How to make cardiology clinical trials more inclusive.

Cardiovascular clinical trials continue to under-represent children, older adults, females and people from ethnic minority groups relative to population disease distribution. Here we describe strategies to foster trial representativeness, with proposed actions at the levels of trial funding, design, conduct and dissemination. In particular, trial representativeness may be increased through broad recruitment strategies and site selection criteria that reflect the diversity of patients in the catchment area, as well as limiting unjustified exclusion criteria and using pragmatic designs that minimize research burden on patients (including embedded and decentralized trials). Trial communications ought to be culturally appropriate; engaging diverse people with lived experience in the co-design of some trial elements may foster this. The demographics of trialists themselves are associated with participant demographics; therefore, trial leadership must be actively diversified. Funding bodies and journals increasingly require the reporting of sociodemographic characteristics of trial participants, and regulatory bodies now provide guidance on increasing trial diversity; these steps may increase the momentum towards change. Although this Perspective focuses on the cardiovascular trial context, many of these strategies could be applied to other fields.

Cardiac Resynchronization Therapy in Ischemic Versus Nonischemic Cardiomyopathy: Patient-Level Meta-Analysis of 7 Randomized Clinical Trials.

BACKGROUND: Data on whether cardiac resynchronization therapy (CRT) results in better clinical and echocardiographic outcomes in patients with nonischemic cardiomyopathy (NICM) vs ischemic cardiomyopathy (ICM) are conflicting. OBJECTIVES: The authors conducted this meta-analysis of 7 clinical trials of CRT to determine the association between etiology of cardiomyopathy and clinical and echocardiographic outcomes. METHODS: The authors analyzed patient-level data using Bayesian Hierarchical Weibull survival regression modeling to determine the association between etiology of cardiomyopathy and time to all-cause death or heart failure hospitalization (HFH). Linear regression was used to assess the association between etiology of cardiomyopathy and echocardiographic measurements. RESULTS: Of 6,252 patients included, 4,717 (75%) were men, median age was 66 years (IQR: 58-73 years), 3,704 (59%) had ICM, and 3,778 (60%) received CRT. CRT increased the time to HFH or all-cause death (HR: 0.67; 95% credible interval [CrI]: 0.56-0.82; P < 0.001) with no difference by etiology of cardiomyopathy (HR ratio: 1.06 [95% CrI: 0.87-1.29]; P = 0.57). Likewise, CRT increased the time to all-cause death (HR: 0.71 [95% CrI: 0.55-0.93]; P = 0.019) with no difference by etiology of cardiomyopathy (HR ratio: 1.06 [95% CrI: 0.80-1.43]; P = 0.70). Echocardiographic data that were available for 2,430 (39%) patients showed that CRT improvements in left ventricular ejection fraction, left ventricular end-diastolic diameter, and left ventricular end-systolic diameter were larger for patients with NICM. CONCLUSIONS: Although CRT led to greater increases in left ventricular ejection fraction and reductions in ventricular dimensions for patients with NICM compared with those with ICM, CRT significantly increased the time to HFH or all-cause death independently of the etiology of cardiomyopathy. Further studies on improving patient selection for CRT are needed.

Takotsubo Syndrome: An International Expert Consensus Report on Practical Challenges and Specific Conditions (Part-1: Diagnostic and Therapeutic Challenges).

In the recent years, there has been a burgeoning interest in Takotsubo syndrome (TTS), which is renowned as a specific form of reversible myocardial dysfunction. Despite the extensive literature available on TTS, clinicians still face several practical challenges associated with the diagnosis and management of this phenomenon. This potentially results in the underdiagnosis and improper management of TTS in clinical practice. The present paper, the first part (part-1) of the consensus report, aims to cover diagnostic and therapeutic challenges associated with TTS along with certain recommendations to combat these challenges.

