A significant proportion of patients with atrial fibrillation (AF) who need thromboembolic protection are not treated with or discontinue oral anticoagulation after its initiation. Undertreatment in clinical practice has not improved sufficiently despite the availability of direct oral anticoagulants, which are associated with less intracranial bleeding than vitamin K antagonists. Multiple reasons account for this phenomenon, including bleeding events or ischemic strokes while on anticoagulation, poor treatment adherence despite best educational attempts, or aversion to drug therapy. Percutaneous left atrial appendage (LAA) closure was introduced as an alternative to pharmacological therapy in AF patients in the early 2000s. Due to significant improvements in procedural safety over the years, left atrial appendage closure (LAAC), predominantly achieved through a percutaneous catheter-based device implantation approach, is increasingly favoured for preventing thromboembolic events in patients who cannot achieve effective anticoagulation or have a high hemorrhagic risk. This focused summary and update of a recently published practical guide, developed within guideline/guidance boundaries, provides a perspective of current evidence of potential indications, benefits, complications and limitations of LAAC for neurologists and stroke physicians who may consider this increasingly utilised therapy.

Atrial fibrillation (AF) is increasingly diagnosed early, close to its first occurrence due to: (i) increased public awareness with self-screening; (ii) health care initiatives including population screening and opportunistic case finding; and (iii) increased use and surveillance of implantable cardiac devices. At its onset, AF is often low burden, and cardiovascular co-morbidities may be absent or at an early stage. Thus, the management of recent-onset AF has become an issue of growing importance. Professional guidelines have traditionally focused on anticoagulant thromboprophylaxis, generally recommending a cautious approach to rhythm control, and priority has been given to rate control to alleviate symptoms. In recent guidelines, the importance of managing lifestyle and co-morbidities has increased. The AF-SCREEN collaboration proposes that a vigorous approach to active management of recent-onset AF may be warranted. This includes addressing co-morbidities and promoting healthy lifestyles to prevent the emergence or progression of AF and associated cardiovascular disease, as well as the initiation of active rhythm control ± anticoagulation to prevent AF-related morbidity and mortality, including stroke and heart failure (HF). Intuitively, intervention early after AF onset would be beneficial since lifestyle and co-morbidity management, plus rhythm control and anticoagulation, are important contributors to improved outcomes in patients with established AF, but robust evidence is lacking for recent-onset AF. There is a delicate balance between achieving favourable outcomes such as preventing strokes, HF and AF progression vs the complications and potential adverse effects of interventions. Given the serious long-term consequences, innovative approaches are necessary to determine the value and risks of initiating active therapy very early in the course of AF. More data are needed to guide the best management of recent-onset AF, bearing AF burden in mind. Long-term studies using large national databases linked to electronic medical records and rhythm monitoring devices offer excellent opportunities. Shorter-term studies focusing on reducing AF burden to slow AF progression and studies focusing on outcomes such as HF could be used in both randomized clinical trials and observational cohort studies.

INTRODUCTION:Acute myocardial injury occurs in about every fourth patient in the early phase after ischemic stroke. It may be caused by an imbalance between myocardial oxygen supply and demand, potentially leading to type 2 myocardial infarction (MI). However, little is known about the prevalence of potential triggers of such demand ischemia in acute stroke. PATIENTS AND METHODS:Consecutive patients with and without post-stroke acute myocardial injury (elevated high-sensitivity cardiac troponin T [hs-cTnT] levels with a rise/fall >20%) were matched for age and sex and retrospectively screened for presence of predefined triggering conditions of myocardial demand ischemia and fulfillment of diagnostic criteria for acute MI. RESULTS:Among 508 stroke patients analyzed (median age 81 [73-86] years, 52% female), predefined potential triggers of demand ischemia were present in 107/254 (42%) patients with acute myocardial injury and in 61/254 (24%) matched controls (adjusted OR 2.30, 95%CI 1.51-3.52, p < 0.001). Patients with a trigger were older, more often female, had more severe strokes, and more often insular cortex involvement. The most prevalent triggers were respiratory failure, sustained hypertension, supraventricular tachyarrhythmia, and hemodynamic shock. MI criteria were fulfilled in 44/254 (17%) patients with acute myocardial injury including 27/44 (61.4%) with a trigger of demand ischemia (i.e. suspected type 2 MI). CONCLUSIONS:Conditions triggering a myocardial oxygen demand/supply mismatch are highly prevalent in patients with acute myocardial injury detected after stroke, notably in those fulfilling the criteria of acute MI. Stroke-specific aspects such as stroke severity or lesion location may play a role in the development of such triggers.

