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Heart failure (HF) and diabetes mellitus (DM) are burdensome chronic diseases with high lifetime risks and numerous studies indicate associations between HF and DM. The objective of this study was to investigate the direct and indirect costs of HF patients with and without DM.Patients with a first-time diagnosis of HF from 1998 to 2016 were identified through nationwide Danish registries and stratified according to DM status into HF with or without DM. The economic healthcare cost analysis was based on both direct costs, including hospitalization, procedures, medication and indirect costs including social welfare and lost productivity. The economic burden was investigated prior to, at, and following diagnosis of HF. Patients with concomitant HF and DM were younger (median age 74 vs. 77), had more comorbidities and fewer were female as compared to patients with HF but without DM. The socioeconomic burden of concomitant HF and DM compared to HF alone was substantially higher; 45% in direct costs (€16,237 vs. €11,184), 35% in home care costs (€3123 vs. €2320), 8% in social transfer income (€17,257 vs. €15,994) and they had 27% lower income (€10,136 vs. €13,845). The economic burden peaked at year of diagnosis, but the difference became increasingly pronounced in the years following the HF diagnosis.Patients with concomitant HF and DM had a significantly higher economic burden compared to patients with HF but without DM.

PURPOSE: Self-assessed poor health status is associated with increased risk of mortality in several cardiovascular conditions, but has not been investigated in patients with endocarditis. We examined health status and mortality in patients with endocarditis.METHODS: This is a re-specified substudy of the randomized POET endocarditis trial, which included 400 patients. Patients completed the single-question self-assessed health status from the Short-Form 36 questionnaire at time of randomization and were categorized as having poor or non-poor (excellent/very good, good, or fair) health status. Self-assessed health status and all-cause mortality were examined by a Cox regression model.RESULTS: Self-assessed health status was completed by 266 (67%) patients with a mean age of 68.0 years (± 11.8), 54 (20%) were females, and 86 (32%) had one or more major concurrent medical conditions besides endocarditis. The self-assessed health status distribution was poor (n = 21, 8%) and non-poor (n = 245, 92%). The median follow-up was 3.3 years and death occurred in 9 (43%) and 48 (20%) patients reporting poor and non-poor health status, respectively, and mortality rates [mortality/100 person-years, 95% confidence interval (CI)] were 18.1 (95% CI 9.4-34.8) and 5.4 (95% CI 4.1-7.2), i.e., the crude hazard ratio for death was 3.4 (95% CI: 1.7-7.0, p CONCLUSION: Self-assessed poor health status compared with non-poor health status as assessed by a single question was associated with a threefold increased long-term mortality in patients with endocarditis. POET ClinicalTrials.gov number, NCT01375257.TRIAL REGISTRY: POET ClinicalTrials.gov number, NCT01375257.

BACKGROUND: The Partial-Oral versus Intravenous Antibiotic Treatment of Endocarditis Trial (POET) found that partial-oral outpatient treatment was non-inferior to conventional in-hospital intravenous treatment in patients with left-sided infective endocarditis. We examined the impact of treatment strategy on levels of anxiety and depression.METHODS: Patients completed the Hospital Anxiety and Depression Scale (HADS) at randomization, at antibiotic completion, and after month 3 and month 6. Changes in anxiety and depression (each subdimension 0-21, high scores indicating worse) were calculated using a repeated measure analysis of covariance model with primary assessment after 6 months. Change in score of 1.7 represented a minimal clinical important difference (MCID).RESULTS: Among the 400 patients enrolled in the POET trial, 263 (66%) completed HADS at randomization with reassessment rates of 86-87% at the three subsequent timepoints. Patients in the partial-oral group and the intravenous group had similar improvements after 6 months in levels of anxiety (-1.8 versus -1.6, P = 0.62) and depression (-2.1 versus -1.9, P = 0.63), although patients in the partial-oral group had numerically lower levels of anxiety and depression throughout. An improvement in MCID scores after 6 months was reported by 47% versus 45% (p = 0.80) patients for anxiety and by 51% versus 54% (p = 0.70) for depression.CONCLUSION: Patients with endocarditis receiving partial-oral outpatient treatment reported similar significant improvements in anxiety and depression at 6 months, as compared to conventionally treated, but numerically lower levels throughout. These findings support the usefulness of partial-oral treatment.

Aims Prevention of adverse outcomes in individuals with high cholesterol levels may be improved by intensified lipid-lowering treatment (LLT). We studied whether treatment goals of low-density lipoprotein cholesterol (LDL-C) were reached within 1 year from baseline (defined as first LDL-C measurement) in a Danish population. Methods and results Danish registries were used to identify all persons in the Northern Region of Denmark who had LDL-C measured between 1997 and 2012 and who were naïve to LLT. Patients were categorized in LDL-C Conclusion Less than half of patients presenting with an LDL-C ≥5 mmol/L start LLT within 1 year, representing a missed opportunity for both primary and secondary prevention of CV disease.

AimTo determine the risk of adverse outcomes across the spectrum of glycated haemoglobin (HbA1c) levels among hospitalized COVID-19 patients with and without diabetes.Materials and methodsDanish nationwide registries were used to study the association between HbA1c levels and 30-day risk of all-cause mortality and the composite of severe COVID-19 infection, intensive care unit (ICU) admission and all-cause mortality. The study population comprised patients hospitalized with COVID-19 (3 March 2020 to 31 December 2020) with a positive polymerase chain reaction (PCR) test and an available HbA1c ≤ 6 months before the first positive PCR test. All patients had at least 30 days of follow-up. Among patients with diabetes, HbA1c was categorized as 64 mmol/mol. Among patients without diabetes, HbA1c was stratified into ResultsWe identified 3295 hospitalized COVID-19 patients with an available HbA1c (56.2% male, median age 73.9 years), of whom 35.8% had diabetes. The median HbA1c was 54 and 37 mmol/mol among patients with and without diabetes, respectively. Among patients with diabetes, the standardized absolute risk difference of the composite outcome was higher with HbA1c 64 mmol/mol (15.1% [95% CI 6.2% to 24.0%]), compared with HbA1c 59 to 64 mmol/mol (reference). Among patients without diabetes, the standardized absolute risk difference of the composite outcome was greater with HbA1c ConclusionsPatients with COVID-19 and HbA1c 64 mmol/mol had a higher associated risk of the composite outcome. Similarly, among patients without diabetes, varying HbA1c levels were associated with higher risk of the composite outcome.

Background Heart failure (HF) imposes a large burden on both the individual and the society. The aim of this study was to investigate the economic burden (either direct or indirect costs) attributed to patients with HF before, at, and after time of diagnosis. Methods and results Using Danish nationwide registries we identified all patients > 18 years with a first-time diagnosis of HF from 1998-2016 and matched them 1:1 with a control group from the background population on age, gender, marital status, and educational level. The economic analysis of the total costs after diagnosis was based on direct costs including hospitalization, procedures, medication, and indirect costs including social welfare and lost productivity to estimate the annual cost of HF. A total of 176 067 HF patients with a median age of 76 (interquartile range 67-84) years and 55% male were included. Patients with HF incurred an average of €17 039 in total annual direct (€11 926) and indirect (€5113) healthcare costs peaking at year of diagnosis compared to €5936 in the control group with the majority attributable to inpatient admissions. The total annual net costs including public transfer after index HF were €11 957 higher in patients with HF compared to controls and the economic consequences were evident more than 2 years prior to the diagnosis of HF. Conclusion Patients with HF impose significantly higher total annual healthcare costs compared to a matched control group with findings evident more than 2 years prior to HF diagnosis.

