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.).

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.

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.

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.

Impact of malignancy on outcomes in European patients with atrial fibrillation: A report from the ESC-EHRA EURObservational research programme in atrial fibrillation general long-term registry.

BACKGROUND: The management of patients with atrial fibrillation (AF) and malignancy is challenging given the paucity of evidence supporting their appropriate clinical management. PURPOSE: To evaluate the outcomes of patients with active or prior malignancy in a contemporary cohort of European AF patients. METHODS: Patients enrolled in the EURObservational Research Programme in AF General Long-Term Registry were categorized into 3 categories: No Malignancy (NoMal), Prior Malignancy (PriorMal) and Active Malignancy (ActiveMal). The primary outcomes were all-cause death and the composite outcome MACE. RESULTS: A total of 10 383 patients were analysed. Of these, 9597 (92.4%) were NoMal patients, 577 (5.6%) PriorMal and 209 (2%) ActiveMal. Lack of any antithrombotic treatment was more prevalent in ActiveMal patients (12.4%) as compared to other groups (5.0% vs 6.3% for PriorMal and NoMal, p < .001). After a median follow-up of 730 days, there were 982 (9.5%) deaths and 950 (9.7%) MACE events. ActiveMal was independently associated with a higher risk for all-cause death (HR 2.90, 95% CI 2.23-3.76) and MACE (HR 1.54, 95% CI 1.03-2.31), as well as any haemorrhagic events and major bleeding (OR 2.42, 95% CI 1.49-3.91 and OR 4.18, 95% CI 2.49-7.01, respectively). Use of oral anticoagulants was not significantly associated with a higher risk for all-cause death or bleeding in ActiveMal patients. CONCLUSIONS: In a large contemporary cohort of AF patients, active malignancy was independently associated with all-cause death, MACE and haemorrhagic events. Use of anticoagulants was not associated with a higher risk of all-cause death in patients with active malignancies.

Pharmacological Management of Atrial Fibrillation: A Century of Expert Opinions in Cecil Textbook of Medicine.

BACKGROUND: Advances in drug therapy for atrial fibrillation (AF) have had a significant impact on the quality of life of a substantial majority of affected persons, which has contributed to a remarkable decrease in the frequency and severity of thromboembolic complications, hospitalizations, and mortality. STUDY QUESTION: What are the milestones of the changes in the expert approach to the pharmacological management of AF in the past century? STUDY DESIGN: To determine the changes in the experts' approach to the management of AF, as presented in a widely used textbook in the United States. DATA SOURCES: The chapters presenting the management of AF in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020. RESULTS: AF was consistently described in Cecil Textbook of Medicine as the most common sustained arrhythmia in adults. The authors emphasized its thromboembolic complications and potential for hemodynamic deterioration. Rate control with digitalis and rhythm control with quinidine were the standard in 1927. The pharmacological advances have focused on atrioventricular nodal blocking for rate control, conversion to and maintenance of sinus rhythm, and preventive anticoagulation. The first new class of drugs for rate control was beta-adrenergic receptor blockers, starting with propranolol which was introduced in 1979, followed by the calcium channel blocker verapamil in 1988. Rhythm control with amiodarone, a potassium channel blocker, has been recommended since 2004, and the sodium channel blockers propafenone and flecainide became part of standard therapy in 2008. Anticoagulation with warfarin was recommended starting in 2000, followed by the introduction of direct thrombin inhibitor in 2012 and factor Xa inhibitors in 2016. CONCLUSIONS: The pharmacological management of AF was unchanged for more than 50 years (1927-1979), a period during which the devastating effects of thromboembolic complications were not addressed. The major therapeutic advance is represented by preventive anticoagulation with the newer, safer, and more user-friendly direct thrombin and factor Xa inhibitors.

Pharmacological Management of Primary Arterial Hypertension: A Century of Expert Opinions in Cecil Textbook of Medicine.