Hypertension is the leading modifiable risk factor for atrial fibrillation (AF) and is estimated to be present in >70% of AF patients. This Frontiers Review was prepared by 29 expert members of the AF-SCREEN International Collaboration to summarize existing evidence and knowledge gaps on links between hypertension, AF, and their cardiovascular sequelae; simultaneous screening for hypertension and AF; and the prevention of AF through antihypertensive therapy. Hypertension and AF are inextricably connected. Both are easily diagnosed, often silent, and frequently treated inadequately. Together, they additively increase the risk of ischemic stroke, heart failure, and many types of dementia, resulting in greater all-cause mortality, considerable disease burden, and increased health care expenditures. Automated upper arm cuff blood pressure devices with implemented technology can be used to simultaneously detect both hypertension and AF. However, positive screening for AF with an oscillometric blood pressure monitor still requires ECG confirmation. The current evidence suggests that high-risk individuals aged ≥65 years or with treatment-resistant hypertension could benefit from AF screening. Since antihypertensive therapy effectively lowers AF risk, particularly in individuals with left ventricular dysfunction, hypertension should be the key target for AF prediction and prevention rather than merely a comorbidity of AF. Nevertheless, several important gaps in knowledge need to be filled over the next years, including the ideal method and selection of patients for simultaneous screening of hypertension and AF and the optimal antihypertensive drug class and blood pressure targets for AF prevention.

AIMS:Intravenous iron has emerged as a guideline-recommended therapy in patients with heart failure and iron deficiency, but the potential sex-related differences in efficacy are unknown. We aimed to assess sex-specific outcomes in the Intravenous Iron in Patients with Systolic Heart Failure and Iron Deficiency to Improve Morbidity & Mortality (FAIR-HF2-DZHK05) trial. METHODS AND RESULTS:FAIR-HF2 included 1105 heart failure patients with a left ventricular ejection fraction ≤45% and iron deficiency. A total of 368 women (mean age 68.7 ± 13.0 years) and 737 men (mean age 70.5 ± 11.0 years) were randomized to intravenous ferric carboxymaltose or placebo. The three primary endpoints were (i) time to cardiovascular death or first heart failure hospitalization, (ii) total heart failure hospitalizations, and (iii) time-to-first event of cardiovascular death or heart failure hospitalization only in patients with transferrin saturation <20% at baseline. The hazard ratio (HR) for the first primary outcome was 1.07 (95% confidence interval [CI] 0.63-1.82, p = 0.80) in women and 0.74 (95% CI 0.57-0.95, p = 0.016) in men, while the rate ratios (RRs) for the second primary outcome were 1.06 (95% CI 0.55-2.05, p = 0.86) and 0.79 (95% CI 0.58-1.08, p = 0.136), respectively, and the HRs for the third primary outcome event were 1.21 (95% CI 0.62-2.36, p = 0.58) and 0.73 (95% CI 0.55-0.97, p = 0.028), respectively. Regarding safety outcomes, the HR for all-cause mortality was 1.46 (95% CI 0.78-2.76, p = 0.24) in women, suggesting increased mortality risk under iron supplementation, in contrast to 0.86 (95% CI 0.64-1.16, p = 0.33) in men (p for interaction = 0.13). CONCLUSIONS:This analysis indicates relevant differential efficacy of intravenous iron in heart failure across both sexes. While men receiving ferric carboxymaltose experienced a clinically relevant reduction in cardiovascular death and heart failure hospitalizations, women did not derive similar benefits. The results are clinically relevant and prompt validation in other large outcome trials of intravenous iron supplementation in heart failure. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov NCT03036462.