Type 1 diabetes is associated with increased cardiovascular (CV) morbidity and mortality, and cardiovascular autonomic neuropathy (CAN) is an important CV risk factor. The study aimed to explore associations between CAN and altered cardiac chamber sizes in persons with type 1 diabetes.This was a cross-sectional study of 71 asymptomatic, normoalbuminuric participants with long-term type 1 diabetes (39 with CAN, determined by1 abnormal autonomic function test) examined with cardiac multi detector computed tomography scans, which allowed measurements of left ventricular mass and all four cardiac chamber volumes. Cardiac chambers were indexed according to body surface area (ml/mPersons with and without CAN had mean ± SD age of 57 ± 7 and 50 ± 8 years (p 0.001) and diabetes duration of 36 ± 11 and 32 ± 9 years (p 0.05), respectively. Increasing autonomic dysfunction, evaluated by decrease in heart rate variability during deep breathing (in beats per minute), was associated with larger right (-0.5, 95% CI -1.0 to -0.0, p 0.05) and trend towards larger left (-0.4, 95% CI -0.8-0.0, p 0.1) ventricular volumes in multivariable linear regression.Our results suggest that impaired autonomic function may be associated with modest enlargement of ventricular volumes; this might be an early sign of progression towards heart failure.

Background: Heart failure (HF) trials initiated in the last century highlighted many differences between men and women. Of particular concern was undertreatment of women compared with men, but much has changed during the past 20 years.\ud \ud Objectives: This study sought to identify these changes, which may give a new perspective on the management of, and outcomes in, women with HF.\ud \ud Methods: The study analyzed 12,058 men and 3,357 women enrolled in 2 large HF with reduced ejection fraction (HFrEF) trials with near identical inclusion and exclusion criteria and the same principal outcomes. Outcomes were adjusted for other prognostic variables including N-terminal pro–B-type natriuretic peptide.\ud \ud Results: Women were older and more often obese than men were, had slightly higher systolic blood pressure and heart rate, and were less likely to have most comorbidities, except hypertension. Women had more symptoms and signs (e.g., pedal edema 23.4% vs 19.9%; p < 0.0001) and worse quality of life—median Kansas City Cardiomyopathy Questionnaire Clinical Summary Score 71.3 (interquartile range: 53.4 to 86.5) versus 81.3 (interquartile range: 65.1 to 92.7; p < 0.0001)—despite similar left ventricular ejection fraction and N-terminal pro–B-type natriuretic peptide. However, women had lower mortality (adjusted hazard ratio: 0.68; 95% confidence interval: 0.62 to 0.74; p < 0.001) and risk of HF hospitalization (hazard ratio: 0.80; 95% confidence interval: 0.72 to 0.89; p < 0.001). Diuretics and anticoagulants were underutilized in women. Device therapy was underused in both men and women, but more so in women (e.g., defibrillator 8.6% vs. 16.6%; p < 0.0001).\ud \ud Conclusions: Although women with HFrEF live longer than men, their additional years of life are of poorer quality, with greater self-reported psychological and physical disability. The explanation for this different sex-related experience of HFrEF is unknown as is whether physicians recognize it. Women continue to receive suboptimal treatment, compared with men, with no obvious explanation for this shortfall.

Background Although randomized clinical trials have shown that implantable cardioverter defibrillators (ICDs) reduce mortality in selected patients, patients on dialysis are excluded from these trials. Thus, data on mortality risk after ICD implantation in these patients are sparse. Purpose To examine all-cause mortality in patients receiving an ICD according to dialysis status and to identify factors associated with all-cause mortality in patients on dialysis. Methods Using Danish nationwide registries from 2000–2017, all patients ≥18 years old undergoing first-time ICD implantation were included. Patients on dialysis were identified prior to ICD implantation and followed for up to five years. The cumulative incidence of all-cause mortality according to dialysis status was assessed. Factors associated with all-cause mortality after ICD implantation in dialysis patients were examined using multivariable Cox proportional hazard regression. Results A total of 14,681 ICD patients were identified, of which 218 (1.5%) were on dialysis prior to ICD implantation. Compared with ICD patients not on dialysis, those on dialysis were younger (median age 64 years [IQR: 58–70] vs. 66 years [IQR: 57–72], p=0.02), more likely to receive an ICD for secondary prophylaxis (69.7% vs 53.7%), and had more comorbidities including ischaemic heart disease (60.6% vs. 46.3%), diabetes (28.4% vs. 20.4%), and peripheral vascular disease (10.1% vs. 5.6%) (p for all The median time to death among ICD patients on dialysis and not on dialysis were 1.3 years (IQR: 0.4–2.8 years] and 2.2 years [IQR: 1.0–3.5 years], respectively. One-year mortality among ICD patients on dialysis (13.0%) was significantly higher compared with ICD patients not on dialysis (4.7%), p Factors associated with increased risk of all-cause mortality among ICD patients on dialysis were age ≥65 years at time of implantation (reference: age 0.05 for all). Cardiovascular causes of death were common both in patients with- and without dialysis, 69.6% and 60.0%, respectively. Conclusion Five-year mortality in ICD patients on dialysis was 42% and twice as high compared with ICD patients not on dialysis. Age ≥65 years, primary prophylactic indication, and diabetes were factors associated with increased mortality. Careful evaluation of the potential benefit from an ICD implantation in dialysis patients is important considering the overall high mortality rates. Funding Acknowledgement Type of funding source: None

Background Current guidelines do not recommend implantable cardioverter defibrillator (ICD) implantation in patients with an estimated survival probability of less than one year. There is still an unmet need to identify patients who are unlikely to benefit from an ICD. Purpose We determined one-year mortality after ICD implantation and associated risk factors of one-year mortality. Methods Using Danish nationwide registries from 2000–2016, we identified patients ≥18 years old undergoing first-time ICD implantation for primary or secondary prevention. Patients were followed for up to one-year from time of ICD implantation. Risk factors associated with one-year mortality after time of ICD implantation were evaluated in multivariable logistic regression models. Results A total of 13,344 patients underwent first-time ICD implantation (median age: 66 years [25th-75th percentile 58–72 years], male=81.3%, secondary prevention=54.6%), of which 647 died (4.8%) within one year of follow-up. Compared with ICD patients who survived for one year, those who died were significantly older (72 years vs. 66 years, p Results from the multivariable logistic regression model are depicted in the Figure. There was a graded relationship between age and one-year mortality, with a greater risk of all-cause mortality with increasing age. In addition, dialysis, chronic renal disease, COPD, malignancy, diabetes, and congestive heart failure were strongly associated with increased risk of one-year all-cause mortality. However, ischaemic heart disease was associated with a lower risk of all-cause mortality (Figure). The one-year risk of death was 13.2% for both patients receiving dialysis and patients with chronic renal disease, respectively. The majority of deaths within one year were attributed to cardiovascular causes (408/647, 63.1%) of which chronic ischaemic heart disease (68/647, 10.5%), acute myocardial infarction (50/647, 7.7%), and atherosclerosis (40/647, 6.2%) were the most common. The most common non-cardiovascular cause of death was malignancy (10.5%). Conclusion In patients with a first-time ICD implantation, 95% survived for more than one year after implantation. While low mortality rates are indicative of relevant patient selection for ICD implantation, advanced age, dialysis, and several comorbidities were all strongly associated with increased one-year mortality, whereas ischaemic heart disease was associated with a lower risk of one-year mortality. Potential benefit of an ICD in such patients should be carefully evaluated before implantation. Funding Acknowledgement Type of funding source: None