BACKGROUND: Advances in drug therapy for primary (or essential) arterial hypertension have contributed to a significant decrease in the frequency and severity of strokes, coronary artery disease and heart failure, and chronic renal insufficiency. STUDY QUESTION: What are the milestones of the changes in the expert approach to the pharmacological management of arterial hypertension in the past century? STUDY DESIGN: To determine the changes in the experts' approach to the management of arterial hypertension, as presented in a widely used textbook in the United States. DATA SOURCES: The chapters presenting the management of arterial hypertension in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020. RESULTS: The pharmacological management of arterial hypertension has had 3 overlapping eras in the timeframe subject to our investigation. In the empiric era (1927-1947), experts were recommending nonspecific interventions for sedation. The premodern era (1955-1963) relied on ganglion blockers, sympathetic blockers, and direct vasodilators. The modern era (1967-2020), which includes drugs used in current clinical practice, saw the introduction of diuretics (1967), beta-blockers (1971), alpha-blockers (1982), calcium channel blockers (1985), angiotensin-converting enzyme inhibitors (1985), angiotensin receptor blockers (2000), and direct renin inhibitors (2008). CONCLUSIONS: The pharmacological management of arterial hypertension has been the focus of intense and successful research and development in the second half of the 20th century.

Evaluation of Ibrutinib Cardiotoxicity By Comparative Use of Speckle-Tracking Technique and Biomarkers.

BACKGROUND: Ibrutinib, a relatively new antineoplastic agent, has multiple cardiovascular effects that are still insufficiently known and evaluated, including subclinical myocardial damage. STUDY QUESTION: The present study aims to assess the role of the myocardial strain, alone and in combination with cardiac biomarkers, in the early detection of ibrutinib-induced cardiotoxicity. STUDY DESIGN: We included 31 outpatients with normal left ventricular ejection fraction (LVEF) on ibrutinib, in a tertiary University Hospital between 2019 and 2020, and evaluated them at inclusion and after 3 months. MEASURES AND OUTCOMES: Data on myocardial strain, cardiac biomarkers [high-sensitive troponin T (hs TnT) and N-terminal probrain natriuretic peptide (NT-proBNP)], and ambulatory electrocardiographic monitoring were collected. RESULTS: Myocardial deformation decreased significantly (P < 0.001) at later evaluation and hs TnT and NT-proBNP increased significantly (P = 0.019 and P = 0.03, respectively). The increase in hs TnT correlated with the increase in the left ventricle global longitudinal strain (LVGLS); in other words, it correlated with the decrease in myocardial deformation. No association was found between LVGLS increase and the increase in NT-proBNP. LVGLS modification was not significantly influenced by age, anemia, or arrhythmia burden quantified by 24-hour Holter monitoring (P = 0.747, P = 0.072, respectively; P = 0.812). LVEF did not change significantly during follow-up. CONCLUSIONS: In patients on ibrutinib, evaluation of myocardial strain is useful in identifying early cardiac drug toxicity, surpassing the sensitivity and specificity limits of LVEF. In these patients, concomitant assessment of hs TnT increases the predictive power for subclinical myocardial involvement.

Epidemiology and impact of frailty in patients with atrial fibrillation in Europe.

BACKGROUND: Frailty is a medical syndrome characterised by reduced physiological reserve and increased vulnerability to stressors. Data regarding the relationship between frailty and atrial fibrillation (AF) are still inconsistent. OBJECTIVES: We aim to perform a comprehensive evaluation of frailty in a large European cohort of AF patients. METHODS: A 40-item frailty index (FI) was built according to the accumulation of deficits model in the AF patients enrolled in the ESC-EHRA EORP-AF General Long-Term Registry. Association of baseline characteristics, clinical management, quality of life, healthcare resources use and risk of outcomes with frailty was examined. RESULTS: Among 10,177 patients [mean age (standard deviation) 69.0 (11.4) years, 4,103 (40.3%) females], 6,066 (59.6%) were pre-frail and 2,172 (21.3%) were frail, whereas only 1,939 (19.1%) were considered robust. Baseline thromboembolic and bleeding risks were independently associated with increasing FI. Frail patients with AF were less likely to be treated with oral anticoagulants (OACs) (odds ratio 0.70, 95% confidence interval 0.55-0.89), especially with non-vitamin K antagonist OACs and managed with a rhythm control strategy, compared with robust patients. Increasing frailty was associated with a higher risk for all outcomes examined, with a non-linear exponential relationship. The use of OAC was associated with a lower risk of outcomes, except in patients with very/extremely high frailty. CONCLUSIONS: In this large cohort of AF patients, there was a high burden of frailty, influencing clinical management and risk of adverse outcomes. The clinical benefit of OAC is maintained in patients with high frailty, but not in very high/extremely frail ones.

Acute rate control in atrial fibrillation: an urgent need for the clinician.