For most patients with chronic, progressive illnesses, maintaining good quality of life (QoL), with preserved functional capacity, is just as crucial as prolonging survival. Patients with heart failure (HF) experience much worse QoL and effort intolerance than both the general population and people with other chronic conditions, since they present a range of physical and psychological symptoms, including shortness of breath, chest discomfort, fatigue, fluid congestion, trouble with sleeping, and depression. These symptoms reduce patients' capacity for daily social and physical activity. Usual endpoints of large-scale trials in chronic HF have mostly been defined to evaluate treatments regarding hospitalizations and mortality, but more recently, patients' priorities and needs expressed with QoL are gaining more awareness and are being more extensively evaluated. This scientific statement aims at discussing the importance of QoL in HF, summarizing the most largely adopted questionnaires in HF care, and providing an overview on their application in trials and the potential for their transition to clinical practice. Finally, by discussing the reasons limiting their application in daily clinical routine and the strategies that may promote their implementation, this statement aims at fostering the systematic integration of the patient's standpoint in HF care.

BACKGROUND:Patients with advanced cancer frequently suffer from frailty associated with vulnerability and adverse outcomes. Our aim was to assess the prevalence of frailty and elucidate the utility of two commonly used frailty questionnaires in an advanced cancer population. METHODS:The Fried Frailty Phenotype (FFP) and Simple FRAIL Questionnaire (SFQ) were assessed in hospitalized patients with mostly advanced cancer. Patients were classified by both questionnaires as frail (3-5 points), pre-frail (1-2 points) and robust (0 points) and followed up for all-cause mortality. Utility was evaluated with correlation and survival analysis. RESULTS:From 11/2017 to 02/2020, 251 mostly advanced cancer patients (61 ± 13 years, 53% men, BMI 25.3 ± 4.8 kg/m2, 78% cancer stage ≥ 3) were prospectively enrolled. In cancer patients, according to the FFP and SFQ, 17%/13% were frail, 52%/41% prefrail and 31%/47% robust. The correlation between both scores was strong (rs = 0.65, p < 0.001). Both scores were predictors of mortality of cancer patients in univariable and multivariable Cox proportional hazards analyses (multivariable adjusted: per 1 point: FFP: HR 1.36, 95% CI, 1.15-1.61, p < 0.001; SFQ: HR 1.29, 95% CI, 1.09-1.52, p = 0.003-adjustment for age, cancer stage/type, anti-cancer therapy naïve, sex, BMI, CKD and anaemia). The time-dependent multivariable adjusted area under the receiver operating characteristic curve for 6-/24-month survival follow-up for the FFP was 0.78 (95% CI, 0.70-0.86)/0.92 (95% CI, 0.87-0.98) and for the SFQ was 0.79 (95% CI, 0.69-0.88)/0.90 (95% CI, 0.83-0.97). CONCLUSION:Frailty and pre-frailty as assessed by FFP and SFQ are commonly found in advanced stage cancer patients. Both questionnaires have a strong correlation and are associated with all-cause mortality in this population. Since the SFQ is easier and quicker to perform, it can be used remotely, and with untrained staff, it might facilitate earlier preventive measures and initiate further actions to mitigate its impact.

Background There is limited published information on outcome adjudication in heart failure (HF) trials, particularly in heart failure with preserved ejection fraction (HFpEF). Objectives The study sought to compare investigator reports with clinical events committee (CEC) adjudication and assess the impact of the SCTI (Standardized Data Collection for Cardiovascular Trials) criteria. Methods In the EMPEROR-Preserved (EMPagliflozin outcome tRial in Patients with chronic heart Failure With Preserved Ejection Fraction) trial, we compared investigator reports with CEC for concordance, treatment effect on primary composite outcome events and components (first event primary heart failure hospitalization [HHF] or cardiovascular [CV] mortality), prognosis after first HHF, total HHF, and trial duration with and without SCTI criteria. Results The CEC confirmed 67.4% investigator-reported events for the primary outcome (CV mortality 82.7%, HHF 66.3%). The HR for treatment effect did not differ between adjudication methods for the primary outcome: investigator reports (HR: 0.77; 95% CI: 0.69-0.87), CEC (HR: 0.79; 95% CI: 0.69-0.90), its components, or total HHFs. The prognosis after the first HHF for all-cause mortality and CV mortality also did not differ between investigator reports and the CEC, nor did investigator reports and HHFs with a different CEC cause. SCTI criteria were present in 92% of CEC HHFs with a similar treatment effect to non-SCTI criteria. The investigator-reported primary events reached the protocol target number 6 months earlier than the CEC (7 months with full SCTI criteria). Conclusions Investigator adjudication is an alternative to a CEC with similar accuracy and faster event accumulation in HFpEF. The use of granular (SCTI) criteria did not improve trial performance. Our data suggest that a broader definition of an HHF event could be particularly beneficial in HFpEF clinical trials. (EMPagliflozin outcome tRial in Patients with chronic heart Failure With Preserved Ejection Fraction; NCT03057951).