Objective To examine the gradual association between self-reported health status and mortality in patients with heart failure (HF) as current research has focused on poor health status and increased risk of mortality. Method This is a substudy of the DANISH (Defibrillator Implantation in Patients with Nonischemic Systolic HF) trial in which 1116 patients were randomized to receive or not receive an implantable cardioverter-defibrillator. Health status was assessed by a single question of the Short-Form 36. Patients were classified as having excellent/very good, good, fair (reference) or poor health status. We assessed the association between health status and mortality using multivariable Cox proportional hazard models. Results Self-reported health status was completed by 943 (84%) patients at randomization with a median follow-up of 67 months and a health status distribution of; excellent/very good (n = 79, 8%), good (n = 369, 39%), fair (n = 409, 43%), and poor (n = 86, 9%). All-cause mortality (death events/ 100 person-years) occurred with gradual differences according to health status from excellent/ very good (2.14), good (3.74), fair (5.21) to poor health status (5.57). The gradual difference yielded a crude hazard ratio (HR) of 0.40, 95% CI 0.20–0.80 (adjusted HR 0.47 (95% CI 0.23–0.95) for excellent/ very good health status, HR 0.71, 95% CI 0.52–0.97 (adjusted HR 0.78 (95% CI 0.56–1.08) for good health status. Poor being worse than fair health status yielded a crude HR of 1.07, 95% CI 0.67–1.69. Conclusion Excellent/very good self-reported health status as assessed by a single question was associated with lower long-term mortality in patients with HF.

Aims: The associations between potassium level and outcomes, the effect of sacubitril–valsartan on potassium level, and whether potassium level modified the effect of sacubitril–valsartan in patients with heart failure and a reduced ejection fraction were studied in PARADIGM‐HF. Several outcomes, including cardiovascular death, sudden death, pump failure death, non‐cardiovascular death and heart failure hospitalization, were examined. Methods and results: A total of 8399 patients were randomized to either enalapril or sacubitril–valsartan. Potassium level at randomization and follow‐up was examined as a continuous and categorical variable (≤3.5, 3.6–4.0, 4.1–4.9, 5.0–5.4 and ≥5.5 mmol/L) in various statistical models. Hyperkalaemia was defined as K+ ≥5.5 mmol/L and hypokalaemia as K+ ≤3.5 mmol/L. Compared with potassium 4.1–4.9 mmol/L, both hypokalaemia [hazard ratio (HR) 2.40, 95% confidence interval (CI) 1.84–3.14] and hyperkalaemia (HR 1.42, 95% CI 1.10–1.83) were associated with a higher risk for cardiovascular death. However, potassium abnormalities were similarly associated with sudden death and pump failure death, as well as non‐cardiovascular death and heart failure hospitalization. Sacubitril–valsartan had no effect on potassium overall. The benefit of sacubitril–valsartan over enalapril was consistent across the range of baseline potassium levels. Conclusions: Although both higher and lower potassium levels were independent predictors of cardiovascular death, potassium abnormalities may mainly be markers rather than mediators of risk for death.

Aims Current treatment guidelines recommend implantable cardioverter-defibrillators (ICDs) in eligible patients with an estimated survival beyond 1 year. There is still an unmet need to identify patients who are unlikely to benefit from an ICD. We determined cause-specific 1-year mortality after ICD implantation and identified associated risk factors. Methods and results Using Danish nationwide registries (2000–2017), we identified 14 516 patients undergoing first-time ICD implantation for primary or secondary prevention. Risk factors associated with 1-year mortality were evaluated using multivariable logistic regression. The median age was 66 years, 81.3% were male, and 50.3% received an ICD for secondary prevention. The 1-year mortality rate was 4.8% (694/14 516). ICD recipients who died within 1 year were older and more comorbid compared to those who survived (72 vs. 66 years, P < 0.001). Risk factors associated with increased 1-year mortality included dialysis [odds ratio (OR): 3.26, confidence interval (CI): 2.37–4.49], chronic renal disease (OR: 2.14, CI: 1.66–2.76), cancer (OR: 1.51, CI: 1.15–1.99), age 70–79 years (OR: 1.65, CI: 1.36–2.01), and age ≥80 years (OR: 2.84, CI: 2.15–3.77). The 1-year mortality rates for the specific risk factors were: dialysis (13.8%), chronic renal disease (13.1%), cancer (8.5%), age 70–79 years (6.9%), and age ≥80 years (11.0%). Overall, the most common causes of mortality were related to cardiovascular diseases (62.5%), cancer (10.1%), and endocrine disorders (5.0%). However, the most common cause of death among patients with cancer was cancer-related (45.7%). Conclusion Among ICD recipients, mortality rates were low and could be indicative of relevant patient selection. Important risk factors of increased 1-year mortality included dialysis, chronic renal disease, cancer, and advanced age.

Background In randomised clinical trials, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium–glucose cotransporter 2 (SGLT-2) inhibitors reduced cardiovascular events in patients with type 2 diabetes (T2D) at high cardiovascular risk, as compared to standard care. However, data comparing these agents in patients with T2D who are at moderate risk is sparse. Methods From Danish national registries, we included patients with T2D previously on metformin monotherapy, who started an additional glucose-lowering agent [GLP-1 RA, SGLT-2 inhibitor, dipeptidyl peptidase-4 (DPP-4) inhibitor, sulfonylurea (SU), or insulin] in the period 2010-2016. Patients with a history of cardiovascular events [heart failure (HF), myocardial infarction (MI) or stroke] were excluded. Patients were followed for up to 2 years. Cause-specific adjusted Cox regression models were used to compare the risk of hospitalisation for HF, a composite endpoint of major adverse cardiovascular events (MACE) (MI, stroke or cardiovascular death), and all-cause mortality for each add-on therapy. Patients who initiated DPP-4 inhibitors were used as reference. Results The study included 46,986 T2D patients with a median age of 61 years and of which 59% were male. The median duration of metformin monotherapy prior to study inclusion was 5.3 years. Add-on therapy was distributed as follows: 13,148 (28%) GLP-1 RAs, 2343 (5%) SGLT-2 inhibitors, 15,426 (33%) DPP-4 inhibitors, 8917 (19%) SUs, and 7152 (15%) insulin. During follow-up, 623 (1.3%, range 0.8-2.1%) patients were hospitalised for HF—hazard ratios (HR) were 1.11 (95% CI 0.89–1.39) for GLP-1 RA, 0.84 (0.52–1.36) for SGLT-2 inhibitors, 0.98 (0.77–1.26) for SU and 1.54 (1.25–1.91) for insulin. The composite MACE endpoint occurred in 1196 (2.5%, range 1.5–3.6%) patients, yielding HRs of 0.82 (0.69–0.97) for GLP-1 RAs, 0.79 (0.56–1.12) for SGLT-2 inhibitors, 1.22 (1.03–1.49) for SU and 1.23 (1.07–1.47) for insulin. 1865 (3.9%, range 1.9–9.0%) died from any cause during follow-up. HRs for all-cause mortality were 0.91 (0.78–1.05) for GLP-1 RAs, 0.79 (0.58–1.07) for SGLT-2 inhibitors, 1.13 (0.99–1.31) for SU and 2.33 (2.08–2.61) for insulin. Conclusion In a nationwide cohort of metformin-treated T2D patients and no history of cardiovascular events, the addition of either GLP-1 RA or SGLT-2 inhibitor to metformin treatment was associated with a similar risk of hospitalisation for HF and death, and a lower risk of MACE for GLP-1 RA when compared with add-on DPP-4 inhibitors. By contrast, initiation of treatment with SU and insulin were associated with a higher risk of MACE. Additionally, insulin was associated with an increased risk of all-cause mortality and hospitalisation for HF.

