prevention and treatment of new-onset cancer in patients with HF, and whether and how guideline-directed medical therapy (GDMT) for HF should be modified when cancer is diagnosed in HF patients. The purpose of this review is to elaborate and discuss the effects of pillar HF pharmacotherapies, as well as digoxin and diuretics on cancer, and to identify areas for further research and novel therapeutic strategies. To this end, in this review, (i) proposed effects and mechanisms of action of guideline-directed HF drugs on cancer derived from pre-clinical data will be described, (ii) the evidence from both observational studies and randomized controlled trials on the effects of guideline-directed medical therapy on cancer incidence and cancer-related outcomes, as synthetized by meta-analyses will be reviewed, and (iii) considerations for future pre-clinical and clinical investigations will be provided.

Anticoagulation with edoxaban in patients with long atrial high-rate episodes ≥24†h.

BACKGROUND AND AIMS: Patients with long atrial high-rate episodes (AHREs) ≥24 h and stroke risk factors are often treated with anticoagulation for stroke prevention. Anticoagulation has never been compared with no anticoagulation in these patients. METHODS: This secondary pre-specified analysis of the Non-vitamin K antagonist Oral anticoagulants in patients with Atrial High-rate episodes (NOAH-AFNET 6) trial examined interactions between AHRE duration at baseline and anticoagulation with edoxaban compared with placebo in patients with AHRE and stroke risk factors. The primary efficacy outcome was a composite of stroke, systemic embolism, or cardiovascular death. The safety outcome was a composite of major bleeding and death. Key secondary outcomes were components of these outcomes and electrocardiogram (ECG)-diagnosed atrial fibrillation. RESULTS: Median follow-up of 2389 patients with core lab-verified AHRE was 1.8 years. AHRE ≥24 h were present at baseline in 259/2389 patients (11%, 78 ± 7 years old, 28% women, CHA2DS2-VASc 4). Clinical characteristics were not different from patients with shorter AHRE. The primary outcome occurred in 9/132 patients with AHRE ≥24 h (4.3%/patient-year, 2 strokes) treated with anticoagulation and in 14/127 patients treated with placebo (6.9%/patient-year, 2 strokes). Atrial high-rate episode duration did not interact with the efficacy (P-interaction = .65) or safety (P-interaction = .98) of anticoagulation. Analyses including AHRE as a continuous parameter confirmed this. Patients with AHRE ≥24 h developed more ECG-diagnosed atrial fibrillation (17.0%/patient-year) than patients with shorter AHRE (8.2%/patient-year; P < .001). CONCLUSIONS: This hypothesis-generating analysis does not find an interaction between AHRE duration and anticoagulation therapy in patients with device-detected AHRE and stroke risk factors. Further research is needed to identify patients with long AHRE at high stroke risk.

Asymptomatic vs. symptomatic atrial fibrillation: Clinical outcomes in heart failure patients.

BACKGROUND: The outcome implications of asymptomatic vs. symptomatic atrial fibrillation (AF) in specific groups of patients according to clinical heart failure (HF) and left ventricular ejection fraction (LVEF) need to be clarified. METHODS: In a prospective observational study, patients were categorized according to overt HF with LVEF≤40 %, or with LVEF>40 %, or without overt HF with LVEF40 %≤ or > 40 %, as well as according to the presence of asymptomatic or symptomatic AF. RESULTS: A total of 8096 patients, divided into 8 groups according to HF and LVEF, were included with similar proportions of asymptomatic AF (ranging from 43 to 48 %). After a median follow-up of 730 [699 -748] days, the composite outcome (all-cause death and MACE) was significantly worse for patients with asymptomatic AF associated with HF and reduced LVEF vs. symptomatic AF patients of the same group (p = 0.004). On adjusted Cox regression analysis, asymptomatic AF patients with HF and reduced LVEF were independently associated with a higher risk for the composite outcome (aHR 1.32, 95 % CI 1.04-1.69) and all-cause death (aHR 1.33, 95 % CI 1.02-1.73) compared to symptomatic AF patients with HF and reduced LVEF. Kaplan-Meier curves showed that HF-LVEF≤40 % asymptomatic patients had the highest cumulative incidence of all-cause death and MACE (p < 0.001 for both). CONCLUSIONS: In a large European cohort of AF patients, the risk of the composite outcome at 2 years was not different between asymptomatic and symptomatic AF in the whole cohort but adverse implications for poor outcomes were found for asymptomatic AF in HF with LVEF≤40 %.

