Apixaban for Stroke Prevention in Subclinical Atrial Fibrillation.

BACKGROUND: Subclinical atrial fibrillation is short-lasting and asymptomatic and can usually be detected only by long-term continuous monitoring with pacemakers or defibrillators. Subclinical atrial fibrillation is associated with an increased risk of stroke by a factor of 2.5; however, treatment with oral anticoagulation is of uncertain benefit. METHODS: We conducted a trial involving patients with subclinical atrial fibrillation lasting 6 minutes to 24 hours. Patients were randomly assigned in a double-blind, double-dummy design to receive apixaban at a dose of 5 mg twice daily (2.5 mg twice daily when indicated) or aspirin at a dose of 81 mg daily. The trial medication was discontinued and anticoagulation started if subclinical atrial fibrillation lasting more than 24 hours or clinical atrial fibrillation developed. The primary efficacy outcome, stroke or systemic embolism, was assessed in the intention-to-treat population (all the patients who had undergone randomization); the primary safety outcome, major bleeding, was assessed in the on-treatment population (all the patients who had undergone randomization and received at least one dose of the assigned trial drug, with follow-up censored 5 days after permanent discontinuation of trial medication for any reason). RESULTS: We included 4012 patients with a mean (±SD) age of 76.8±7.6 years and a mean CHA2DS2-VASc score of 3.9±1.1 (scores range from 0 to 9, with higher scores indicating a higher risk of stroke); 36.1% of the patients were women. After a mean follow-up of 3.5±1.8 years, stroke or systemic embolism occurred in 55 patients in the apixaban group (0.78% per patient-year) and in 86 patients in the aspirin group (1.24% per patient-year) (hazard ratio, 0.63; 95% confidence interval [CI], 0.45 to 0.88; P = 0.007). In the on-treatment population, the rate of major bleeding was 1.71% per patient-year in the apixaban group and 0.94% per patient-year in the aspirin group (hazard ratio, 1.80; 95% CI, 1.26 to 2.57; P = 0.001). Fatal bleeding occurred in 5 patients in the apixaban group and 8 patients in the aspirin group. CONCLUSIONS: Among patients with subclinical atrial fibrillation, apixaban resulted in a lower risk of stroke or systemic embolism than aspirin but a higher risk of major bleeding. (Funded by the Canadian Institutes of Health Research and others; ARTESIA ClinicalTrials.gov number, NCT01938248.).

Cardiac Resynchronization Therapy Improves Outcomes in Patients With Intraventricular Conduction Delay But Not Right Bundle Branch Block: A Patient-Level Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Benefit from cardiac resynchronization therapy (CRT) varies by QRS characteristics; individual randomized trials are underpowered to assess benefit for relatively small subgroups. METHODS: The authors analyzed patient-level data from pivotal CRT trials (MIRACLE [Multicenter InSync Randomized Clinical Evaluation], MIRACLE-ICD [Multicenter InSync ICD Randomized Clinical Evaluation], MIRACLE-ICD II [Multicenter InSync ICD Randomized Clinical Evaluation II], REVERSE [Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction], RAFT [Resynchronization-Defibrillation for Ambulatory Heart Failure], BLOCK-HF [Biventricular Versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block], COMPANION [Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure], and MADIT-CRT [Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy]) using Bayesian Hierarchical Weibull survival regression models to assess CRT benefit by QRS morphology (left bundle branch block [LBBB], n=4549; right bundle branch block [RBBB], n=691; and intraventricular conduction delay [IVCD], n=1024) and duration (with 150-ms partition). The continuous relationship between QRS duration and CRT benefit was also examined within subgroups defined by QRS morphology. The primary end point was time to heart failure hospitalization (HFH) or death; a secondary end point was time to all-cause death. RESULTS: Of 6264 patients included, 25% were women, the median age was 66 [interquartile range, 58 to 73] years, and 61% received CRT (with or without an implantable cardioverter defibrillator). CRT was associated with an overall lower risk of HFH or death (hazard ratio [HR], 0.73 [credible interval (CrI), 0.65 to 0.84]), and in subgroups of patients with QRS ≥150 ms and either LBBB (HR, 0.56 [CrI, 0.48 to 0.66]) or IVCD (HR, 0.59 [CrI, 0.39 to 0.89]), but not RBBB (HR 0.97 [CrI, 0.68 to 1.34]; Pinteraction <0.001). No significant association for CRT with HFH or death was observed when QRS was <150 ms (regardless of QRS morphology) or in the presence of RBBB. Similar relationships were observed for all-cause death. CONCLUSIONS: CRT is associated with reduced HFH or death in patients with QRS ≥150 ms and LBBB or IVCD, but not for those with RBBB. Aggregating RBBB and IVCD into a single "non-LBBB" category when selecting patients for CRT should be reconsidered. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: NCT00271154, NCT00251251, NCT00267098, and NCT00180271.