Importance:Uncertainty remains about the efficacy of intravenous iron in patients with heart failure and iron deficiency. Objective:To assess the efficacy and safety of ferric carboxymaltose in patients with heart failure and iron deficiency. Design, Setting, and Participants:This multicenter, randomized clinical trial enrolled 1105 patients with heart failure (defined as having a left ventricular ejection fraction of ≤45%) and iron deficiency (serum ferritin level <100 ng/mL; or if transferrin saturation was <20%, a serum ferritin level between 100 ng/mL and 299 ng/mL) at 70 clinic sites in 6 European countries from March 2017 to November 2023. The median follow-up was 16.6 months (IQR, 7.9-29.9 months). Intervention:Administration of ferric carboxymaltose (n = 558) initially given at an intravenous dose of up to 2000 mg that was followed by 500 mg every 4 months (unless stopping criteria were met) vs a saline placebo (n = 547). Main Outcomes and Measures:The primary end point events were (1) time to cardiovascular death or first heart failure hospitalization, (2) total heart failure hospitalizations, and (3) time to cardiovascular death or first heart failure hospitalization in patients with a transferrin saturation less than 20%. All end point events were measured through follow-up. The end points would be considered statistically significant if they fulfilled at least 1 of the following conditions: (1) P ≤ .05 for all 3 of the end point comparisons, (2) P ≤ .025 for 2 of the end point comparisons, or (3) P ≤ .0167 for any of the 3 end point comparisons (Hochberg procedure). Results:Of the 1105 participants (mean age, 70 years [SD, 12 years]; 33% were women), cardiovascular death or first heart failure hospitalization (first primary outcome) occurred in 141 in the ferric carboxymaltose group vs 166 in the placebo group (hazard ratio, 0.79 [95% CI, 0.63-0.99]; P = .04). The second primary outcome (total heart failure hospitalizations) occurred 264 times in the ferric carboxymaltose group vs 320 times in the placebo group (rate ratio, 0.80 [95% CI, 0.60-1.06]; P = .12). The third primary outcome (cardiovascular death or first heart failure hospitalization in patients with a transferrin saturation <20%) occurred in 103 patients in the ferric carboxymaltose group vs 128 patients in the placebo group (hazard ratio, 0.79 [95% CI, 0.61-1.02], P = .07). A similar amount of patients had at least 1 serious adverse event in the ferric carboxymaltose group (269; 48.2%) vs in the placebo group (273; 49.9%) (P = .61). Conclusions and Relevance:In patients with heart failure and iron deficiency, ferric carboxymaltose did not significantly reduce the time to first heart failure hospitalization or cardiovascular death in the overall cohort or in patients with a transferrin saturation less than 20%, or reduce the total number of heart failure hospitalizations vs placebo. Trial Registration:ClinicalTrials.gov Identifier: NCT03036462.