Aims Recurrent hospitalizations are a major part of the disease burden in heart failure (HF), but conventional analyses consider only the first event. We compared the effect of sacubitril/valsartan vs. enalapril on recurrent events, incorporating all HF hospitalizations and cardiovascular (CV) deaths in PARADIGM-HF, using a variety of statistical approaches advocated for this type of analysis. Methods and results In PARADIGM-HF, a total of 8399 patients were randomized and followed for a median of 27 months. We applied various recurrent event analyses, including a negative binomial model, the Wei, Lin and Weissfeld (WLW), and Lin, Wei, Ying and Yang (LWYY) methods, and a joint frailty model, all adjusted for treatment and region. Among a total of 3181 primary endpoint events (including 1251 CV deaths) during the trial, only 2031 (63.8%) were first events (836 CV deaths). Among a total of 1195 patients with at least one HF hospitalization, 410 (34%) had at least one further HF hospitalization. Sacubitril/valsartan compared with enalapril reduced the risk of recurrent HF hospitalization using the negative binomial model [rate ratio (RR) 0.77, 95% confidence interval (CI) 0.67-0.89], the WLW method [hazard ratio (HR) 0.79, 95% CI 0.71-0.89], the LWYY method (RR 0.78, 95% CI 0.68-0.90), and the joint frailty model (HR 0.75, 95% CI 0.66-0.86) (all P Conclusions In PARADIGM-HF, approximately one third of patients with a primary endpoint (time-to-first) experienced a further event. Compared with enalapril, sacubitril/valsartan reduced both first and recurrent events. The treatment effect size was similar, regardless of the statistical approach applied.

Aims: Elevated serum uric acid concentration (SUA) has been associated with an increased risk of cardiovascular disease, but this may be due to unmeasured confounders. We examined the association between SUA and outcomes as well as the effect of sacubitril/valsartan on SUA in patients with heart failure with reduced ejection fraction (HFrEF) in PARADIGM-HF. Methods and results: The association between SUA and the primary composite outcome of cardiovascular death or heart failure (HF) hospitalization, its components, and all-cause mortality was examined using Cox regression analyses among 8213 patients using quintiles (Q1–Q5) of SUA adjusted for baseline prognostic variables including estimated glomerular filtration rate (eGFR), diuretic dose, and log N-terminal pro-brain natriuretic peptide. Change in SUA from baseline over 12 months was also evaluated in each treatment group. Patients in Q5 (SUA ≥8.6 mg/dL) compared with Q1 (

Aims: Employment status at time of first heart failure (HF) hospitalization may be an indicator of both self‐perceived and objective health status. In this study, we examined the association between employment status and the risk of all‐cause mortality and recurrent HF hospitalization in a nationwide cohort of patients with HF. Methods and results: We identified all patients of working age (18–60 years) with a first HF hospitalization in the period 1997–2015 in Denmark, categorized according to whether or not they were part of the workforce at time of the index admission. The primary outcome was death from any cause and the secondary outcome was readmission for HF. Cumulative incidence curves, binomial regression and Cox regression models were used to assess outcomes. Of 25 571 patients with a first hospitalization for HF, 15 428 (60%) were part of the workforce at baseline. Patients in the workforce were significantly younger (53 vs. 55 years) more likely to be male (75% vs 64%) and less likely to have diabetes (13% vs 22%) and chronic obstructive pulmonary disease (5% vs 10%) (all P < 0.0001). Not being part of the workforce was associated with a significantly higher risk of death [hazard ratio (HR) 1.59; 95% confidence interval (CI) 1.50–1.68] and rehospitalization for HF (HR 1.09; 95% CI 1.05–1.14), in analyses adjusted for age, sex, co‐morbidities, education level, calendar time, and duration of first HF hospitalization. Conclusion: Not being part of the workforce at time of first HF hospitalization was independently associated with increased mortality and recurrent HF hospitalization.

Aims Because of concerns about the safety of aliskiren in patients with diabetes, study treatment was stopped prematurely in the Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failuRE (ATMOSPHERE). We examined outcomes and treatment effect in these patients compared with those without diabetes. Methods and results ATMOSPHERE included 7016 patients with heart failure and a reduced ejection fraction (HFrEF) randomly assigned to enalapril plus aliskiren, aliskiren alone, or enalapril. At baseline, 1944 (27.7%) patients had diabetes. Median follow-up was shorter in patients with diabetes compared with those without (24 months vs. 46 months). Among patients with diabetes, the primary endpoint of cardiovascular death or hospitalization for heart failure occurred in 216 patients (33.1%) in the enalapril group (reference), 172 (27.4%) in the aliskiren group [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.67–1.00; P = 0.053], and 196 (29.5%) in the combination group (HR 0.86, 95% CI 0.71–1.04; P = 0.13). The effects of the treatments studied did not differ significantly compared with patients without diabetes. In patients with diabetes, aliskiren monotherapy was associated with a lower risk of symptomatic hypotension compared to enalapril [42 (6.7%) vs. 65 (10.0%); P = 0.04], whereas other adverse events were generally balanced between the three groups. Conclusion In patients with HFrEF and diabetes, there was no signal of harm and a trend towards benefit when direct renin inhibition monotherapy was compared with an angiotensin-converting enzyme inhibitor, whereas combined aliskiren and enalapril treatment led to more adverse events with no improvement in outcomes. Treatment effects did not differ in patients with diabetes compared with those without. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00853658.

PURPOSE: The "distressed" (Type D) personality trait has been reported to be over-represented in patients with heart failure (HF) compared to the background population and may provide prognostic information for mortality. We examined the association between Type D personality and outcomes in the DANISH trial (The Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators in Patients with Non-ischemic Systolic Heart Failure on Mortality).METHODS: The DANISH trial included a total of 1116 patients with non-ischemic HF on guideline-recommended therapy. Type D personality was assessed with the Type D Scale (DS14) at baseline and investigated through follow-up accordingly. Multivariable Cox proportional hazard models were used to compare hazard ratios (HR) of cardiovascular and all-cause mortality.RESULTS: Type D personality assessment was completed by 873 (78%) patients at baseline and Type D personality was found in 120 (14%) patients. The median follow-up was 67 months (interquartile range [IQR] 48-83). Among patients with versus without Type D personality, 22% versus 19% died from all-cause yielding similar incidence rates of 4.62 (95% CI 3.14-6.87) versus 3.95 (95% CI 3.37-4.66) per 100 person-years. The adjusted risk of all-cause mortality was not significantly different in patients with versus without Type D personality with an adjusted HR of 1.31 (95% CI 0.84-2.03, p = 0.23) with similar results for cardiovascular death (HR 1.46 (95% CI 0.88-2.44, p = 0.15).CONCLUSION: Type D personality was not significantly associated with increased risk of all-cause mortality or cardiovascular death in patients with non-ischemic HF.