Takotsubo Syndrome: An International Expert Consensus Report on Practical Challenges and Specific Conditions (Part-2: Specific Entities, Risk Stratification and Challenges After Recovery).

Takotsubo syndrome (TTS) still remains as an enigmatic phenomenon. In particular, long-term challenges (including clinical recurrence and persistent symptoms) and specific entities in the setting of TTS have been the evolving areas of interest. On the other hand, a significant gap still exists regarding the proper risk-stratification of this phenomenon in the short and long terms. The present paper, the second part (part-2) of the consensus report, aims to discuss less well-known aspects of TTS including specific entities, challenges after recovery and risk-stratification.

Characteristics of gene expression in epicardial adipose tissue and subcutaneous adipose tissue in patients at risk for heart failure undergoing coronary artery bypass grafting.

BACKGROUND: Epicardial adipose tissue (EAT) surrounds the heart and is hypothesised to play a role in the development of heart failure (HF). In this study, we first investigated the differences in gene expression between epicardial adipose tissue (EAT) and subcutaneous adipose tissue (SAT) in patients undergoing elective coronary artery bypass graft (CABG) surgery (n = 21; 95% male). Secondly, we examined the association between EAT and SAT in patients at risk for HF stage A (n = 12) and in pre-HF patients, who show signs but not symptoms of HF, stage B (n = 9). RESULTS: The study confirmed a distinct separation between EAT and SAT. In EAT 17 clusters of genes were present, of which several novel gene modules are associated with characteristics of HF. Notably, seven gene modules showed significant correlation to measures of HF, such as end diastolic left ventricular posterior wall thickness, e'mean, deceleration time and BMI. One module was particularly distinct in EAT when compared to SAT, featuring key genes such as FLT4, SEMA3A, and PTX3, which are implicated in angiogenesis, inflammation regulation, and tissue repair, suggesting a unique role in EAT linked to left ventricular dysfunction. Genetic expression was compared in EAT across all pre-HF and normal phenotypes, revealing small genetic changes in the form of 18 differentially expressed genes in ACC/AHA Stage A vs. Stage B. CONCLUSIONS: The roles of subcutaneous and epicardial fat are clearly different. We highlight the gene expression difference in search of potential modifiers of HF progress. The true implications of our findings should be corroborated in other studies since HF ACC/AHA stage B patients are common and carry a considerable risk for progression to symptomatic HF.

Anticoagulation in device-detected atrial fibrillation with or without vascular disease: a combined analysis of the NOAH-AFNET 6 and ARTESiA trials.

BACKGROUND AND AIMS: The optimal antithrombotic therapy in patients with device-detected atrial fibrillation (DDAF) is unknown. Concomitant vascular disease can modify the benefits and risks of anticoagulation. METHODS: These pre-specified analyses of the NOAH-AFNET 6 (n=2534 patients) and ARTESiA (n=4012 patients) trials compared anticoagulation to no anticoagulation in patients with DDAF with or without vascular disease, defined as prior stroke/transient ischemic attack, coronary or peripheral artery disease. Efficacy outcomes were the primary outcomes of both trials, a composite of stroke, systemic arterial embolism (SE), myocardial infarction, pulmonary embolism or cardiovascular death, and stroke or SE. Safety outcomes were major bleeding or major bleeding and death. RESULTS: In patients with vascular disease (NOAH-AFNET 6 56%, ARTESiA 46.0%), stroke, myocardial infarction, systemic or pulmonary embolism, or cardiovascular death occurred at 3.9%/patient-year with and 5.0%/patient-year without anticoagulation (NOAH-AFNET 6), and 3.2%/patient-year with and 4.4%/patient-year without anticoagulation (ARTESiA). Without vascular disease, outcomes were equal with and without anticoagulation (NOAH-AFNET 6 2.7%/patient-year, ARTESiA 2.3%/patient-year in both randomised groups). Meta-analysis found consistent results across both trials (I2heterogeneity=6%) with a trend for interaction with randomised therapy (pinteraction=0.08). Stroke/SE behaved similarly. Anticoagulation increased major bleeding in vascular disease patients (edoxaban 2.1%/patient-year, no anticoagulation 1.3%/patient-year; apixaban 1.7%/patient-year; no anticoagulation 1.1%/patient-year; incidence rate ratio 1.55 [1.10-2.20]) and without vascular disease (edoxaban 2.2%/patient-year; no anticoagulation 0.6%/patient-year; apixaban 1.4%/patient-year; no anticoagulation 1.1%/patient-year, incidence rate ratio 1.93 [0.72-5.20]). CONCLUSIONS: Patients with DDAF and vascular disease are at higher risk of stroke and cardiovascular events and may derive a greater benefit from anticoagulation than patients with DDAF without vascular disease.