Uncertainty remains about the efficacy of intravenous iron in patients with heart failure and iron deficiency. To assess the efficacy and safety of ferric carboxymaltose in patients with heart failure and iron deficiency. This multicenter, randomized clinical trial enrolled 1105 patients with heart failure (defined as having a left ventricular ejection fraction of ≤45%) and iron deficiency (serum ferritin level <100 ng/mL; or if transferrin saturation was <20%, a serum ferritin level between 100 ng/mL and 299 ng/mL) at 70 clinic sites in 6 European countries from March 2017 to November 2023. The median follow-up was 16.6 months (IQR, 7.9-29.9 months). Administration of ferric carboxymaltose (n = 558) initially given at an intravenous dose of up to 2000 mg that was followed by 500 mg every 4 months (unless stopping criteria were met) vs a saline placebo (n = 547). The primary end point events were (1) time to cardiovascular death or first heart failure hospitalization, (2) total heart failure hospitalizations, and (3) time to cardiovascular death or first heart failure hospitalization in patients with a transferrin saturation less than 20%. All end point events were measured through follow-up. The end points would be considered statistically significant if they fulfilled at least 1 of the following conditions: (1) P ≤ .05 for all 3 of the end point comparisons, (2) P ≤ .025 for 2 of the end point comparisons, or (3) P ≤ .0167 for any of the 3 end point comparisons (Hochberg procedure). Of the 1105 participants (mean age, 70 years [SD, 12 years]; 33% were women), cardiovascular death or first heart failure hospitalization (first primary outcome) occurred in 141 in the ferric carboxymaltose group vs 166 in the placebo group (hazard ratio, 0.79 [95% CI, 0.63-0.99]; P = .04). The second primary outcome (total heart failure hospitalizations) occurred 264 times in the ferric carboxymaltose group vs 320 times in the placebo group (rate ratio, 0.80 [95% CI, 0.60-1.06]; P = .12). The third primary outcome (cardiovascular death or first heart failure hospitalization in patients with a transferrin saturation <20%) occurred in 103 patients in the ferric carboxymaltose group vs 128 patients in the placebo group (hazard ratio, 0.79 [95% CI, 0.61-1.02], P = .07). A similar amount of patients had at least 1 serious adverse event in the ferric carboxymaltose group (269; 48.2%) vs in the placebo group (273; 49.9%) (P = .61). In patients with heart failure and iron deficiency, ferric carboxymaltose did not significantly reduce the time to first heart failure hospitalization or cardiovascular death in the overall cohort or in patients with a transferrin saturation less than 20%, or reduce the total number of heart failure hospitalizations vs placebo. ClinicalTrials.gov Identifier: NCT03036462.

Background:The SECURE trial (NCT02596126) demonstrated the efficacy of the cardiovascular polypill ("CV-Polypill"-acetyl salicylic acid, atorvastatin and ramipril) in reducing the risk of recurrent major cardiovascular events compared with standard care when initiated within six months of a myocardial infarction. This analysis aimed to estimate the cost-effectiveness of the CV-Polypill from the Spanish healthcare perspective using SECURE trial data. Methods:A decision analytic Markov modelling approach was conducted to compare the CV-Polypill with standard care over a lifetime time horizon. Six parametric distributions were fitted to SECURE trial data on time to reinfarction, stroke or death (cardiovascular or non-cardiovascular). Cost and utility data were sourced from literature. Respective model outputs were discounted at 3%. The model captured direct medical costs associated with treatment acquisition and acute/ongoing cardiovascular events. Probabilistic sensitivity analyses (PSA) and scenario analyses were conducted. Findings:The CV-Polypill is dominant (improves health outcomes and reduces costs) in 84·8% of PSA iterations (848/1000 iterations), and cost effective in 89·3% of PSA iterations (893/1000 iterations) at a €30,000 threshold. Secondary prevention with the CV-Polypill reduces the recurrence of cardiovascular events and costs over the time horizon, from the Spanish healthcare perspective. A range of scenario analyses were conducted, demonstrating the robustness of the results when different inputs and assumptions were varied. Interpretation:The CV-Polypill is a dominant strategy in secondary cardiovascular prevention, compared with standard care, from the Spanish healthcare perspective. The CV-Polypill should be considered as a secondary prevention for Spanish patients, like those enrolled in SECURE, at hospital discharge. Funding:By Ferrer International.

AIMS:The Heart Failure Frailty Score (HFFS) is a novel, multidimensional tool to assess frailty in patients with heart failure (HF). It has been developed to overcome limitations of existing frailty assessment tools while being practical for clinical use. The HFFS reflects the concept of frailty as a multidimensional, dynamic and potentially reversible state, which increases vulnerability to stressors and risk of poor outcomes in patients with HF. METHODS AND RESULTS:The HFFS was developed through a Delphi consensus process involving 54 international experts. This approach involved iterative rounds of questionnaires and interviews, where a panel of experts provided their opinions on specific questions prepared by the Steering Committee. The experts were invited to vote and share their views anonymously, using a 5-point Likert scale over iterative rounds. An 80% threshold was set for agreement or disagreement for each statement. Twenty-two variables from four domains (clinical, functional, psycho-cognitive and social) have been selected for inclusion in the HFFS after the third round of the Delphi process. A shorter version (S-HFFS), including 10 variables, has also been developed for daily clinical use. CONCLUSIONS:The HFFS is a new multidimensional tool for the identification of frailty in patients with HF. It should also enables healthcare providers to identify potential 'red flags' for frailty in order to develop personalized care plans. The next step will be to validate the new score in patients with HF.