Benefit of cardiac resynchronization therapy among older patients: A patient-level meta-analysis.

BACKGROUND: Cardiac resynchronization therapy (CRT) reduces heart failure hospitalizations (HFH) and mortality for guideline-indicated patients with heart failure (HF). Most patients with HF are aged ≥70 years but such patients are often under-represented in randomized trials. METHODS: Patient-level data were combined from 8 randomized trials published 2002-2013 comparing CRT to no CRT (n = 6,369). The effect of CRT was estimated using an adjusted Bayesian survival model. Using age as a categorical (<70 vs ≥70 years) or continuous variable, the interaction between age and CRT on the composite end point of HFH or all-cause mortality or all-cause mortality alone was assessed. RESULTS: The median age was 67 years with 2436 (38%) being 70+; 1,554 (24%) were women; 2,586 (41%) had nonischemic cardiomyopathy and median QRS duration was 160 ms. Overall, CRT was associated with a delay in time to the composite end point (adjusted hazard ratio [aHR] 0.75, 95% credible interval [CI] 0.66-0.85, P = .002) and all-cause mortality alone (aHR of 0.80, 95% CI 0.69-0.96, P = .017). When age was treated as a categorical variable, there was no interaction between age and the effect of CRT for either end point (P > .1). When age was treated as a continuous variable, older patients appeared to obtain greater benefit with CRT for the composite end point (P for interaction = .027) with a similar but nonsignificant trend for mortality (P for interaction = .35). CONCLUSION: Reductions in HFH and mortality with CRT are as great or greater in appropriately indicated older patients. Age should not be a limiting factor for the provision of CRT.

Cardiac resynchronization therapy in patients with a prior history of atrial fibrillation: Insights from four major clinical trials.

AIMS: To investigate the association of cardiac resynchronization therapy (CRT) on outcomes among participants with and without a history of atrial fibrillation (AF). METHODS: Individual-patient-data from four randomized trials investigating CRT-Defibrillators (COMPANION, MADIT-CRT, REVERSE) or CRT-Pacemakers (COMPANION, MIRACLE) were analyzed. Outcomes were time to a composite of heart failure hospitalization or all-cause mortality or to all-cause mortality alone. The association of CRT on outcomes for patients with and without a history of AF was assessed using a Bayesian-Weibull survival regression model adjusting for baseline characteristics. RESULTS: Of 3964 patients included, 586 (14.8%) had a history of AF; 2245 (66%) were randomized to CRT. Overall, CRT reduced the risk of the primary composite endpoint (hazard ratio [HR]: 0.69, 95% credible interval [CI]: 0.56-0.81). The effect was similar (posterior probability of no interaction = 0.26) in patients with (HR: 0.78, 95% CI: 0.55-1.10) and without a history of AF (HR: 0.67, 95% CI: 0.55-0.80). In these four trials, CRT did not reduce mortality overall (HR: 0.82, 95% CI: 0.66-1.01) without evidence of interaction (posterior probability of no interaction = 0.14) for patients with (HR: 1.09, 95% CI: 0.70-1.74) or without a history of AF (HR: 0.70, 95% CI: 0.60-0.97). CONCLUSION: The association of CRT on the composite endpoint or mortality was not statistically different for patients with or without a history of AF, but this could reflect inadequate power. Our results call for trials to confirm the benefit of CRT recipients with a history of AF.