Machine learning-based prediction of 1-year all-cause mortality in patients undergoing CRT implantation: validation of the SEMMELWEIS-CRT score in the European CRT Survey I dataset.

Aims: We aimed to externally validate the SEMMELWEIS-CRT score for predicting 1-year all-cause mortality in the European Cardiac Resynchronization Therapy (CRT) Survey I dataset-a large multi-centre cohort of patients undergoing CRT implantation. Methods and results: The SEMMELWEIS-CRT score is a machine learning-based tool trained for predicting all-cause mortality in patients undergoing CRT implantation. This tool demonstrated impressive performance during internal validation but has not yet been validated externally. To this end, we applied it to the data of 1367 patients from the European CRT Survey I dataset. The SEMMELWEIS-CRT predicted 1-year mortality with an area under the receiver operating characteristic curve (AUC) of 0.729 (0.682-0.776), which concurred with the performance measured during internal validation [AUC: 0.768 (0.674-0.861), P = 0.466]. Moreover, the SEMMELWEIS-CRT score outperformed multiple conventional statistics-based risk scores, and we demonstrated that a higher predicted probability is not only associated with a higher risk of death [odds ratio (OR): 1.081 (1.061-1.101), P < 0.001] but also with an increased risk of hospitalizations for any cause [OR: 1.013 (1.002-1.025), P = 0.020] or for heart failure [OR: 1.033 (1.015-1.052), P < 0.001], a less than 5% improvement in left ventricular ejection fraction [OR: 1.033 (1.021-1.047), P < 0.001], and lack of improvement in New York Heart Association functional class compared with baseline [OR: 1.018 (1.006-1.029), P = 0.003]. Conclusion: In the European CRT Survey I dataset, the SEMMELWEIS-CRT score predicted 1-year all-cause mortality with good discriminatory power, which confirms the generalizability and demonstrates the potential clinical utility of this machine learning-based risk stratification tool.

Characterizing atrial fibrillation in patients with and without heart failure across the ejection fraction spectrum: Incidence, prevalence, and treatment strategies.

AIMS: Heart failure (HF) and atrial fibrillation (AF) often coexist. We explored AF incidence, prevalence, and treatment strategies in patients with versus without HF across the ejection fraction (EF) spectrum. METHODS AND RESULTS: We analysed patients with HF from the Swedish HF Registry (1 December 2005-31 December 2021), matched 1:1 by sex, age, and county of residence to patients without HF from Statistics Sweden. Two study cohorts were derived (i) to assess AF prevalence and treatments, and (ii) to evaluate AF incidence and related predictors. Overall, 195 106 patients were considered, 50% of them with HF (of whom 54% with HF with reduced [HFrEF], 23% mildly reduced [HFmrEF], and 23% with preserved EF [HFpEF]). From 2006 to 2021, AF prevalence increased in both patients with (57% to 58%) and without HF (8% to 11%). HF patients, particularly if with HFrEF, were more likely receiving AF treatments than those without HF. Over time, antiarrhythmic use decreased, while rate control drugs and oral anticoagulant use, and AF-related procedures increased, regardless of HF and EF. During a median follow-up of 3.7 years, in 86 210 patients without AF, incident AF risk was two-fold higher in HF versus non-HF (hazard ratio [HR] 2.76, 95% confidence interval [CI] 2.45-3.12), highest in HFpEF (HR 3.12, 95% CI 2.65-3.67) versus HFrEF (HR 2.68, 95% CI 2.34-3.06) and HFmrEF (HR 2.53, 95% CI 2.17-2.94). CONCLUSIONS: Atrial fibrillation prevalence, anticoagulant use, and AF-related procedures increased over time regardless of HF, with HF patients more likely receiving AF treatments. In HF, despite higher AF prevalence and incidence in HFpEF, AF treatment use remained modest, calling for further implementation.