Background/Objectives: The aim of this study was to evaluate the impact of chronic heart failure (CHF), chronic kidney dysfunction (CKD), and the combined CHF-CKD comorbidity on the outcomes of rehabilitation in stroke patients. Methods: A total of 586 patients who had suffered a stroke (mean age, 70 ± 13; 47.6% female; 72.4% ischemic and 27.6% hemorrhagic strokes) and who were admitted immediately after acute stroke care to a rehabilitation center were included in this cohort study and followed up with until their death or discharge from the rehabilitation center. The clinical characteristics of the patients were obtained from their medical records. The relationship between the background comorbidities (CHF, CKD, and concurrent CHF-CKD) and fatal and non-fatal unfavorable outcomes (emergency readmission to a primary hospital or transfer to a long-term care facility in a vegetative or minimally conscious state) were investigated. Results: Unfavorable outcomes were more common in the groups with background CHF and/or CKD. From the Cox multivariate analysis, both CHF and CKD were independent prognostic factors for the occurrence of unfavorable outcomes, with a hazard ratio (HR) of 2.28 (95% CI = 1.2–4.29; p-value = 0.01) and 2.19 (95% CI = 1.24–3.87; p-value = 0.007), respectively. Moreover, the combined CHF-CKD comorbidity showed a more than 5-fold increased risk of an adverse post-stroke outcome (HR of 5.8; 95% CI = 2.5–13.44; p-value < 0.001). Conclusions: The combined CHF-CKD comorbidity is an important independent complicating factor that, along with other known influencing factors, can affect unfavorable post-stroke outcomes more than CHF or CKD alone, and necessitates critical attention to its diagnosis and management as a separate mixed syndrome.

AIMS:Prior randomized trials have reported conflicting evidence regarding the efficacy of intravenous (IV) iron in patients with heart failure with reduced ejection fraction (HFrEF) and iron deficiency (ID). METHODS AND RESULTS:FAIR-HF2 is a double-blind, randomized, controlled trial evaluating the efficacy of IV ferric carboxymaltose in patients with HFrEF and ID. We report the baseline characteristics of enrolled patients and compare them with other major trials of IV iron in HFrEF (FAIR-HF, CONFIRM-HF, AFFIRM-AHF, IRONMAN, and HEART-FID). A total of 1105 patients were randomized between March 2017 and November 2023. Most patients were men (67%) and median age was 72 (interquartile range [IQR] 63-79) years. More than one-third had a heart failure hospitalization within the preceding 12 months (36%), and 53% were hospitalized at randomization. Common comorbidities included hypertension (79%), coronary artery disease (74%), dyslipidaemia (67%), and diabetes (46%). The median left ventricular ejection fraction was 58% (IQR 42-77) and mean estimated glomerular filtration rate was 58 (IQR 42-77) ml/min/1.73 m2. A total of 1064 (96%) patients were on renin-angiotensin system inhibitors (angiotensin receptor-neprilysin inhibitors [ARNI] 38%), 1016 (92%) on beta-blockers, and 779 (71%) on mineralocorticoid receptor antagonists; and 261 (24%) of patients were on sodium-glucose cotransporter 2 (SGLT2) inhibitors, which is much higher than prior trials. A higher proportion of patients had ischaemic HFrEF (78%) compared to preceding trials. The baseline median haemoglobin (g/dl) was 12.7 (IQR 11.8-13.4), median serum ferritin (μg/dl) was 63 (IQR 36-90), and median transferrin saturation (%) was 16.5 (IQR 11.8-22.9), resembling that of other trials. The mean 6-min walk distance at enrolment was 314 ± 118 m. CONCLUSION:The FAIR-HF2 trial represents a contemporary cohort of patients with baseline characteristics mostly similar to prior trial populations. Use of SGLT2 inhibitors and ARNI in FAIR-HF2 was higher than in prior trials. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov ID NCT03036462.