Background Heart failure (HF) imposes a large burden on the individual as well as society and the aim of this study was to investigate the economic burden attributed to direct and indirect costs of patients with HF before, at, and after time of diagnosis. Methods Using Danish nationwide registries we identified all patients >18 years with a first-time diagnosis of HF from 1998–2016 and matched them 1:1 with a control group from the background population on age, gender, marital status, and educational level. The economic analysis of the total costs after diagnosis was based on direct costs including hospitalization, procedures, medication, and indirect costs including social welfare and lost productivity to estimate the annual cost of HF. Results We included a total of 176,067 HF patients with a median age of 76 years, and 55% were male. Patients with HF incurred an average of €17,039 in sum of total annual direct (€11,926) and indirect (€5,113) health-care costs peaking at year of diagnosis compared to €5,936 in the control group with the majorityattributable to inpatient admissions. The total annual net costs including social transfer after index HF were €11,957 higher in patients with HF compared to controls and the economic consequences increased markedly 2 years prior to the diagnosis of HF (Figure 1). Conclusion Patients with HF impose significantly higher total annual health-care costs compared to a matched control group with findings evident more than 2 years prior to HF diagnosis Acknowledgement/Funding Novartis

Background Heart failure (HF) imposes a major economic burden, however the individual management for patients vary potentially leading to large cost heterogeneity. The aim of this study was to investigate the total direct health cost stratified across the spectrum of cost groups. Methods Using Danish nationwide registries from 2012 to 2015 we identified all patients >18 years with a first-time diagnosis of HF. Total health costs were investigated using two perspectives; at index and after 3 years (including index). We investigated the cost of patients in the highest cost group (highest 10%) vs. the lowest cost group (lowest 10%). A multivariable logistic regression was used to identify variables associated with being in the highest cost decile compared to the rest (90%). Results A total of 11,170 patients with HF were included and those in the highest cost decile (n=1,117, 10%) were younger (69 vs. 75 years), more males (43 vs. 34%), and more inpatients (83 vs. 70%) compared to the rest of the patients (n=10,053, 90%). Patients in the highest cost decile (10%) incurred a 30 times higher cost with a mean total health cost in index year of €86,607 compared to €2,893 for patients in lowest cost decile (10%) (Figure 1A). Results were similar for 3 years aggregated (€139,473 vs. €4,086), corresponding to a 34 times higher cost. At index year, variables associated with being in the highest cost decile included young age, male sex, inpatient admittance, renal disease, and several other comorbidities (Figure 1B). Conclusion Among patients with HF a large total direct health cost heterogeneity exists with younger age, inpatient admittance, male sex, and comorbidities being associated with a higher likelihood of belonging to the highest cost group. Acknowledgement/Funding Novartis

BACKGROUND: Prevalent diabetes at the time of heart failure (HF) diagnosis is associated with a higher risk of death, but the incidence and prognostic importance of new-onset diabetes in patients with established HF remains unknown.METHODS: Patients with a first hospitalization for HF in the period 2003-2014 were included and stratified according to history of diabetes. Annual incidence rates of new-onset diabetes were calculated and time-dependent multivariable Cox regression models were used to compare the risk of death in patients with prevalent and new-onset diabetes with patients without diabetes as reference. The model was adjusted for age, sex, duration of HF, educational level and comorbidity. Covariates were continuously updated throughout follow-up.RESULTS: A total of 104,522 HF patients were included in the study, of which 21,216 (19%) patients had diabetes at baseline, and 8164 (10%) developed new-onset diabetes during a mean follow-up of 3.9 years. Patients with new-onset diabetes and prevalent diabetes were slightly younger than patients without diabetes (70 vs. 74 and 77, respectively), more likely to be men (62% vs. 60% and 54%), and had more comorbidities expect for ischemic heart disease, hypertension and chronic kidney disease which were more prevalent among patients with prevalent diabetes. Incidence rates of new-onset diabetes increased from around 2 per 100 person-years in the first years following HF hospitalization up to 3 per 100 person-years after 5 years of follow-up. A total of 61,424 (59%) patients died during the study period with event rates per 100 person-years of 21.5 for new-onset diabetes, 17.9 for prevalent diabetes and 13.9 for patients without diabetes. Compared to patients without diabetes, new-onset diabetes was associated with a higher risk of death (adjusted HR 1.47; 95% CI 1.42-1.52) and prevalent diabetes was associated with an intermediate risk (HR 1.19; 95% CI, 1.16-1.21).CONCLUSION: Following the first HF hospitalization, the incidence of new-onset diabetes was around 2% per year, rising to 3% after 5 years of follow-up. New-onset diabetes was associated with an increased risk of death, compared to HF patients with prevalent diabetes (intermediate risk) and HF patients without diabetes.

AIM: The Danish Study to Assess the Efficacy of Implantable Cardioverter-Defibrillators (ICD) in Patients with Non-ischaemic Systolic Heart Failure (HF) on Mortality (DANISH) found no overall effect on all-cause mortality. The effect of ICD implantation on health-related quality of life (HRQoL) remains to be established as previous trials have demonstrated conflicting results. We investigated the impact of ICD implantation on HRQoL in patients with non-ischaemic systolic HF, a prespecified secondary endpoint in DANISH.METHODS AND RESULTS: In DANISH, a total of 1116 patients with non-ischaemic systolic HF were randomly assigned (1:1) to ICD implantation or usual clinical care (control). Patients completed disease-specific HRQoL as assessed by Minnesota Living with Heart Failure Questionnaire (MLHFQ; 0-105, high indicating worse). Changes in HRQoL 8 months after randomization were assessed with a mixed-effects model. At randomization, MLHFQ was completed by 935 (84%) patients (n = 472 in the ICD group and n = 463 in the control group) and was reassessed in 274 (58%) and 292 (63%) patients, respectively after 8 months for the primary analysis. Patients in the ICD group vs. the control group had similar improvements in MLHFQ after 8 months [least square mean -7.0 vs. -4.2 (P = 0.13)]. A clinically relevant improvement (decrease ≥5) in the MLHFQ overall score at 8 months was observed in 151 patients in the ICD group and 148 patients in the control group [55% vs. 51%, respectively (P = 0.25)].CONCLUSION: Implantable cardioverter-defibrillator implantation in patients with non-ischaemic systolic HF did not significantly alter HRQoL compared with patients randomized to usual clinical care.

Background NT-proBNP (N-terminal pro-B-type natriuretic peptide) is useful in diagnosis and prognostication in heart failure (HF). We examined the relationship between NT-proBNP and outcomes in patients with HF and preserved ejection fraction, with and without atrial fibrillation (AF). Methods and Results Among 3835 HF with preserved ejection fraction patients enrolled in the I-Preserve (Irbesartan in Heart Failure With Preserved Systolic Function trial) or TOPCAT trial (Treatment of Preserved Cardiac Function in Heart Failure With an Aldosterone Antagonist), 719 (19%) patients had AF on their baseline ECG. Median (Q1–Q3) levels of NT-proBNP were 1286 pg/mL (778–2072) in those with AF and 288 pg/mL (122–704) in those without ( P Conclusions Event rates in HF with preserved ejection fraction patients without AF and with NT-proBNP Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifiers: NCT00094302 and NCT00095238.