Rate and rhythm control are still considered equivalent strategies for symptom control using the Atrial Fibrillation Better Care algorithm recommended by the recent atrial fibrillation guideline. In acute situations or critically ill patients, a personalized approach should be used for rapid rhythm or rate control. Even though electrical cardioversion is generally indicated in haemodynamically unstable patients or for rapid effective rhythm control in critically ill patients, this is not always possible due to the high percentage of failure or relapses in such patients. Rate control remains the background therapy for all these patients, and often rapid rate control is mandatory. Short and rapid-onset-acting beta-blockers are the most suitable drugs for acute rate control. Esmolol was the classical example; however, landiolol a newer very selective beta-blocker, recently included in the European atrial fibrillation guideline, has a more favourable pharmacokinetic and pharmacodynamic profile with less haemodynamic interference and is better appropriate for critically ill patients.

Impact of clinical phenotypes on management and outcomes in European atrial fibrillation patients: a report from the ESC-EHRA EURObservational Research Programme in AF (EORP-AF) General Long-Term Registry.

BACKGROUND: Epidemiological studies in atrial fibrillation (AF) illustrate that clinical complexity increase the risk of major adverse outcomes. We aimed to describe European AF patients' clinical phenotypes and analyse the differential clinical course. METHODS: We performed a hierarchical cluster analysis based on Ward's Method and Squared Euclidean Distance using 22 clinical binary variables, identifying the optimal number of clusters. We investigated differences in clinical management, use of healthcare resources and outcomes in a cohort of European AF patients from a Europe-wide observational registry. RESULTS: A total of 9363 were available for this analysis. We identified three clusters: Cluster 1 (n = 3634; 38.8%) characterized by older patients and prevalent non-cardiac comorbidities; Cluster 2 (n = 2774; 29.6%) characterized by younger patients with low prevalence of comorbidities; Cluster 3 (n = 2955;31.6%) characterized by patients' prevalent cardiovascular risk factors/comorbidities. Over a mean follow-up of 22.5 months, Cluster 3 had the highest rate of cardiovascular events, all-cause death, and the composite outcome (combining the previous two) compared to Cluster 1 and Cluster 2 (all P < .001). An adjusted Cox regression showed that compared to Cluster 2, Cluster 3 (hazard ratio (HR) 2.87, 95% confidence interval (CI) 2.27-3.62; HR 3.42, 95%CI 2.72-4.31; HR 2.79, 95%CI 2.32-3.35), and Cluster 1 (HR 1.88, 95%CI 1.48-2.38; HR 2.50, 95%CI 1.98-3.15; HR 2.09, 95%CI 1.74-2.51) reported a higher risk for the three outcomes respectively. CONCLUSIONS: In European AF patients, three main clusters were identified, differentiated by differential presence of comorbidities. Both non-cardiac and cardiac comorbidities clusters were found to be associated with an increased risk of major adverse outcomes.

Antithrombotic therapy for stroke prevention in patients with atrial fibrillation who survive an intracerebral haemorrhage: results of an EHRA survey.

The aim of this survey is to provide a snapshot of current practice regarding antithrombotic therapy (ATT) in patients with atrial fibrillation (AF) comorbid with intracerebral haemorrhage (ICH). An online survey was distributed to members of the European Heart Rhythm Association. A total of 163 clinicians responded, mostly cardiologists or electrophysiologists (87.7%), predominantly working in University hospitals (61.3%). Most respondents (47.2%) had seen one to five patients with AF comorbid with ICH in the last 12 months. Among patients sustaining an ICH on oral anticoagulation (OAC), 84.3% respondents would consider some form of ATT post-ICH, with 73.2% preferring to switch from a vitamin-K antagonist (VKA) to a non-VKA oral anticoagulant (NOAC) and 37.2% preferring to switch from one NOAC to another. Most (36.6%) would restart OAC >30 days post-ICH. Among patients considered unable to take OAC, left atrial appendage occlusion procedure was the therapy of choice in 73.3% respondents. When deciding on ATT, respondents considered patient's CHA2DS2-VASc score, ICH type, demographics, risk factors, and patient adherence. The main reason for not restarting or commencing ATT was concern about recurrent ICH (80.8%). National or international clinical guidelines would be advantageous to support decision-making (84.3%). Other helpful resources reported were multidisciplinary team involvement (46.9%) and patient education (82%). In summary, most survey respondents would prescribe OAC therapy for patients with AF who have sustained an ICH on OAC and would restart OAC >30 days post-ICH. The risk of recurrent ICH was the main reason for not prescribing any ATT post-ICH.