Apixaban vs Aspirin According to CHA2DS2-VASc Score in Subclinical Atrial Fibrillation: Insights From ARTESiA.

BACKGROUND: ARTESiA (Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation) demonstrated that apixaban, compared with aspirin, significantly reduced stroke and systemic embolism (SE) but increased major bleeding in patients with subclinical atrial fibrillation. OBJECTIVES: To help inform decision making, the authors evaluated the efficacy and safety of apixaban according to baseline CHA2DS2-VASc score. METHODS: We performed a subgroup analysis according to baseline CHA2DS2-VASc score and assessed both the relative and absolute differences in stroke/SE and major bleeding. RESULTS: Baseline CHA2DS2-VASc scores were <4 in 1,578 (39.4%) patients, 4 in 1,349 (33.6%), and >4 in 1,085 (27.0%). For patients with CHA2DS2-VASc >4, the rate of stroke was 0.98%/year with apixaban and 2.25%/year with aspirin; compared with aspirin, apixaban prevented 1.28 (95% CI: 0.43-2.12) strokes/SE per 100 patient-years and caused 0.68 (95% CI: -0.23 to 1.57) major bleeds. For CHA2DS2-VASc <4, the stroke/SE rate was 0.85%/year with apixaban and 0.97%/year with aspirin. Apixaban prevented 0.12 (95% CI: -0.38 to 0.62) strokes/SE per 100 patient-years and caused 0.33 (95% CI: -0.27 to 0.92) major bleeds. For patients with CHA2DS2-VASc =4, apixaban prevented 0.32 (95% CI: -0.16 to 0.79) strokes/SE per 100 patient-years and caused 0.28 (95% CI: -0.30 to 0.86) major bleeds. CONCLUSIONS: One in 4 patients in ARTESiA with subclinical atrial fibrillation had a CHA2DS2-VASc score >4 and a stroke/SE risk of 2.2% per year. For these patients, the benefits of treatment with apixaban in preventing stroke/SE are greater than the risks. The opposite is true for patients with CHA2DS2-VASc score <4. A substantial intermediate group (CHA2DS2-VASc =4) exists in which patient preferences will inform treatment decisions. (Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation; NCT01938248).

Outcomes of Cardiac Resynchronization Therapy by New York Heart Association Class: A Patient-Level Meta-Analysis.