Background Long duration of diabetes mellitus (DM) is associated with an increased risk of infection, however no studies have yet focused on the duration of DM and the associated risk of infective endocarditis (IE). Methods Patients with DM were identified through the Danish Prescription Registry, 1996–2015. Duration of DM was split in follow-up periods of: 0–5 years, 5–10 years, 10–15 years, and >15 years. Multivariable adjusted Poisson regression was used to calculate incidence rate ratios (IRR) according to study groups. DM late-stage complications and the associated risk of IE were investigated as time-varying covariates using the validated Diabetes Complications Severity Index (DCSI). Results We included 299,551 patients with DM. In patients with DM duration of 0–5 years, 5–10 years, 10–15 years, and >15 years, the incidence rates of IE were 0.24, 0.33, 0.58, and 0.96 cases of IE/1000 person years, respectively. Patients with DM duration 5–10 years, 10–15 years, and >15 years were associated with a higher risk of IE with an IRR of 1.24 (95% CI: 1.02–1.51), 1.92 (95% CI: 1.52–2.43) and 3.05 (95% CI: 2.11–4.40), respectively, compared with DM duration 0–5 years. Patients with a DCSI score of 2, 3 and >3 were associated with a higher risk of IE compared with patients with a DCSI score of 0, IRR = 1.78 (95% CI: 1.34–2.36), IRR = 2.34 (95% CI: 1.73–3.16), and IRR = 2.59 (95% CI: 1.92–3.48), respectively. Conclusion This study shows a stepwise increase in the risk of IE with DM duration and severity independent of age and known comorbidity.

Aims: Type 1 diabetes entails increased cardiovascular morbidity and cardiac chamber sizes are associated with cardiovascular disease. The aim of this study was to compare cardiac chamber sizes in normoalbuminuric persons with type 1 diabetes to a background population without diabetes. Methods: In a cross-sectional study, we examined 71 normoalbuminuric persons with long-term type 1 diabetes without known cardiovascular disease using cardiac multi-detector computed tomography. Cardiac chamber sizes and left ventricular remodelling were compared to persons without diabetes from the Copenhagen General Population Study. Results: Participants were median (interquartile range) 54 (48–60) (type 1 diabetes) and 57 (50–64) (without diabetes) years old and 59% were men (both groups). Participants with type 1 diabetes had smaller left ventricular mass (−3.5 g/m2, 95% confidence interval −5.8 to −1.3) and left (−4.0 mL/m2, 95% confidence interval −6.9 to −1.0) and right (−11.7 mL/m2, 95% confidence interval −15.4 to −7.9) ventricular volumes in multivariable analyses (adjusted for age, sex, body composition, blood pressure and antihypertensive medication), but no differences in atrial volumes. Conclusion: Persons with long-term type 1 diabetes had smaller left ventricular mass and biventricular volumes, yet similar atrial sizes, compared to a background population without diabetes. These findings may reflect subclinical development of diabetic cardiomyopathy.

AIMS: Familial hypercholesterolemia (FH) is a common genetic disorder causing accelerated atherosclerosis and premature cardiovascular disease. The aim of this study was to examine the prevalence and prognostic significance of possible FH in patients with myocardial infarction (MI).METHODS AND RESULTS: By individual-level linkage of data from the Eastern Danish Heart Registry and national administrative registries, a study population of patients referred for coronary angiography due to MI was selected. The study population was divided into "unlikely FH" and "possible FH" based on the Dutch Lipid Clinic Network criteria, which included a plasma low-density lipoprotein cholesterol (LDL-C) and age for onset of cardiac disease. A score of ≥3 points was used as the cutpoint between the 2 groups. Among the study population of 13,174 MI patients, 1,281 (9.7%) had possible FH. These patients were younger (59.1 vs 65.7 years, P ≤ .0001), had similar levels of comorbidities, and were treated more aggressively with cholesterol-lowering drugs compared with patients with unlikely FH. During a median of 3.3 years of follow-up, the unadjusted and adjusted event rates of recurrent MI were higher in patients with possible FH compared with unlikely FH (16% vs 11%, adjusted hazard ratio 1.28, 95% CI 1.09-1.51, P = .003.). Differences in adjusted all-cause mortality were not statistically significant (17% vs 23%, adjusted hazard ratio 0.89 [0.74-1.04], P = .1).CONCLUSION: We found that MI patients with possible FH have higher risk of recurrent MI but similar risk of mortality compared with unlikely FH patients. Further studies on secondary prevention are warranted.

Type 1 diabetes is associated with increased risk of cardiovascular disease and the diabetic complication cardiovascular autonomic neuropathy in itself entails increased cardiovascular risk by mechanisms not yet fully understood. Arterial calcification is an important predictor of cardiovascular events; the aim of this study was to investigate the level of generalised arterial calcification in patients with long-term, normoalbuminuric type 1 diabetes and the association with cardiovascular autonomic neuropathy, as these factors have not been investigated in type 1 diabetes.Participants were examined for calcification of coronary and carotid arteries through non-contrast multi-detector computed tomography scans. Generalised arterial calcification was defined as the presence of calcium in both the coronary and carotid arteries.A total of 53 patients with type 1 diabetes were included. Coronary and carotid artery calcium scores were correlated ( r = 0.720, p 0.0001). Cardiovascular autonomic neuropathy was associated with increased coronary ( p = 0.002) and carotid ( p = 0.001) artery calcium scores. Seventeen of 20 patients with cardiovascular autonomic neuropathy (85%) demonstrated generalised arterial calcification compared to 11 (33%) patients without cardiovascular autonomic neuropathy; patients with cardiovascular autonomic neuropathy had an odds ratio of 11.3 (95% confidence interval = 2.7-47.1, p 0.001) for generalised arterial calcification.Cardiovascular autonomic neuropathy is associated with increased level of generalised arterial calcification in patients with normoalbuminuric, long-term type 1 diabetes.

OBJECTIVE Although diabetes is well known to be common in prevalent heart failure (HF) and portends a poor prognosis, the role of diabetes in the development of incident HF is less well understood. We studied the role of diabetes in the transition from asymptomatic left ventricular systolic dysfunction (ALVSD) to overt HF in the prevention arm of the Studies of Left Ventricular Dysfunction (SOLVD-P). RESEARCH DESIGN AND METHODS We examined the development of symptomatic HF, HF hospitalization, and cardiovascular death according to diabetes status at baseline in patients in SOLVD-P. These outcomes were analyzed by using cumulative incidence curves and Cox regression models adjusted for age, sex, and other prognostic factors, including randomized treatment, HF severity, and comorbidity. RESULTS Of the 4,223 eligible participants, 647 (15%) had diabetes at baseline. Patients with diabetes were older and had a higher average weight, systolic blood pressure, and heart rate. During the median follow-up of 36 months, 861 of the 3,576 patients without diabetes (24%) developed HF compared with 214 of the 647 patients with diabetes (33%). In unadjusted analyses, patients with diabetes had a higher risk of development of HF (hazard ratio 1.53 [95% CI 1.32–1.78]; P < 0.001), HF hospitalization (2.04 [1.65–2.52]; P < 0.0001), and the composite outcome of development of HF or cardiovascular death (1.48 [1.30–1.69]; P < 0.001). The effect of enalapril on outcomes was not modified by diabetes status. CONCLUSIONS In patients with ALVSD, diabetes is associated with an increased risk of developing HF. Development of HF is associated with an increased risk of death irrespective of diabetes status.