Prognosis of CRT-treated and CRT-untreated unselected population with LBBB in Stockholm County.

AIMS: Left bundle branch block (LBBB) might be the first finding of cardiovascular diseases but also the prerequisite for cardiac resynchronization therapy (CRT) in heart failure (HF) with reduced ejection fraction (HFrEF). The prognosis for patients with LBBB and the implications of CRT in an unselected real-world setting are the focus of our study. METHODS AND RESULTS: A central electrocardiogram (ECG) database and national registers have been screened to identify patients with LBBB. Predictors of HF and the use of CRT were identified with Cox models. The hazard ratios (HRs) of death, cardiovascular death (CVD), and HF hospitalization (HFH) were estimated according to CRT use. Of 5359 patients with LBBB and QRS > 150 ms, median age 76 years, 36% were female. At the time of index ECG, 41% had a previous history of HF and 27% developed HF. Among 1053 patients with a class I indication for CRT, only 60% received CRT with a median delay of 137 days, and it was associated with a lower risk of death [HR: 0.45, 95% confidence interval (CI): 0.36-0.57], CVD (HR: 0.47, 95% CI: 0.35-0.63), and HFH (HR: 0.56, 95% CI: 0.48-0.66). The age of over 75 years and the diagnosis of dementia and chronic obstructive pulmonary disease were predictors of CRT non-use, while having a pacing/defibrillator device independently predicted CRT use. CONCLUSION: In an unselected LBBB population, CRT is underused but of great value for HF patients. Therefore, it is crucial to find ways of better implementing and understanding CRT utilization and characteristics that influence the management of our patients.

The evolving state of cardiac resynchronization therapy and conduction system pacing: 25 years of research at EP Europace journal.

Cardiac resynchronization therapy (CRT) was proposed in the 1990s as a new therapy for patients with heart failure and wide QRS with depressed left ventricular ejection fraction despite optimal medical treatment. This review is aimed first to describe the rationale and the physiologic effects of CRT. The journey of the landmark randomized trials leading to the adoption of CRT in the guidelines since 2005 is also reported showing the high level of evidence for CRT. Different alternative pacing modalities of CRT to conventional left ventricular pacing through the coronary sinus have been proposed to increase the response rate to CRT such as multisite pacing and endocardial pacing. A new emerging alternative technique to conventional biventricular pacing, conduction system pacing (CSP), is a promising therapy. The different modalities of CSP are described (Hirs pacing and left bundle branch area pacing). This new technique has to be evaluated in clinical randomized trials before implementation in the guidelines with a high level of evidence.

Electrical management of heart failure: from pathophysiology to treatment.

Electrical disturbances, such as atrial fibrillation (AF), dyssynchrony, tachycardia, and premature ventricular contractions (PVCs), are present in most patients with heart failure (HF). While these disturbances may be the consequence of HF, increasing evidence suggests that they may also cause or aggravate HF. Animal studies show that longer-lasting left bundle branch block, tachycardia, AF, and PVCs lead to functional derangements at the organ, cellular, and molecular level. Conversely, electrical treatment may reverse or mitigate HF. Clinical studies have shown the superiority of atrial and pulmonary vein ablation for rhythm control and AV nodal ablation for rate control in AF patients when compared with medical treatment. Ablation of PVCs can also improve left ventricular function. Cardiac resynchronization therapy (CRT) is an established adjunct therapy currently undergoing several interesting innovations. The current guideline recommendations reflect the safety and efficacy of these ablation therapies and CRT, but currently, these therapies are heavily underutilized. This review focuses on the electrical treatment of HF with reduced ejection fraction (HFrEF). We believe that the team of specialists treating an HF patient should incorporate an electrophysiologist in order to achieve a more widespread use of electrical therapies in the management of HFrEF and should also include individual conditions of the patient, such as body size and gender in therapy fine-tuning.