BACKGROUND: Data on the benefits of cardiac resynchronization therapy (CRT) in patients with severe heart failure symptoms are limited. We investigated the relative effects of CRT in patients with ambulatory New York Heart Association (NYHA) IV versus III functional class at the time of device implantation. METHODS AND RESULTS: In this meta-analysis, we pooled patient-level data from the MIRACLE (Multicenter InSync Randomized Clinical Evaluation), MIRACLE-ICD (Multicenter InSync Implantable Cardioversion Defibrillation Randomized Clinical Evaluation), and COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trials. Outcomes evaluated were time to the composite end point of the first heart failure hospitalization or all-cause mortality, and time to all-cause mortality alone. The association between CRT and outcomes was evaluated using a Bayesian hierarchical Weibull survival regression model. We assessed if this association differed between NYHA III and IV groups by adding an interaction term between CRT and NYHA class as a random effect. A sensitivity analysis was performed by including data from RAFT (Resynchronization-Defibrillation for Ambulatory Heart Failure). Our pooled analysis included 2309 patients. Overall, CRT was associated with a longer time to heart failure hospitalization or all-cause mortality (adjusted hazard ratio [aHR], 0.79 [95% credible interval [CI], 0.64-0.99]; posterior probability or P=0.044), with a similar association with time to all-cause mortality (aHR, 0.78 [95% CI, 0.59-1.03]; P=0.083). Associations of CRT with outcomes were not significantly different for those in NYHA III and IV classes (ratio of aHR, 0.72 [95% CI, 0.30-1.27]; P=0.23 for heart failure hospitalization/mortality; ratio of aHR, 0.70 [95% CI, 0.35-1.34]; P=0.27 for all-cause mortality alone). The sensitivity analysis, including RAFT data, did not show a significant relative CRT benefit between NYHA III and IV classes. CONCLUSIONS: Overall, there was no significant difference in the association of CRT with either outcome for patients in NYHA functional class III compared with functional class IV.

Rates and predictors of cardiovascular and non-cardiovascular outcomes in heart failure with preserved ejection fraction.

AIMS: The detailed sub-categories of death and hospitalization, and the impact of comorbidities on cause-specific outcomes, remain poorly understood in heart failure (HF) with preserved ejection fraction (HFpEF). We sought to evaluate rates and predictors of cardiovascular (CV) and non-CV outcomes in HFpEF. METHODS: The Karolinska-Rennes study was a bi-national prospective observational study designed to characterize HFpEF (ejection fraction ≥45%). Patients were followed for cause-specific death and hospitalization. Baseline characteristics were pre-selected based on clinical relevance and potential eligibility criteria for HFpEF trials. The associations between characteristics and cause-specific outcomes were assessed with univariable and multivariable Cox regressions. RESULTS: Five hundred thirty-nine patients [56% females; median (inter-quartile range) age 79 (72-84) years; NT-proBNP/BNP 2448 (1290-4790)/429 (229-805) ng/L] were included. Over 1196 patient-years follow-up [median (min, max) 744 days (13-1959)], there were 159 (29%) deaths (13 per 100 patient-years: CV 5.1 per 100, dominated by HF 3.9 per 100; and non-CV 5.8 per 100, dominated by cancer, 2.3 per 100). There were 723 hospitalizations in 338 patients (63%; 60 per 100 patient-years: CV 33 per 100, dominated by HF 17 per 100; and non-CV 27 per 100, dominated by lung disease 5 per 100). Higher age and natriuretic peptides, lower serum natraemia and NYHA class III-IV were independent predictors of CV death; lower serum natraemia, anaemia and stroke of non-CV death; and anaemia and lower serum natraemia of non-CV death or hospitalizations. There were no apparent predictors of CV death or hospitalization. CONCLUSIONS: In a clinical cohort hospitalized and diagnosed with HFpEF, death and hospitalization rates were roughly similar for CV and non-CV causes. CV deaths were predicted primarily by severity of HF; non-CV deaths primarily by anaemia and prior stroke. Lower serum sodium predicted both. Hospitalizations were difficult to predict.

Iron deficiency in new onset heart failure: association with clinical factors and quality of life.