Coronary artery tortuosity and mid-term all-cause mortality of patients with ischemia and non-obstructive coronary arteries.

Background: Coronary artery tortuosity (CAT) is a frequently encountered angiographic feature of patients with ischemia and non-obstructive coronary arteries (INOCA). However, there is limited data regarding the possible correlation between CAT and all-cause mortality in these patients. Aim: To assess the survival prognostic implications of CAT in INOCA patients and the predictors of all-cause mid-term mortality of these patients. Methods: All consecutive INOCA patients, with preserved ejection fraction evaluated for clinical ischemia by coronary angiography in our department between January 2014 and December 2020 were considered for inclusion. Patients with epicardial coronary artery stenosis ≥ 50%, severe pulmonary hypertension, or decompensated extra cardiac disease were excluded. Eleid classification was used for CAT severity characterization. We assessed all-cause mortality in January 2023. Results: Our sample included 328 INOCA patients. 15.54% died during the mean follow-up of 3.75 ± 1.32 years. 79.88% had CAT. CAT patients were older (65.10±9.09 versus 61.24±10.02 years, p=0.002), and more often female (67.18% versus 31.82%, p<0.001). CAT was inversely correlated with all-cause mid-term mortality (OR 0.35, 95%CI 0.16 - 0.77, p=0.01). CAT severity had no impact on survival. In CAT patients the initial multivariable analysis identified NT-proBNP levels (HR 3.96, p=0.01), diabetes mellitus (DM) (HR 4.76, p=0.003), and atrial fibrillation (HR 2.68, p=0.06) as independent predictors of all-cause mortality. In the final analysis, NT-proBNP and DM were the main independent predictors of survival. Conclusions : In our INOCA cohort, CAT patients were older and more likely female. CAT was inversely correlated with mid-term all-cause mortality. NT-proBNP and DM were the main independent predictors of mortality of CAT patients.

Sarcopenia assessed by total psoas index - is it correlated with post-operative complications in all digestive cancers?

Background and aims: In cancer patients sarcopenia may be a predictor for postoperative complications of curative or palliative surgery. Several indices including the total psoas area index (TPAI) are proposed for the diagnosis of this condition, but there is no validated cut-off point.Our study aimed to assess the role of TPAI as a marker for sarcopenia and to compare the utility of previously proposed cut-off values for predicting post-operative complications in patients with digestive cancers undergoing surgery. Methods: We retrospectively included all adult patients with digestive cancers admitted to a tertiary center for elective surgery between January and December 2019. Sarcopenia was considered based on TPAI evaluated on abdominal computed tomography (CT) and for analysis we used different cut-off points published by various authors. The primary endpoint was the occurrence of any complications as defined by the Clavien-Dindo classification. The secondary endpoints were fistula development, low- versus high-grade Clavien-Dindo post-operative complications, moderate or severe anemia at discharge, major bleeding, hypoalbuminemia at discharge, and decrease in albumin levels by at least 1g/dL. Results: We included 155 patients with a mean age of 64.78 ± 11.40 years, of which 59.35% were males; 58.06% developed postoperative complications. TPAI evaluated as a continuous variable was not a predictor for the development of post-operative complications neither in the general study sample, nor in the gender subgroups of patients. Sarcopenia defined by previously proposed cut-off values was not a predictor of the secondary end-points either. Conclusion: TPAI as a sole parameter for defining sarcopenia was not a predictor for postoperative complications in patients undergoing surgery for digestive neoplasia.

Anticoagulation with Edoxaban in Patients with Atrial High-Rate Episodes.