Atrial fibrillation (AF) is one of the most common cardiac diseases and a complicating comorbidity for multiple associated diseases. Many clinical decisions regarding AF are currently based on the binary recognition of AF being present or absent with the categorical appraisal of AF as continued or intermittent. Assessment of AF in clinical trials is largely limited to the time to (first) detection of an AF episode. Substantial evidence shows, however, that the quantitative characteristic of intermittent AF has a relevant impact on symptoms, onset, and progression of AF and AF-related outcomes, including mortality. Atrial fibrillation burden is increasingly recognized as a suitable quantitative measure of intermittent AF that provides an estimate of risk attributable to AF, the efficacy of antiarrhythmic treatment, and the need for oral anticoagulation. However, the diversity of assessment methods and the lack of a consistent definition of AF burden prevent a wider clinical applicability and validation of actionable thresholds of AF burden. To facilitate progress in this field, the AF burden Consensus Group, an international and multidisciplinary collaboration, proposes a unified definition of AF burden. Based on current evidence and using a modified Delphi technique, consensus statements were attained on the four main areas describing AF burden: Defining the characteristics of AF burden, the recording principles, the clinical relevance in major clinical conditions, and implementation as an outcome in the clinic and in clinical trials. According to this consensus, AF burden is defined as the proportion of time spent in AF expressed as a percentage of the recording time, undertaken during a specified monitoring duration. A pivotal requirement for validity and comparability of AF burden assessment is a continuous or near-continuous duration of monitoring that needs to be reported together with the AF burden assessment. This proposed unified definition of AF burden applies independent of comorbidities and outcomes. However, the disease-specific actionable thresholds of AF burden need to be defined according to the targeted clinical outcomes in specific populations. The duration of the longest episode of uninterrupted AF expressed as a time duration should also be reported when appropriate. A unified definition of AF burden will allow for comparability of clinical study data to expand evidence and to establish actionable thresholds of AF burden in various clinical conditions. This proposed definition of AF burden will support risk evaluation and clinical treatment decisions in AF-related disease. It will further promote the development of clinical trials studying the clinical relevance of intermittent AF. A unified approach on AF burden will finally inform the technology development of heart rhythm monitoring towards validated technology to meet clinical needs.

Central autonomic dysfunction is common in acute stroke and is associated with cardiovascular complications and increased mortality. The aim of this review is to present novel diagnostic and therapeutic approaches to the management of this disorder and the latest data on its impact on the clinical outcome after stroke. We performed a narrative review of recent literature, with a particular focus on articles related to underlying pathophysiological mechanisms of cardiac autonomic dysregulation, the role of cardiac autonomic dysregulation in the activation of neuroinflammatory response and the development of cardiovascular, respiratory and metabolic complications in patients with ischemic and hemorrhagic stroke. The assessment of central autonomic dysfunction by non-invasive diagnostic techniques, including heart rate variability and baroreflex sensitivity, has gained wide practical application in recent years, and they may have a predictive role for evaluating disease prognosis. The emerging evidence derived from recent trials demonstrates that the presence of autonomic imbalance may lead to increased mortality and have an adverse effect on post-stroke rehabilitation. The early detection and treatment of central autonomic system dysfunction may lead to improved survival of patients with stroke. Among the available therapeutic approaches, neuromodulatory techniques and pharmacological interventions are promising strategies which may be implemented as part of standard acute stroke care to improve patient recovery. Future studies are warranted to address the long-term effects of potential therapeutic agents on the modulation of cardiovascular autonomic function in stroke survivors.