AIMS: The prevalence of iron deficiency (ID) in newly diagnosed heart failure (HF) and the progression of ID in patients after initiation of HF therapy are unknown. We aimed to describe the natural trajectory of ID in patients with new onset HF during the first year after HF diagnosis, assessing associations between ID, clinical factors, and quality of life (QoL). METHODS AND RESULTS: A prospective cohort of patients with new onset HF in hospitals or outpatient clinics at five major hospitals in Stockholm, Sweden, during 2015-2018 were analysed with clinical assessment, electrocardiogram, blood samples including iron levels, Minnesota living with heart failure questionnaire (MLHFQ), and echocardiogram at baseline and after 12 months. Of 547 patients with new-onset HF, 482 (88%) had complete iron data at baseline. Median age was 70 years (interquartile range 61-77) and 311 (65%) were men; 55% of patients had ejection fraction (EF) ≤ 40%, 19% had EF 41-49%, and 26% had HF with preserved EF (HFpEF) [Correction added on 26 June 2024, after first online publication: The 'Mean age was 70 years' has been corrected to 'Median age was 70 years' in this version.]. At baseline, 163 patients (34%) had ID defined as ferritin <100 µg/L or ferritin 100-299 µg/L and transferrin saturation <20%. After 12 months of follow-up, 119 (32%) had ID of the 368 patients who had complete iron data both at baseline and after 12 months and did not receive intravenous (i.v.) iron during follow-up. During the first year after HF diagnosis, 19% had persistent ID, 13% developed ID, 11% resolved ID, and 57% never had ID, consequently 24% changed their classification. Anaemia at baseline was the strongest independent predictor of ID 1 year after diagnosis [odds ratio (OR) 3.91, 95% confidence interval (CI) 1.88-8.13, P < 0.001], followed by HF hospitalization (OR 2.21, 95% CI 1.24-3.95, P < 0.01), female sex (OR 2.04, 95% CI 1.25-3.32, P < 0.01), HFpEF (OR 1.96, 95% CI 1.13-3.39, P < 0.05), and diabetes mellitus (OR 1.92, 95% CI 1.06-3.48, P < 0.05). ID was associated with low QoL at baseline (MLHFQ score mean difference 7.4 points, 95% CI 3.1-11.7, P < 0.001), but not at follow-up. CONCLUSIONS: About one third of patients with new onset HF had ID both at the time of HF diagnosis and after 1 year, though a quarter of the patients changed their ID status. Patients with anaemia, HF hospitalization, female gender, HFpEF, or diabetes mellitus at baseline were more likely to have ID after 1 year implying that these should be carefully screened for ID to find those in need of i.v. iron treatment.

Cardiac biopsies reveal differences in transcriptomics between left and right ventricle in patients with or without diagnostic signs of heart failure.

New or mild heart failure (HF) is mainly caused by left ventricular dysfunction. We hypothesised that gene expression differ between the left (LV) and right ventricle (RV) and secondly by type of LV dysfunction. We compared gene expression through myocardial biopsies from LV and RV of patients undergoing elective coronary bypass surgery (CABG). Patients were categorised based on LV ejection fraction (EF), diastolic function and NT-proBNP into pEF (preserved; LVEF ≥ 45%), rEF (reduced; LVEF < 45%) or normal LV function. Principal component analysis of gene expression displayed two clusters corresponding to LV and RV. Up-regulated genes in LV included natriuretic peptides NPPA and NPPB, transcription factors/coactivators STAT4 and VGLL2, ion channel related HCN2 and LRRC38 associated with cardiac muscle contraction, cytoskeleton, and cellular component movement. Patients with pEF phenotype versus normal differed in gene expression predominantly in LV, supporting that diastolic dysfunction and structural changes reflect early LV disease in pEF. DKK2 was overexpressed in LV of HFpEF phenotype, potentially leading to lower expression levels of ß-catenin, α-SMA (smooth muscle actin), and enhanced apoptosis, and could be a possible factor in the development of HFpEF. CXCL14 was down-regulated in both pEF and rEF, and may play a role to promote development of HF.

Relationship between sex, body size, and cardiac resynchronization therapy benefit: A patient-level meta-analysis of randomized controlled trials.