BACKGROUND: Device-detected atrial high-rate episodes (AHREs) are atrial arrhythmias detected by implanted cardiac devices. AHREs resemble atrial fibrillation but are rare and brief. Whether the occurrence of AHREs in patients without atrial fibrillation (as documented on a conventional electrocardiogram [ECG]) justifies the initiation of anticoagulants is not known. METHODS: We conducted an event-driven, double-blind, double-dummy, randomized trial involving patients 65 years of age or older who had AHREs lasting for at least 6 minutes and who had at least one additional risk factor for stroke. Patients were randomly assigned in a 1:1 ratio to receive edoxaban or placebo. The primary efficacy outcome was a composite of cardiovascular death, stroke, or systemic embolism, evaluated in a time-to-event analysis. The safety outcome was a composite of death from any cause or major bleeding. RESULTS: The analysis population consisted of 2536 patients (1270 in the edoxaban group and 1266 in the placebo group). The mean age was 78 years, 37.4% were women, and the median duration of AHREs was 2.8 hours. The trial was terminated early, at a median follow-up of 21 months, on the basis of safety concerns and the results of an independent, informal assessment of futility for the efficacy of edoxaban; at termination, the planned enrollment had been completed. A primary efficacy outcome event occurred in 83 patients (3.2% per patient-year) in the edoxaban group and in 101 patients (4.0% per patient-year) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.60 to 1.08; P = 0.15). The incidence of stroke was approximately 1% per patient-year in both groups. A safety outcome event occurred in 149 patients (5.9% per patient-year) in the edoxaban group and in 114 patients (4.5% per patient-year) in the placebo group (hazard ratio, 1.31; 95% CI, 1.02 to 1.67; P = 0.03). ECG-diagnosed atrial fibrillation developed in 462 of 2536 patients (18.2% total, 8.7% per patient-year). CONCLUSIONS: Among patients with AHREs detected by implantable devices, anticoagulation with edoxaban did not significantly reduce the incidence of a composite of cardiovascular death, stroke, or systemic embolism as compared with placebo, but it led to a higher incidence of a composite of death or major bleeding. The incidence of stroke was low in both groups. (Funded by the German Center for Cardiovascular Research and others; NOAH-AFNET 6 ClinicalTrials.gov number, NCT02618577; ISRCTN number, ISRCTN17309850.).

Perspectives and Future Directions of Anticoagulant Therapy in Coronary Artery Disease Patients.

Antiplatelet agents are routinely used to treat patients with chronic atherosclerotic coronary artery disease. Treatment with the addition of a low dose of rivaroxaban as dual-pathway inhibition (DPI) decreases ischaemic events at the expense of increased bleeding. At present, the balance between thrombotic and bleeding risks must be carefully weighed up when considering DPI. However, with the introduction of activated coagulation factor XI inhibitors, which have fewer bleeding effects, the use of DPI in patients with atherosclerotic cardiovascular diseases could be extended.

Antithrombotic Therapy in Arterial Thrombosis and Thromboembolism in COVID-19: An American College of Chest Physicians Expert Panel Report.

BACKGROUND: Evidence increasingly shows that the risk of thrombotic complications in COVID-19 is associated with a hypercoagulable state. Several organizations have released guidelines for the management of COVID-19-related coagulopathy and prevention of VTE. However, an urgent need exists for practical guidance on the management of arterial thrombosis and thromboembolism in this setting. RESEARCH QUESTION: What is the current available evidence informing the prevention and management of arterial thrombosis and thromboembolism in patients with COVID-19? STUDY DESIGN AND METHODS: A group of approved panelists developed key clinical questions by using the Population, Intervention, Comparator, and Outcome (PICO) format that address urgent clinical questions regarding prevention and management of arterial thrombosis and thromboembolism in patients with COVID-19. Using MEDLINE via PubMed, a literature search was conducted and references were screened for inclusion. Data from included studies were summarized and reviewed by the panel. Consensus for the direction and strength of recommendations was achieved using a modified Delphi survey. RESULTS: The review and analysis of the literature based on 11 PICO questions resulted in 11 recommendations. Overall, a low quality of evidence specific to the population with COVID-19 was found. Consequently, many of the recommendations were based on indirect evidence and prior guidelines in similar populations without COVID-19. INTERPRETATION: The existing evidence and panel consensus do not suggest a major departure from the management of arterial thrombosis according to recommendations predating the COVID-19 pandemic. Data on the optimal strategies for prevention and management of arterial thrombosis and thromboembolism in patients with COVID-19 are sparse. More high-quality evidence is needed to inform management strategies in these patients.

The portrait of a stranger: the hypereosinophilic syndrome with cardiac involvement.