The European Heart Journal: fulfilling the mission.

In September 2020, the new Editors of the European Heart Journal (EHJ) wrote the following in their inaugural editorial: "The fundamental mission of the Journal remains the reduction of the global burden of cardiovascular disease. We aspire to advance this aim by worldwide teamwork to communicate practice-changing research, inspire clinical cardiologists, and pursue rigour and transparency in the application of science at the service of human health. The Journal will strive to lead the field in its impact, influence, and reach". After more than one year of experience the Editors hope the cardiological community will agree that they are fulfilling this mission. As stewards of the EHJ, the Editor's primary goal is not solely to achieve a high Impact Factor (which attests to the scientific quality and influence of our publications) but also to elevate the practice of cardiovascular medicine worldwide. Accordingly, various initiatives of the EHJ strive to strengthen further links among Editors, Authors, Reviewers and Readers through a series of coordinated and diverse activities, including webinars, active social media presence, and active participation at congresses worldwide. The Editors are proud to serve one of the most important scientific journals in cardiovascular medicine.

A systematic review and meta-analysis of beta-blockers and renin-angiotensin system inhibitors for preventing left ventricular dysfunction due to anthracyclines or trastuzumab in patients with breast cancer.

AIMS: Trastuzumab and anthracyclines, often used in the treatment of breast cancer, may impair myocardial function, and reduce left ventricular ejection fraction (LVEF), potentially causing heart failure. Randomized controlled trials (RCTs) have evaluated the effects of beta-blockers (BBs), angiotensin receptor blockers (ARBs), and angiotensin-converting enzyme inhibitors (ACEI) on trastuzumab- and anthracycline-associated cardiotoxicity. We report a meta-analysis of these RCTs in patients with breast cancer. METHODS AND RESULTS: The primary analysis was on the effect of BBs and ACEI/ARBs on LVEF in patients treated with either trastuzumab or anthracyclines. A secondary analysis was done investigating the effect of BBs or ACEI/ARBs on LVEF in trastuzumab and anthracycline treatments. Only RCTs were included using the search term 'ARBs, ACEIs, BBs, anthracyclines, trastuzumab, and breast cancer' in PubMed, Embase, and CENTRAL up to 31 March 2021. A meta-analysis was conducted to estimate the mean difference (MD) in LVEF between intervention and placebo groups at follow-up. A total of nine RCTs (n = 1362) were included in the analysis. All patients were women. BBs and ACEI/ARBs were shown to attenuate the decline in LVEF during trastuzumab and anthracycline treatments [MD: 2.4; 95% confidence interval (CI): 0.3-4.2 and MD: 1.5; 95% CI: -0.6 to 3.7]. Compared with placebo, LVEF was significantly higher in patients assigned to BB or ACEI/ARB on trastuzumab (MD: 2.3; 95% CI: 0.0-4.6) but not on anthracyclines (MD: 1.9; 95% CI: -0.5 to 4.2). CONCLUSION: Both BB and ACEI/ARB therapies were associated with the preservation of LVEF during trastuzumab and anthracycline-containing regimens as compared with placebo, suggesting both to be beneficial.

Cardiac resynchronization therapy with or without defibrillator in patients with heart failure.