Relation of outcomes to ABC (Atrial Fibrillation Better Care) pathway adherent care in European patients with atrial fibrillation: an analysis from the ESC-EHRA EORP Atrial Fibrillation General Long-Term (AFGen LT) Registry.

AIMS: There has been an increasing focus on integrated, multidisciplinary, and holistic care in the treatment of atrial fibrillation (AF). The 'Atrial Fibrillation Better Care' (ABC) pathway has been proposed to streamline integrated care in AF. We evaluated the impact on outcomes of an ABC adherent management in a contemporary real-life European-wide AF cohort. METHODS AND RESULTS: Patients enrolled in the ESC-EHRA EURObservational Research Programme in AF General Long-Term Registry with baseline data to evaluate ABC criteria and available follow-up data were considered for this analysis. Among the original 11 096 AF patients enrolled, 6646 (59.9%) were included in this analysis, of which 1996 (30.0%) managed as ABC adherent. Patients adherent to ABC care had lower CHA2DS2-VASc and HAS-BLED scores (mean ± SD, 2.68 ± 1.57 vs. 3.07 ± 1.90 and 1.26 ± 0.93 vs. 1.58 ± 1.12, respectively; P < 0.001). At 1-year follow-up, patients managed adherent to ABC pathway compared to non-adherent ones had a lower rate of any thromboembolic event (TE)/acute coronary syndrome (ACS)/cardiovascular (CV) death (3.8% vs. 7.6%), CV death (1.9% vs. 4.8%), and all-cause death (3.0% vs. 6.4%) (all P < 0.0001). On Cox multivariable regression analysis, ABC adherent care showed an association with a lower risk of any TE/ACS/CV death [hazard ratio (HR): 0.59, 95% confidence interval (CI): 0.44-0.79], CV death (HR: 0.52, 95% CI: 0.35-0.78), and all-cause death (HR: 0.57, 95% CI: 0.43-0.78). CONCLUSION: In a large contemporary cohort of European AF patients, a clinical management adherent to ABC pathway for integrated care is associated with a significant lower risk for cardiovascular events, CV death, and all-cause death.

Pharmacological Management of Heart Failure: A Century of Expert Opinions in Cecil Textbook of Medicine.

BACKGROUND: Drug therapy for heart failure influences quality of life and work potential of affected persons and has contributed to decrease in hospitalizations and cardiovascular mortality. The current approach is the result of incremental progress in understanding the pathophysiology of the syndrome, introduction of new molecules, and repurposing existing drugs. STUDY QUESTION: What are the milestones of the changes in the expert clinicians' approach to the pharmacological management in the past century? STUDY DESIGN: To determine the changes in the experts' approach to the management of heart failure, as presented in a widely used textbook in the United States. DATA SOURCES: The chapters on the management of heart failure in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020. RESULTS: In 1927, heart failure was treated with powdered leaf or tincture of digitalis, mercury chloride, and theophylline. Patients with acute pulmonary edema received injections of atropine, adrenaline, and ouabain. The therapeutic milestones in heart failure were the introduction of loop diuretics and aldosterone antagonists (1971), vasodilator treatment with hydralazine and nitroglycerine (1979-1985), angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and selective beta-adrenergic blockers (1992-2000), and sacubitril-valsartan (2016). For acute pulmonary edema, the durable milestone was the treatment with morphine and furosemide (1971). CONCLUSIONS: The pharmacological management of heart failure in the past century has progressed in fits and starts, with latent periods between significant advances lasting 8-40 years. In chronological order, the major advances were efficient diuresis, afterload reduction, and blunting the neurohormonal response to hemodynamic stress and cardiac remodeling.

Stroke Risk Scores as Predictors of Severe Outcomes in Atrial Fibrillation: A Comprehensive Review.