Aims Nearly 60% of the world's population lives in Asia but little is known about the characteristics and outcomes of Asian patients with heart failure with reduced ejection fraction (HFrEF) compared to other areas of the world. Methods and results We pooled two, large, global trials, with similar design, in 13 174 patients with HFrEF (patient distribution: China 833, India 1390, Japan 209, Korea 223, Philippines 223, Taiwan 199 and Thailand 95, Western Europe 3521, Eastern Europe 4758, North America 613, and Latin America 1110). Asian patients were younger (55.0–63.9 years) than in Western Europe (67.9 years) and North America (66.6 years). Diuretics and devices were used less, and digoxin used more, in Asia. Mineralocorticoid receptor antagonist use was higher in China (66.3%), the Philippines (64.1%) and Latin America (62.8%) compared to Europe and North America (range 32.8% to 49.6%). The rate of cardiovascular death/heart failure hospitalization was higher in Asia (e.g. Taiwan 17.2, China 14.9 per 100 patient‐years) than in Western Europe (10.4) and North America (12.8). However, the adjusted risk of cardiovascular death was higher in many Asian countries than in Western Europe (except Japan) and the risk of heart failure hospitalization was lower in India and in the Philippines than in Western Europe, but significantly higher in China, Japan, and Taiwan. Conclusion Patient characteristics and outcomes vary between Asia and other regions and between Asian countries. These variations may reflect several factors, including geography, climate and environment, diet and lifestyle, health care systems, genetics and socioeconomic influences.

Rasmus Rørth,1 Emil L Fosbøl,1 Kristian Kragholm,2 Ulrik M Mogensen,1,3 Pardeep S Jhund,3 Mark C Petrie,3 Christian Torp-Pedersen,4 Gunnar H Gislason,5 John JV McMurray,3 Lars Køber,1 Søren L Kristensen1,3 1Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; 2Department of Anesthesiology and Intensive Care Medicine, Cardiovascular Research Centre, Aalborg University Hospital, Aalborg, Denmark; 3BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK; 4Department of Health, Science and Technology, Aalborg University, Aalborg, Denmark; 5Department of Cardiology, Gentofte/Herlev University Hospital, Copenhagen, Denmark Background: Heart failure (HF) has a major impact on a patient’s quality of life and functional status. This impact may be sufficiently profound to prevent independent living although how often this is the case is unknown. We examined the need for domiciliary assistance and admission to a nursing home following first HF hospitalization. Methods: In nationwide Danish registries, we identified a cohort of patients discharged alive after a first-time HF hospitalization in the period 2008–2014 who were matched 1:5 with comparison subjects based on age and sex and followed for 5 years. Results: We included 37,547 patients (69% men) discharged after a first-time HF-hospitalization and 187,735 comparison subjects. The 5-year incidence of initiation of domiciliary care was 24.1% [23.7%–24.6%] among HF patients and 9.2% [9.1%–9.4%] among the comparison cohort and yielded a corresponding adjusted HR of 2.02 [1.96–2.09]. Covariates associated with initiation of domiciliary support included older age (HR 1.08 [1.07–1.08] per 1 year increase in age), living alone (HR 2.09 [2.04–2.15]) and comorbidities. The 5-year incidence of nursing home admission was 3.9% [3.7%–4.0%] among HF patients and 1.7% [1.7%–1.8%] among the comparison cohort and this resulted in an adjusted HR of 1.91 [1.77–2.06]. Covariates associated with nursing home admission included older age (HR 1.10 [1.10–1.11]), living alone (HR 2.15 [2.02–2.28]) and history of stroke (HR 2.71 [2.53–2.90]). Conclusion: Hospitalization for HF is associated with increased need for domiciliary support and nursing home admissions. Older age, living alone, and comorbidities were associated with higher risk of both outcomes. Keywords: domiciliary care, nursing home admission, heart failure, epidemiology

Aims Recurrent hospitalizations are a major part of the disease burden in heart failure (HF), but conventional analyses consider only the first event. We compared the effect of sacubitril/valsartan vs. enalapril on recurrent events, incorporating all HF hospitalizations and cardiovascular (CV) deaths in PARADIGM‐HF, using a variety of statistical approaches advocated for this type of analysis. Methods and results In PARADIGM‐HF, a total of 8399 patients were randomized and followed for a median of 27 months. We applied various recurrent event analyses, including a negative binomial model, the Wei, Lin and Weissfeld (WLW), and Lin, Wei, Ying and Yang (LWYY) methods, and a joint frailty model, all adjusted for treatment and region. Among a total of 3181 primary endpoint events (including 1251 CV deaths) during the trial, only 2031 (63.8%) were first events (836 CV deaths). Among a total of 1195 patients with at least one HF hospitalization, 410 (34%) had at least one further HF hospitalization. Sacubitril/valsartan compared with enalapril reduced the risk of recurrent HF hospitalization using the negative binomial model [rate ratio (RR) 0.77, 95% confidence interval (CI) 0.67–0.89], the WLW method [hazard ratio (HR) 0.79, 95% CI 0.71–0.89], the LWYY method (RR 0.78, 95% CI 0.68–0.90), and the joint frailty model (HR 0.75, 95% CI 0.66–0.86) (all P

Background Atrial fibrillation (AF) is common in heart failure (HF), but the outcome by type of AF is largely unknown. Objectives This study investigated outcomes related to type of AF (paroxysmal, persistent or permanent, or new onset) in 2 recent large trials in patients with HF with reduced ejection fraction. Methods The study analyzed patients in the PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) and ATMOSPHERE (Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure) trials. Multivariable Cox regression models were used to estimate hazard ratios (HRs) for outcomes related to AF type. Results Of 15,415 patients, 5,481 (35.6%) had a history of AF at randomization, and of these, 1,645 (30.0%) had paroxysmal AF. Compared with patients without AF, patients with paroxysmal AF at randomization had a higher risk of the primary composite endpoint of cardiovascular death or HF hospitalization (HR: 1.20; 95% confidence interval [CI]: 1.09 to 1.32; p < 0.001), HF hospitalization (HR: 1.34; 95% CI: 1.19 to 1.51; p < 0.001), and stroke (HR: 1.34; 95% CI: 1.02 to 1.76; p = 0.037), whereas the corresponding risks in patients with persistent or permanent AF were not elevated. Neither type of AF was associated with higher mortality. New onset AF was associated with the greatest risk of adverse outcomes: primary endpoint (HR: 2.21; 95% CI: 1.80 to 2.71), HF hospitalization (HR: 2.11; 95% CI: 1.58 to 2.81), stroke (HR: 2.20; 95% CI: 1.25 to 3.88), and all-cause mortality (HR: 2.26; 95% CI: 1.86 to 2.74), all p values < 0.001, compared with patients without AF. Anticoagulants were used less often in patients with paroxysmal (53%) and new onset (16%) AF than in patients with persistent or permanent AF (71%). Conclusions Among HF patients with a history of AF, those with paroxysmal AF were at greater risk of HF hospitalization and stroke than were patients with persistent or permanent AF, underlining the importance of anticoagulant therapy. New onset AF was associated with increased risk of all outcomes. (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255) (Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure [ATMOSPHERE]; NCT00853658)