AIMS: Randomized data on the efficacy/safety of cardiac resynchronization therapy with vs. without defibrillator (CRT-D,-P) in heart failure with reduced ejection fraction (HFrEF) are scarce. We aimed to evaluate survival associated with use of CRT-D vs. CRT-P in a contemporary cohort with HFrEF. METHODS AND RESULTS: Patients from Swedish HF Registry treated with CRT-D/CRT-P and fulfilling criteria for primary prevention defibrillator use were included. Logistic regression was used to evaluate predictors of CRT-D non-use. All-cause mortality was compared in CRT-D vs. CRT-P by Cox regression in a 1 : 1 propensity-score-matched cohort. Of 1988 patients with CRT, 1108 (56%) had CRT-D and 880 (44%) CRT-P. Older age, higher ejection fraction (EF), female sex, and the lack of referral to HF nurse-led outpatient clinic were major determinants of CRT-D non-use. After matching, 645 CRT-D patients were compared with 645 with CRT-P. The CRT-D use was associated with lower 1- and 3-year all-cause mortality [hazard ratio (HR):0.76, 95% confidence interval (CI):0.58-0.98; HR: 0.82, 95% CI: 0.68-0.99, respectively]. Results were consistent in all pre-specified subgroups except for CRT-D use being associated with lower 3-year mortality in patients with an EF < 30% but not in those with an EF ≥ 30% (HR: 0.73, 95% CI: 0.59-0.89 and HR: 1.24, 95% CI: 0.83-1.85, respectively; P-interaction = 0.02). CONCLUSION: In a contemporary HFrEF cohort, CRT-D was associated with lower mortality compared with CRT-P. The CRT-D use was less likely in older patients, females, and in patients not referred to HF nurse-led outpatient clinic. Our findings support the use of CRT-D vs. CRT-P in HFrEF, in particular with severely reduced EF.

European Society of Cardiology Quality Indicators for the care and outcomes of cardiac pacing: developed by the Working Group for Cardiac Pacing Quality Indicators in collaboration with the European Heart Rhythm Association of the European Society of Cardiology.

AIMS: To develop a suite of quality indicators (QIs) for the evaluation of the care and outcomes for adults undergoing cardiac pacing. METHODS AND RESULTS: Under the auspice of the Clinical Practice Guideline Quality Indicator Committee of the European Society of Cardiology (ESC), the Working Group for cardiac pacing QIs was formed. The Group comprised Task Force members of the 2021 ESC Clinical Practice Guidelines on Cardiac Pacing and Cardiac Resynchronization Therapy, members of the European Heart Rhythm Association, international cardiac device experts, and patient representatives. We followed the ESC methodology for QI development, which involved (i) the identification of the key domains of care by constructing a conceptual framework of the management of patients receiving cardiac pacing, (ii) the development of candidate QIs by conducting a systematic review of the literature, (iii) the selection of the final set of QIs using a modified-Delphi method, and (iv) the evaluation of the feasibility of the developed QIs. Four domains of care were identified: (i) structural framework, (ii) patient assessment, (iii) pacing strategy, and (iv) clinical outcomes. In total, seven main and four secondary QIs were selected across these domains and were embedded within the 2021 ESC Guidelines on Cardiac Pacing and Cardiac Resynchronization therapy. CONCLUSION: By way of a standardized process, 11 QIs for cardiac pacing were developed. These indicators may be used to quantify adherence to guideline-recommended clinical practice and have the potential to improve the care and outcomes of patients receiving cardiac pacemakers.

Optimized Implementation of cardiac resynchronization therapy - a call for action for referral and optimization of care.

Cardiac resynchronization therapy (CRT) is one of the most effective therapies for heart failure with reduced ejection fraction and leads to improved quality of life, reductions in heartfailure hospitalization rates and reduces all-cause mortality. Nevertheless, up to two-thirds ofeligible patients are not referred for CRT. Furthermore, post implantation follow-up is oftenfragmented and suboptimal, hampering the potential maximal treatment effect. This jointposition statement from three ESC Associations, HFA, EHRA and EACVI focuses onoptimized implementation of CRT. We offer theoretical and practical strategies to achievemore comprehensive CRT referral and post-procedural care by focusing on four actionabledomains; (I) overcoming CRT under-utilization, (II) better understanding of pre-implantcharacteristics, (III) abandoning the term 'non-response' and replacing this by the concept ofdisease modification, and (IV) implementing a dedicated post-implant CRT care pathway.

Optimized implementation of cardiac resynchronization therapy: a call for action for referral and optimization of care.