BACKGROUND: Atrial fibrillation (AF) is the most frequent sustained arrhythmia. It increases the risk of stroke, heart failure, death, hospitalizations, and costs. AREA OF UNCERTAINTY: Several scores were introduced to stratify the stroke risk and need for anticoagulation in patients (pts) with AF . CHA2DS2-VASc, the most frequently used score, as well as other stroke risk scores have been additionally applied to estimate outcomes for different other conditions, with inhomogeneous results. To date, there has been no consensus regarding the usefulness of these scores to estimate outcomes outside of thromboembolic risk assessment, and their value in estimating different end-point outcomes is still a subject of debate. We conducted this review to investigate whether the stroke risk scores' utility can be extended for the prediction of other severe outcomes in pts with AF. DATA SOURCES: We searched PubMed database and included studies that stratified the outcome of pts with AF by different stroke risk scores. We also included studies with a separate analysis of the pts with AF subpopulation. RESULTS: Mortality rates increased with higher CHADS2 [from 2.28% (2.00%-2.58%) to 13.2% (8.24%-20.8%) per year] and CHA2DS2-VASc scores [risk ratio 1.26 (1.21-1.32), P < 0.0001 for score ≥3]. CHADS2 and CHA2DS2-VASc predicted poor outcome in stroke [odds ratio (OR) ranging 1.42-6 for CHADS2 and 1.3-7.3 for CHA2DS2-VASc]. Acute myocardial infarction rates increased with higher CHADS2 [OR 2.120 (1.942-2.315) P < 0.001] and CHA2DS2-VASc [OR 1.63 (1.53-1.75), P < 0.001]. Limited data were reported for ABC( Age, Biomarkers, Clinical histoty) and R2CHADS2. No statistically significant correlation was found for major bleeding. CONCLUSIONS: CHADS2 and CHA2DS2-VASc are useful tools in identifying pts with AF at higher risk for all-cause death, regardless of other pathologies. Both scores correlated with the development of acute myocardial infarction, cardiovascular hospitalization, outcome in stroke, major adverse cardiovascular events, and major adverse cardiovascular and cerebral events, but not with serious bleeding.

Comparative role of hematological indices for the assessment of in-hospital outcome of heart failure patients.

Background. The mutual relation between heart failure (HF) and inflammation is reflected in blood cell homeostasis. Neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR) and platelet-lymphocyte ratio (PLR) were linked to HF severity and prognosis. Aims. Our objective was to compare the three ratios for predicting in-hospital outcome of HF patients, in order to establish which is best suited for clinical practice. Methods. Consecutive HF patients admitted to a Cardiology Department from a tertiary hospital were retrospectively evaluated for inclusion. Readmissions and pathologies modifying the hematological indices were excluded. Extended length of hospital stay (LOS) was considered over 7 d. In-hospital all-cause mortality was evaluated. Results: The hematological indices in heart failure (HI-HF) cohort included 1299 patients with a mean age of 72.35 ± 10.45 years, 51.96% women. 2.85% died during hospitalization. 22.17% had extended LOS. In Cox regression for in-hospital mortality alongside parameters from the OPTIMIZE-HF proposed model, all three ratios were independent predictors of mortality. In Cox regression including NT-proBNP, dyspnea at rest, chronic obstructive pulmonary disease (COPD), age and systolic blood pressure, only MLR was an independent predictor of in-hospital mortality (HR 1.68, 95% CI 1.22 - 2.32, p = .002). In multivariable logistic regression, all three ratios independently predicted extended LOS. MLR > 0.48 associated the highest probability (OR 1.76, 95% CI 1.25 - 2.46, p = .001). Conclusions. Hematological indices could be cost-effective and easily available auxiliary biomarkers for in-hospital prognosis of HF patients. We propose MLR > 0.48 as the strongest predictor of in-hospital mortality and prolonged hospitalization.

Symptom management strategies: Rhythm vs rate control in patients with atrial fibrillation in the Balkan region: Data from the BALKAN-AF survey.

BACKGROUND: Symptom-focused management is one of the cornerstones of optimal atrial fibrillation (AF) therapy. OBJECTIVES: To evaluate the use of rhythm control and rate control strategy. Second, to identify predictors of the use of amiodarone in patients with rhythm control and of the use of rhythm control strategy in patients with paroxysmal AF in the Balkans. METHODS: Prospective enrolment of consecutive patients from seven Balkan countries to the BALKAN-AF survey was performed. RESULTS: Of 2712 enrolled patients, 2522 (93.0%) with complete data were included: 1622 (64.3%) patients were assigned to rate control strategy and 900 (35.7%) to rhythm control. Patients with rhythm control were younger, more often hospitalised for AF and with less comorbidities (all P < .05) than those with rate control. Symptom score [European Heart Rhythm Association (EHRA)] was not an independent predictor of a rhythm control strategy [odds ratio (OR) 0.99, 95% confidence interval (CI) 0.90-1.10, P = .945]. The most commonly chosen antiarrhythmic agents were amiodarone (49.7%), followed by propafenone (24.3%). CONCLUSION: More than one-third of patients in the BALKAN-AF survey received a rhythm control strategy, and these patients tended to be younger with less comorbidities than those managed with rate control. EHRA symptom score is not significantly associated with rhythm control strategy. The most commonly used antiarrhythmic agents were amiodarone, followed by propafenone.