INTRODUCTION: Hypereosinophilic syndrome is a rare clinical condition, and cardiac involvement confers a poor prognosis. Hypereosinophilic myocarditis is a medical emergency and targeted treatment should be started promptly even before a definitive diagnosis could be made. CASE PRESENTATION: A 27-year-old female patient is hospitalized for exertional dyspnea, chest pain, and fatigue for the past 2 weeks. She also describes left leg paresthesias. Clinical examination was in normal limits. ECG showed sinus tachycardia, QS pattern in V1-V4, and diffuse flattened T waves. Laboratory tests revealed increased inflammatory markers, hypereosinophilia, elevated cardiac enzymes, high NT-proBNP. Echocardiography revealed LV dysfunction (EF 31%), while cardiac MRI showed diffuse delayed enhancement with predominant subendocardial disposition. The electromyogram was suggestive of left tibial nerve neuropathy. We interpreted the case as eosinophilic myocarditis with an urgent requirement of therapy and initiated high-dose glucocorticoid therapy and the GDMT 4-pillar heart failure treatment. We excluded common infectious, myeloproliferative syndromes, and frequent associated autoimmune diseases. With prednisone, the eosinophil count rapidly normalized and we gradually tapered the dose by 5 mg per week, however continuing with heart failure therapy. At monthly follow-up visits, there was a significant clinical improvement, with normalization of the eosinophilic count, and a near-normalization of myocardial function. The only symptom that persisted was paresthesias linked to left tibial neuropathy. CONCLUSION: The surprisingly rapid and favorable course of the disease offers a high index of suspicion for a toxic or a reactive transitory etiology, however still unidentified. In our case, the cause of eosinophilia remained unknown, although we managed to narrow down the possible etiologies. A surprisingly good clinical response was obtained with non-specific treatment targeting mainly hyperosinophilic myocarditis.

Factors Associated with Progression of Atrial Fibrillation and Impact on All-Cause Mortality in a Cohort of European Patients.

BACKGROUND: Paroxysmal atrial fibrillation (AF) may often progress towards more sustained forms of the arrhythmia, but further research is needed on the factors associated with this clinical course. METHODS: We analyzed patients enrolled in a prospective cohort study of AF patients. Patients with paroxysmal AF at baseline or first-detected AF (with successful cardioversion) were included. According to rhythm status at 1 year, patients were stratified into: (i) No AF progression and (ii) AF progression. All-cause death was the primary outcome. RESULTS: A total of 2688 patients were included (median age 67 years, interquartile range 60-75, females 44.7%). At 1-year of follow-up, 2094 (77.9%) patients showed no AF progression, while 594 (22.1%) developed persistent or permanent AF. On multivariable logistic regression analysis, no physical activity (odds ratio [OR] 1.35, 95% CI 1.02-1.78), valvular heart disease (OR 1.63, 95% CI 1.23-2.15), left atrial diameter (OR 1.03, 95% CI 1.01-1.05), or left ventricular ejection fraction (OR 0.98, 95% CI 0.97-1.00) were independently associated with AF progression at 1 year. After the assessment at 1 year, the patients were followed for an extended follow-up of 371 days, and those with AF progression were independently associated with a higher risk for all-cause death (adjusted hazard ratio 1.77, 95% CI 1.09-2.89) compared to no-AF-progression patients. CONCLUSIONS: In a contemporary cohort of AF patients, a substantial proportion of patients presenting with paroxysmal or first-detected AF showed progression of the AF pattern within 1 year, and clinical factors related to cardiac remodeling were associated with progression. AF progression was associated with an increased risk of all-cause mortality.

The complex interplay between right ventricular dysfunction and atrial fibrillation - a narrative review.

Atrial fibrillation (AF) is one of the most common sustained arrhythmias in clinical practice, associated with multiple comorbidities and complication. The potential predictors of AF onset and perpetuation or specific drivers of complications need future investigation. Right ventricular (RV) dysfunction plays an important role in the development of new-onset AF warranting in-depth analysis in relation to AF. RV may play a significant role in a better characterization of the cardiac substrate of AF patients. The relation between RV dysfunction and AF is bidirectional as AF may be one of the causes of RV dysfunction and their coexistence worsens the overall patient prognosis. Our aim is to present in a narrative review the most relevant data regarding the complex relationship between AF and RV dysfunction.

The platelet to lymphocyte ratio in heart failure: a comprehensive review.

Introduction: At the crossroads of heart failure (HF) and systemic inflammation, platelets and lymphocytes are both influenced as well as actively participating in the bidirectional relationship. The platelet to lymphocyte ratio (PLR) could therefore be a marker of severity. This review aimed to assess the role of PLR in HF. Methods: We searched the PubMed (MEDLINE) database using the keywords "platelet", "thrombocyte", "lymphocyte", "heart failure", "cardiomyopathy", "implantable cardioverter defibrillator", "cardiac resynchronization therapy" and "heart transplant". Results: We identified 320 records. 21 studies were included in this review, with a total of 17,060 patients. PLR was associated with age, HF severity, and comorbidity burden. Most studies reported the predictive power for all-cause mortality. Higher PLR was associated with in-hospital and short-term mortality in univariable analysis, however, it was not consistently an independent predictor for this outcome. PLR > 272.9 associated an adjusted HR of 3.22 (95%CI 1.56 - 5.68, p<0.001) for 30-day fatality. During long-term follow-up from 6 months to 5 years, PLR was an independent predictor of mortality in most studies, with cut-off values ranging from > 150 to > 194.97 and adjusted HR from 1.47 (95%CI 1.06 - 2.03, p=0.019) to 5.65 (95%CI 2.47-12.96, p<0.001). PLR > 173.09 had an adjusted OR 2.89 (95%CI 1.17-7.09, p=0.021) for predicting response to cardiac resynchronization therapy. PLR was not associated with outcomes after cardiac transplant or implantable cardioverter-defibrillator. Conclusion: Increased PLR could be an auxiliary biomarker of severity and survival prognosis in HF patients.