Cardiac resynchronization therapy (CRT) is one of the most effective therapies for heart failure with reduced ejection fraction and leads to improved quality of life, reductions in heart failure hospitalization rates and all-cause mortality. Nevertheless, up to two-thirds of eligible patients are not referred for CRT. Furthermore, post-implantation follow-up is often fragmented and suboptimal, hampering the potential maximal treatment effect. This joint position statement from three European Society of Cardiology Associations, Heart Failure Association (HFA), European Heart Rhythm Association (EHRA) and European Association of Cardiovascular Imaging (EACVI), focuses on optimized implementation of CRT. We offer theoretical and practical strategies to achieve more comprehensive CRT referral and post-procedural care by focusing on four actionable domains: (i) overcoming CRT under-utilization, (ii) better understanding of pre-implant characteristics, (iii) abandoning the term 'non-response' and replacing this by the concept of disease modification, and (iv) implementing a dedicated post-implant CRT care pathway.

Reorganization of heart failure management and improved outcome - the 4D HF Project.

OBJECTIVES: Heart failure (HF) management is suboptimal in Sweden despite available evidence-based guidelines. To improve HF treatment, a comprehensive HF management program (4D project) was implemented in the Stockholm County (>2.1 million inhabitants). Design. A standardized care program centralized at five hospital-based HF clinics was implemented in 2014-2017. We registered from 2012 to 2017: (1) numbers of referrals and visits to HF clinics, (2) numbers of hospital admitted patients per million inhabitants, (3) dispensed HF medications after admission, and (4) covariate-adjusted 1-year all-cause mortality or HF readmission. Results. Yearly visits to the five HF outpatient clinics increased 3.4 times from 3,372 to 11,527. Dispensed HF drug prescriptions increased, in particular, for readmitted patients, compared to 2012 (p<.0001). Total number of hospital admitted HF patients as well as new-onset or readmitted HF patients decreased by 16, 13, and 20%, respectively (p < .0001). The combined 1-year mortality or HF readmission over the period was 48% (n = 17,124/35,880) and improved per year (HR 0.98 [0.97-0.99], p < .001) from 2012. Conclusion. A comprehensive standardized care HF management program including expanded HF clinics was associated with improved evidence-based medication, reduced HF hospitalization, and improvement of the combined outcome of 1-year mortality or HF readmission in Stockholm.

Imaging predictors of response to cardiac resynchronization therapy: left ventricular work asymmetry by echocardiography and septal viability by cardiac magnetic resonance.

AIMS: Left ventricular (LV) failure in left bundle branch block is caused by loss of septal function and compensatory hyperfunction of the LV lateral wall (LW) which stimulates adverse remodelling. This study investigates if septal and LW function measured as myocardial work, alone and combined with assessment of septal viability, identifies responders to cardiac resynchronization therapy (CRT). METHODS AND RESULTS: In a prospective multicentre study of 200 CRT recipients, myocardial work was measured by pressure-strain analysis and viability by cardiac magnetic resonance (CMR) imaging (n = 125). CRT response was defined as ≥15% reduction in LV end-systolic volume after 6 months. Before CRT, septal work was markedly lower than LW work (P < 0.0001), and the difference was largest in CRT responders (P < 0.001). Work difference between septum and LW predicted CRT response with area under the curve (AUC) 0.77 (95% CI: 0.70-0.84) and was feasible in 98% of patients. In patients undergoing CMR, combining work difference and septal viability significantly increased AUC to 0.88 (95% CI: 0.81-0.95). This was superior to the predictive power of QRS morphology, QRS duration and the echocardiographic parameters septal flash, apical rocking, and systolic stretch index. Accuracy was similar for the subgroup of patients with QRS 120-150 ms as for the entire study group. Both work difference alone and work difference combined with septal viability predicted long-term survival without heart transplantation with hazard ratio 0.36 (95% CI: 0.18-0.74) and 0.21 (95% CI: 0.072-0.61), respectively. CONCLUSION: Assessment of myocardial work and septal viability identified CRT responders with high accuracy.

Association Between Use of Primary-Prevention Implantable Cardioverter-Defibrillators and Mortality in Patients With Heart Failure: A Prospective Propensity Score-Matched Analysis From the Swedish Heart Failure Registry.