Characteristics and Outcomes in Patients With COVID-19 and Acute Ischemic Stroke: The Global COVID-19 Stroke Registry.

Recent case-series of small size implied a pathophysiological association between coronavirus disease 2019 (COVID-19) and severe large-vessel acute ischemic stroke. Given that severe strokes are typically associated with poor prognosis and can be very efficiently treated with recanalization techniques, confirmation of this putative association is urgently warranted in a large representative patient cohort to alert stroke clinicians, and inform pre- and in-hospital acute stroke patient pathways. We pooled all consecutive patients hospitalized with laboratory-confirmed COVID-19 and acute ischemic stroke in 28 sites from 16 countries. To assess whether stroke severity and outcomes (assessed at discharge or at the latest assessment for those patients still hospitalized) in patients with acute ischemic stroke are different between patients with COVID-19 and non-COVID-19, we performed 1:1 propensity score matching analyses of our COVID-19 patients with non-COVID-19 patients registered in the Acute Stroke Registry and Analysis of Lausanne Registry between 2003 and 2019. Between January 27, 2020, and May 19, 2020, 174 patients (median age 71.2 years; 37.9% females) with COVID-19 and acute ischemic stroke were hospitalized (median of 12 patients per site). The median National Institutes of Health Stroke Scale was 10 (interquartile range [IQR], 4-18). In the 1:1 matched sample of 336 patients with COVID-19 and non-COVID-19, the median National Institutes of Health Stroke Scale was higher in patients with COVID-19 (10 [IQR, 4-18] versus 6 [IQR, 3-14]), P=0.03; (odds ratio, 1.69 [95% CI, 1.08-2.65] for higher National Institutes of Health Stroke Scale score). There were 48 (27.6%) deaths, of which 22 were attributed to COVID-19 and 26 to stroke. Among 96 survivors with available information about disability status, 49 (51%) had severe disability at discharge. In the propensity score-matched population (n=330), patients with COVID-19 had higher risk for severe disability (median mRS 4 [IQR, 2-6] versus 2 [IQR, 1-4], P<0.001) and death (odds ratio, 4.3 [95% CI, 2.22-8.30]) compared with patients without COVID-19. Our findings suggest that COVID-19 associated ischemic strokes are more severe with worse functional outcome and higher mortality than non-COVID-19 ischemic strokes.

Stroke prevention in elderly patients with non-valvular atrial fibrillation in the BALKAN-AF survey.

BACKGROUND: Atrial fibrillation (AF) is common amongst the elderly, but this group tends to be suboptimally treated. Limited data are available on the stroke prevention strategies in the elderly, especially in the Balkan region. AIM: We investigated the use of oral anticoagulant therapy (OAC) amongst elderly AF patients in clinical practice in the Balkan region. METHOD: A 12-week prospective snapshot survey (2014-2015) of consecutive non-valvular AF patients was conducted in Albania, Bosnia and Herzegovina, Bulgaria, Croatia, Montenegro, Romania and Serbia. Data were collected via an electronic case report form. RESULTS: Of 2671 patients, 418 (15.6%) were ≥80 years old. Overall, OAC was used in 1965 patients (73.6%). Compared with younger patients, the elderly (age ≥ 80) had a higher mean CHA2 DS2 -VASc score (3.22 ± 1.71 vs 4.89 ± 1.35, P < .001) and more often a HAS-BLED score of ≥3 (n = 198 [47.0%] vs n = 625 [27.3%], P < .001), but were less likely to receive OAC (n = 269 [64.4%] vs n = 1696 [75.3%], odds ratio [OR] 0.91; 95%CI 0.86-0.97, P = .003). There was no significant association between OAC use and mean CHA2 DS2 -VASc (OR 0.86; 95%CI 0.75-1.00, P = .053) or HAS-BLED score (OR 1.21; 95%CI 0.81-1.81, P = .349) in the elderly. CONCLUSION: In the BALKAN-AF Survey, elderly AF patients were less likely to receive the guideline-adherent treatment despite their less favourable risk profile. Since OAC nonuse among the elderly was not associated with increased HAS-BLED score, factors other than patients' risk profile could influence the implementation of guideline-adherent treatment for thromboprophylaxis in the elderly AF patients.