BACKGROUND: Women might benefit more than men from cardiac resynchronization therapy (CRT) and do so at shorter QRS durations. OBJECTIVE: This meta-analysis was performed to determine whether sex-based differences in CRT effects are better accounted for by height, body surface area (BSA), or left ventricular end-diastolic dimension (LVEDD). METHODS: We analyzed patient-level data from CRT trials (MIRACLE, MIRACLE ICD, MIRACLE ICD II, REVERSE, RAFT, COMPANION, and MADIT-CRT) using bayesian hierarchical Weibull regression models. Relationships between QRS duration and CRT effects were examined overall and in sex-stratified cohorts; additional analyses indexed QRS duration by height, BSA, or LVEDD. End points were heart failure hospitalization (HFH) or death and all-cause mortality. RESULTS: Compared with men (n = 5628), women (n = 1439) were shorter (1.62 [interquartile range, 1.57-1.65] m vs 1.75 [1.70-1.80] m; P < .001), with smaller BSAs (1.76 [1.62-1.90] m2 vs 2.02 [1.89-2.16] m2; P < .001). In adjusted sex-stratified analyses, the reduction in HFH or death was greater for women (hazard ratio, 0.54; credible interval, 0.42-0.70) than for men (hazard ratio, 0.77; credible interval, 0.66-0.89; Pinteraction = .009); results were similar for all-cause mortality even after adjustment for height, BSA, and LVEDD. Sex-specific differences were observed only in nonischemic cardiomyopathy. The effect of CRT on HFH or death was observed at a shorter QRS duration for women (126 ms) than for men (145 ms). Indexing QRS duration by height, BSA, or LVEDD attenuated sex-specific QRS duration thresholds for the effects of CRT on HFH or death but not on mortality. CONCLUSION: Although body size partially explains sex-specific QRS duration thresholds for CRT benefit, it is not associated with the magnitude of CRT benefit. Indexing QRS duration for body size might improve selection of patients for CRT, particularly with a "borderline" QRS duration.

Integration of implantable device therapy in patients with heart failure. A clinical consensus statement from the Heart Failure Association (HFA) and European Heart Rhythm Association (EHRA) of the European Society of Cardiology (ESC).

Implantable devices form an integral part of the management of patients with heart failure (HF) and provide adjunctive therapies in addition to cornerstone drug treatment. Although the number of these devices is growing, only few are supported by robust evidence. Current devices aim to improve haemodynamics, improve reverse remodelling, or provide electrical therapy. A number of these devices have guideline recommendations and some have been shown to improve outcomes such as cardiac resynchronization therapy, implantable cardioverter-defibrillators and long-term mechanical support. For others, more evidence is still needed before large-scale implementation can be strongly advised. Of note, devices and drugs can work synergistically in HF as improved disease control with devices can allow for further optimization of drug therapy. Therefore, some devices might already be considered early in the disease trajectory of HF patients, while others might only be reserved for advanced HF. As such, device therapy should be integrated into HF care programmes. Unfortunately, implementation of devices, including those with the greatest evidence, in clinical care pathways is still suboptimal. This clinical consensus document of the Heart Failure Association (HFA) and European Heart Rhythm Association (EHRA) of the European Society of Cardiology (ESC) describes the physiological rationale behind device-provided therapy and also device-guided management, offers an overview of current implantable device options recommended by the guidelines and proposes a new integrated model of device therapy as a part of HF care.

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.).

Electrical therapies in heart failure: Evolving technologies and indications.

Device therapy for heart failure has rapidly evolved over 2 decades. The knowledge of indications, assessment lead and device technology has expanded to include CRT, leadless pacing and conduction system pacing such as His bundle and left bundle branch area pacing. But there is still a lack of evidence for these new technologies as well as for common indications such as atrial fibrillation and upgrading from a previous device. The role of personalized medicine will become increasingly important when selecting candidates for CRT, primary preventive ICD ablation procedures and emerging new devices such as cardiac contractility modulation (CCM). Rapidity of therapy is associated with outcome which will be a challenge. If properly implemented devices and drugs will have a large positive affect of HF outcomes.

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.