BACKGROUND: Most randomized trials on implantable cardioverter-defibrillator (ICD) use for primary prevention of sudden cardiac death in heart failure with reduced ejection fraction enrolled patients >20 years ago. We investigated the association between ICD use and all-cause mortality in a contemporary heart failure with reduced ejection fraction cohort and examined relevant subgroups. METHODS: Patients from the Swedish Heart Failure Registry fulfilling the European Society of Cardiology criteria for primary-prevention ICD were included. The association between ICD use and 1-year and 5-year all-cause and cardiovascular (CV) mortality was assessed by Cox regression models in a 1:1 propensity score-matched cohort and in prespecified subgroups. RESULTS: Of 16 702 eligible patients, only 1599 (10%) had an ICD. After matching, 1305 ICD recipients were compared with 1305 nonrecipients. ICD use was associated with a reduction in all-cause mortality risk within 1 year (hazard ratio, 0.73 [95% CI, 0.60-0.90]) and 5 years (hazard ratio, 0.88 [95% CI, 0.78-0.99]). Results were consistent in all subgroups including patients with versus without ischemic heart disease, men versus women, those aged <75 versus ≥75 years, those with earlier versus later enrollment in the Swedish heart failure registry, and patients with versus without cardiac resynchronization therapy. CONCLUSIONS: In a contemporary heart failure with reduced ejection fraction population, ICD for primary prevention was underused, although it was associated with reduced short- and long-term all-cause mortality. This association was consistent across all the investigated subgroups. These results call for better implementation of ICD therapy.

Future research prioritization in cardiac resynchronization therapy.

BACKGROUND: Although cardiac resynchronization therapy (CRT) is effective for some patients with heart failure and a reduced left ventricular ejection fraction (HFrEF), evidence gaps remain for key clinical and policy areas. The objective of the study was to review the data on the effects of CRT for patients with HFrEF receiving pharmacological therapy alone or pharmacological therapy and an implantable cardioverter-defibrillator (ICD) and then, informed by a diverse group of stakeholders, to identify evidence gaps, prioritize them, and develop a research plan. METHODS: Relevant studies were identified using PubMed and EMBASE and ongoing trials using clinicaltrials.gov. Forced-ranking prioritization method was applied by stakeholders to reach a consensus on the most important questions. Twenty-six stakeholders contributed to the expanded list of evidence gaps, including key investigators from existing randomized controlled trials and others representing different perspectives, including patients, the public, device manufacturers, and policymakers. RESULTS: Of the 18 top-tier evidence gaps, 8 were related to specific populations or subgroups of interest. Seven were related to the comparative effectiveness and safety of CRT interventions or comparators, and 3 were related to the association of CRT treatment with specific outcomes. The association of comorbidities with CRT effectiveness ranked highest, followed by questions about the effectiveness of CRT among patients with atrial fibrillation and the relationship between gender, QRS morphology and duration, and outcomes for patients either with CRT plus ICD or with ICD. CONCLUSIONS: Evidence gaps presented in this article highlight numerous, important clinical and policy questions for which there is inconclusive evidence on the role of CRT and provide a framework for future collaborative research.

Increased iron absorption in patients with chronic heart failure and iron deficiency.

BACKGROUND: Iron deficiency (ID) is common in patients with chronic heart failure (CHF), but the underlying causes are not fully understood. We investigated whether ID is associated with decreased iron absorption in patients with CHF. METHODS AND RESULTS: We performed an oral iron-absorption test in 30 patients and 12 controls. The patients had CHF with reduced (n = 15) or preserved (n = 15) ejection fraction and ID, defined as s-ferritin < 100 µg/L, or s-ferritin 100-299 µg/L and transferrin saturation < 20%. The controls had no HF or ID and were of similar age and gender. Blood samples were taken before and 2 hours after ingestion of 100 mg ferroglycin sulphate. The primary endpoint was the delta plasma iron at 2 hours. The delta plasma iron was higher in the group with HF than in the control group (median increase 83.8 [61.5;128.5] µg/dL in HF vs 47.5 [30.7;61.5] µg/dL in controls, P = 0.001), indicating increased iron absorption. There was no significant difference between the groups with preserved or reduced ejection fraction (P = 0.46). CONCLUSION: We found increased iron absorption in patients with CHF and ID compared to controls without ID and HF, indicating that reduced iron absorption is not a primary cause of the high prevalence of ID in patients with CHF. CLINICAL TRIAL REGISTRATION: EudraCT 2017-000158-21.