One in six ischaemic stroke patients has an embolic stroke of undetermined source (ESUS), defined as a stroke with unclear aetiology despite recommended diagnostic evaluation. The overall cardiovascular risk of ESUS is high and it is important to optimize strategies to prevent recurrent stroke and other cardiovascular events. The aim of clinicians when confronted with a patient not only with ESUS but also with any other medical condition of unclear aetiology is to identify the actual cause amongst a list of potential differential diagnoses, in order to optimize secondary prevention. However, specifically in ESUS, this may be challenging as multiple potential thromboembolic sources frequently coexist. Also, it can be delusively reassuring because despite the implementation of specific treatments for the individual pathology presumed to be the actual thromboembolic source, patients can still be vulnerable to stroke and other cardiovascular events caused by other pathologies already identified during the index diagnostic evaluation but whose thromboembolic potential was underestimated. Therefore, rather than trying to presume which particular mechanism is the actual embolic source in an ESUS patient, it is important to assess the overall thromboembolic risk of the patient through synthesis of the individual risks linked to all pathologies present, regardless if presumed causally associated or not. In this paper, a multi-disciplinary panel of clinicians/researchers from various backgrounds of expertise and specialties (cardiology, internal medicine, neurology, radiology and vascular surgery) proposes a comprehensive multi-dimensional assessment of the overall thromboembolic risk in ESUS patients through the composition of individual risks associated with all prevalent pathologies.

A significant proportion of patients who suffer from atrial fibrillation (AF) and are in need of thromboembolic protection are not treated with oral anticoagulation or discontinue this treatment shortly after its initiation. This undertreatment has not improved sufficiently despite the availability of direct oral anticoagulants which are associated with less major bleeding than vitamin K antagonists. Multiple reasons account for this, including bleeding events or ischaemic strokes whilst on anticoagulation, a serious risk of bleeding events, poor treatment compliance despite best educational attempts, or aversion to drug therapy. An alternative interventional therapy, which is not associated with long-term bleeding and is as effective as vitamin K anticoagulation, was introduced over 20 years ago. Because of significant improvements in procedural safety over the years, left atrial appendage closure, predominantly achieved using a catheter-based, device implantation approach, is increasingly favoured for the prevention of thromboembolic events in patients who cannot achieve effective anticoagulation. This management strategy is well known to the interventional cardiologist/electrophysiologist but is not more widely appreciated within cardiology or internal medicine. This article introduces the devices and briefly explains the implantation technique. The indications and device follow-up are more comprehensively described. Almost all physicians who care for adult patients will have many with AF. This practical guide, written within guideline/guidance boundaries, is aimed at those non-implanting physicians who may need to refer patients for consideration of this new therapy, which is becoming increasingly popular.

BACKGROUND:Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve outcome in patients with heart failure (HF) and reduce serum uric acid (SUA). The relevance of this metabolic effect in patients with heart failure with preserved ejection fraction (HFpEF) is unclear. OBJECTIVES:The authors investigated the effect of empagliflozin on SUA levels in relation to the therapeutic efficacy in patients with HFpEF. METHODS:This post hoc analysis of the EMPEROR-Preserved (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction; NCT03057951) trial assessed the clinical effect of SUA reduction in relation to the outcome endpoints of the trial (composite primary outcome of cardiovascular mortality or hospitalization for HF, its individual components, and all-cause mortality in patients with HFpEF). RESULTS:Hyperuricemia (SUA >5.7 mg/dL for women, >7.0 mg/dL for men) was prevalent in 49% of patients. Elevated SUA (highest tertile SUA 8.8 ± 1.4 g/dL) was associated with advanced HF severity and with higher risk of adverse outcome (primary endpoint HR: 1.23 [95% CI: 0.98-1.53]; P = 0.07; HF hospitalization HR: 1.42 [95% CI: 1.08-1.86]; P = 0.01). SUA was reduced early (after 4 weeks vs placebo -0.99 ± 0.03 mg/dL; P < 0.0001) and throughout follow-up, with reduction in all prespecified subgroups. Empagliflozin reduced clinical events of hyperuricemia (acute gout, gouty arthritis, or initiation of antigout therapy) by 38% (HR: 0.62 [95% CI: 0.51-0.76]; P < 0.0001). The treatment benefit on the primary endpoint was not influenced by baseline SUA (HR: 0.79 [95% CI: 0.69-0.90]; P = 0.0004). The change in SUA was an independent correlate of the treatment benefit on the primary endpoint (P = 0.07). CONCLUSIONS:Hyperuricemia is a common complication in HFpEF and is related to advanced disease severity and adverse outcome. Empagliflozin induced a rapid and sustained reduction of SUA levels and of clinical events related to hyperuricemia.