Prognostic Impact of Severe Atrial Functional Tricuspid Regurgitation in Atrial Fibrillation Patients.

Background and Aim: Atrial fibrillation (AF) is an epidemic disease with a significant global health impact. Atrial functional tricuspid regurgitation (AF-TR) is a more recently acknowledged complication of AF. The main purpose of this study was to determine the prognostic value of severe AF-TR in patients with AF, and its determinants. Methods: In this retrospective, observational study, we included AF patients admitted consecutively to a tertiary clinical hospital between January 2018 and February 2020, irrespective of cause of hospitalization. Patients with organic TR, significant pulmonary hypertension, left ventricular ejection fraction < 50%, those with implanted cardiac devices and those with in-hospital mortality were excluded. Severe TR was defined according to current guidelines. Median follow-up time was 34 (28−39) months. Primary endpoint was all-cause mortality. Results: We included 246 AF patients, with a mean age of 71.5 ± 9.4 years. 86.2% had AF-TR, while 8.1% had severe AF-TR. Mortality rate was 8.5%. Right atrial diameter (p = 0.005), systolic pulmonary artery pressure (sPAP) (p = 0.015) and NT-proBNP (p = 0.026) were independent predictors for the presence of severe valvular dysfunction. In multivariable survival analysis, severe AF-TR, was an independent predictor of all-cause mortality (HR 5.4, 95% CI 1.1−26.2, p = 0.035). Conclusion: Severe AF-TR was an independent predictor of mortality in AF patients, while mild/moderate AF-TR apparently had no impact on prognosis.

Clinical complexity and impact of the ABC (Atrial fibrillation Better Care) pathway in patients with atrial fibrillation: a report from the ESC-EHRA EURObservational Research Programme in AF General Long-Term Registry.

BACKGROUND: Clinical complexity is increasingly prevalent among patients with atrial fibrillation (AF). The 'Atrial fibrillation Better Care' (ABC) pathway approach has been proposed to streamline a more holistic and integrated approach to AF care; however, there are limited data on its usefulness among clinically complex patients. We aim to determine the impact of ABC pathway in a contemporary cohort of clinically complex AF patients. METHODS: From the ESC-EHRA EORP-AF General Long-Term Registry, we analysed clinically complex AF patients, defined as the presence of frailty, multimorbidity and/or polypharmacy. A K-medoids cluster analysis was performed to identify different groups of clinical complexity. The impact of an ABC-adherent approach on major outcomes was analysed through Cox-regression analyses and delay of event (DoE) analyses. RESULTS: Among 9966 AF patients included, 8289 (83.1%) were clinically complex. Adherence to the ABC pathway in the clinically complex group reduced the risk of all-cause death (adjusted HR [aHR]: 0.72, 95%CI 0.58-0.91), major adverse cardiovascular events (MACEs; aHR: 0.68, 95%CI 0.52-0.87) and composite outcome (aHR: 0.70, 95%CI: 0.58-0.85). Adherence to the ABC pathway was associated with a significant reduction in the risk of death (aHR: 0.74, 95%CI 0.56-0.98) and composite outcome (aHR: 0.76, 95%CI 0.60-0.96) also in the high-complexity cluster; similar trends were observed for MACEs. In DoE analyses, an ABC-adherent approach resulted in significant gains in event-free survival for all the outcomes investigated in clinically complex patients. Based on absolute risk reduction at 1 year of follow-up, the number needed to treat for ABC pathway adherence was 24 for all-cause death, 31 for MACEs and 20 for the composite outcome. CONCLUSIONS: An ABC-adherent approach reduces the risk of major outcomes in clinically complex AF patients. Ensuring adherence to the ABC pathway is essential to improve clinical outcomes among clinically complex AF patients.