Do Patients With Acute Heart Failure and Preserved Ejection Fraction Have Heart Failure at Follow-Up: Implications of the Framingham Criteria.

BACKGROUND: Heart failure (HF) with preserved ejection fraction (HFpEF) may be misdiagnosed. We assessed prevalence and consistency of Framingham criteria signs and symptoms in acute vs subsequent stable HFpEF. METHODS: Three hundred ninety-nine patients with acute HFpEF according to Framingham criteria were re-assessed in stable condition. Four definitions of HFpEF at follow-up: (1) Framingham criteria alone, (2) Framingham criteria and natriuretic peptides (NPs), (3) Framingham criteria, NPs, and European Society of Cardiology HF guidelines echocardiographic criteria, (4) Framingham criteria, NPs, and the Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON) trial echocardiographic criteria. RESULTS: At follow-up, HFpEF was still present in 27%, 22%, 21%, and 22%, respectively. Most prevalent in acute HFpEF were dyspnea at exertion (90%), pulmonary rales (71%), persisting at follow-up in 70% and 13%, respectively. Characteristics at acute HF with greater or lesser odds of stable HFpEF; (1) jugular venous distention (odds ratio [OR] 1.80, 95% confidence interval [CI] 1.13-2.87; P = .013) and pleural effusion (OR 0.45, 95% CI 0.24-0.85; P = .014) and (4), older age (1.04, 95% CI 1.01-1.08; P = .014) and tachycardia (>100 bpm) 0.52, 95% CI 0.27-1.00; P = .048). CONCLUSIONS: In patients with acute HFpEF, one-quarter met the HF definition according to Framingham criteria at ambulatory follow-up. The proportion of patients with postdischarge HFpEF was largely unaffected by additional echocardiographic or NP criteria Older age and jugular venous distention at acute presentation predicted persistent HFpEF at follow-up, whereas pleural effusion and tachycardia may yield false HFpEF diagnoses. This finding has implications for HFpEF trial design.

Metabolomic Profile in HFpEF vs HFrEF Patients.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) are associated with metabolic derangements, which may have different pathophysiological implications. METHODS AND RESULTS: In new-onset HFpEF (EF of ≥50%, n = 46) and HFrEF (EF of <40%, n = 75) patients, 109 endogenous plasma metabolites including amino acids, phospholipids and acylcarnitines were assessed using targeted metabolomics. Differentially altered metabolites and associations with clinical characteristics were explored. Patients with HFpEF were older, more often female with hypertension, atrial fibrillation, and diabetes compared with patients with HFrEF. Patients with HFpEF displayed higher levels of hydroxyproline and symmetric dimethyl arginine, alanine, cystine, and kynurenine reflecting fibrosis, inflammation and oxidative stress. Serine, cGMP, cAMP, l-carnitine, lysophophatidylcholine (18:2), lactate, and arginine were lower compared with patients with HFrEF. In patients with HFpEF with diabetes, kynurenine was higher (P = .014) and arginine lower (P = .014) vs patients with no diabetes, but did not differ with diabetes status in HFrEF. Decreasing kynurenine was associated with higher eGFR only in HFpEF (Pinteraction = .020). CONCLUSIONS: Patients with new-onset HFpEF compared with patients with new-onset HFrEF display a different metabolic profile associated with comorbidities, such as diabetes and kidney dysfunction. HFpEF is associated with indices of increased inflammation and oxidative stress, impaired lipid metabolism, increased collagen synthesis, and downregulated nitric oxide signaling. Together, these findings suggest a more predominant systemic microvascular endothelial dysfunction and inflammation linked to increased fibrosis in HFpEF compared with HFrEF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03671122 https://clinicaltrials.gov.