Employment status at time of first heart failure (HF) hospitalization may be an indicator of both self-perceived and objective health status. In this study, we examined the association between employment status and the risk of all-cause mortality and recurrent HF hospitalization in a nationwide cohort of patients with HF.We identified all patients of working age (18-60 years) with a first HF hospitalization in the period 1997-2015 in Denmark, categorized according to whether or not they were part of the workforce at time of the index admission. The primary outcome was death from any cause and the secondary outcome was readmission for HF. Cumulative incidence curves, binomial regression and Cox regression models were used to assess outcomes. Of 25 571 patients with a first hospitalization for HF, 15 428 (60%) were part of the workforce at baseline. Patients in the workforce were significantly younger (53 vs. 55 years) more likely to be male (75% vs 64%) and less likely to have diabetes (13% vs 22%) and chronic obstructive pulmonary disease (5% vs 10%) (all P 0.0001). Not being part of the workforce was associated with a significantly higher risk of death [hazard ratio (HR) 1.59; 95% confidence interval (CI) 1.50-1.68] and rehospitalization for HF (HR 1.09; 95% CI 1.05-1.14), in analyses adjusted for age, sex, co-morbidities, education level, calendar time, and duration of first HF hospitalization.Not being part of the workforce at time of first HF hospitalization was independently associated with increased mortality and recurrent HF hospitalization.

Because of concerns about the safety of aliskiren in patients with diabetes, study treatment was stopped prematurely in the Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failuRE (ATMOSPHERE). We examined outcomes and treatment effect in these patients compared with those without diabetes.ATMOSPHERE included 7016 patients with heart failure and a reduced ejection fraction (HFrEF) randomly assigned to enalapril plus aliskiren, aliskiren alone, or enalapril. At baseline, 1944 (27.7%) patients had diabetes. Median follow-up was shorter in patients with diabetes compared with those without (24 months vs. 46 months). Among patients with diabetes, the primary endpoint of cardiovascular death or hospitalization for heart failure occurred in 216 patients (33.1%) in the enalapril group (reference), 172 (27.4%) in the aliskiren group [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.67-1.00; P = 0.053], and 196 (29.5%) in the combination group (HR 0.86, 95% CI 0.71-1.04; P = 0.13). The effects of the treatments studied did not differ significantly compared with patients without diabetes. In patients with diabetes, aliskiren monotherapy was associated with a lower risk of symptomatic hypotension compared to enalapril [42 (6.7%) vs. 65 (10.0%); P = 0.04], whereas other adverse events were generally balanced between the three groups.In patients with HFrEF and diabetes, there was no signal of harm and a trend towards benefit when direct renin inhibition monotherapy was compared with an angiotensin-converting enzyme inhibitor, whereas combined aliskiren and enalapril treatment led to more adverse events with no improvement in outcomes. Treatment effects did not differ in patients with diabetes compared with those without. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00853658.

Objectives The influence of choice of endpoint on trial size, duration, and interpretation of results was examined in patients with heart failure who were enrolled in BEST (Beta-blocker Evaluation of Survival Trial). Background The choice of endpoints in heart failure trials has evolved over the past 3 decades. Methods In the BEST trial, we used Cox regression analysis to examine the effect of bucindolol on the current standard composite of cardiovascular death or heart failure hospitalization (CVD/HFH) compared with the original primary mortality endpoint and the expanded composite that included emergency department (ED) visits. We also undertook an analysis of recurrent events primarily using the Lin, Wei, Ying, and Yang model. Results Overall, 448 (33%) patients on placebo and 411 (30%) patients on bucindolol died (hazard ratio [HR]: 0.90; 95% confidence interval [CI]: 0.78 to 1.02; p = 0.11). A total of 730 (54%) patients experienced CVD/HFH on placebo and 624 (46%) on bucindolol (HR: 0.80; 95% CI: 0.72 to 0.89; p < 0.001). Adding ED visits increased these numbers to 768 (57%) and 668 (49%), respectively (HR: 0.81; 95% CI: 0.73 to 0.90; p < 0.001). A total of 568 (42%) patients on placebo experienced HFH compared with 476 (35%) patients on bucindolol (HR: 0.78; 95% CI: 0.69 to 0.89; p < 0.001), with a total of 1,333 and 1,124 admissions, respectively. With the same statistical assumptions, using the composite endpoint instead of all-cause mortality would have reduced the trial size by 40% and follow-up duration by 69%. The rate ratio for recurrent events (CVD/HFH) was 0.83 (95% CI: 0.73 to 0.94; p = 0.003). Conclusions Choice of endpoint has major implications for trial size and duration, as well as interpretation of results. The value of broader composite endpoints and inclusion of recurrent events needs further investigation. (Beta Blocker Evaluation in Survival Trial [BEST]

Background Patients with heart failure (HF) and atrial fibrillation (AF) have higher circulating levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide) than HF patients without AF. There is uncertainty about the prognostic importance of a given concentration of NT-proBNP in HF patients with and without AF. We investigated this question in a large cohort of patients with HF and reduced ejection fraction. Methods and Results We studied 14 737 patients with HF and reduced ejection fraction and a measurement of NT-proBNP at time of screening, enrolled in either the PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) or the ATMOSPHERE trial (Aliskiren Trial to Minimize Outcomes in Patients With Heart Failure), of whom 3575 (24%) had AF on their baseline ECG. Median (Q1, Q3) levels of NT-proBNP were 1817 pg/mL (1095–3266 pg/mL) in those with AF and 1271 pg/mL (703–2569 pg/mL) in those without ( P P Conclusions HF and reduced ejection fraction patients with AF had higher NT-proBNP than those without AF. However, above a concentration of 400 pg/mL (representing most patients in each group), NT-proBNP had similar predictive value for adverse cardiovascular outcomes, irrespective of AF status. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier NCT00853658 (ATMOSPHERE) and NCT01035255 (PARADIGM-HF).

Angiotensin converting enzyme inhibitors (ACE-I), are beneficial both in heart failure with reduced ejection fraction (HF-REF) and after myocardial infarction (MI). We examined the effects of the angiotensin-receptor neprilysin inhibitor sacubitril/valsartan, compared with the ACE-I enalapril, on coronary outcomes in PARADIGM-HF.We examined the effect of sacubitril/valsartan compared with enalapril on the following outcomes: i) the primary composite endpoint of cardiovascular (CV) death or HF hospitalization, ii) a pre-defined broader composite including, in addition, MI, stroke, and resuscitated sudden death, and iii) a post hoc coronary composite of CV-death, non-fatal MI, angina hospitalization or coronary revascularization. At baseline, of 8399 patients, 3634 (43.3%) had a prior MI and 4796 (57.1%) had a history of any coronary artery disease. Among all patients, compared with enalapril, sacubitril/valsartan reduced the risk of the primary outcome (HR 0.80 [0.73-0.87], P.001), the broader composite (HR 0.83 [0.76-0.90], P.001) and the coronary composite (HR 0.83 [0.75-0.92], P.001). Although each of the components of the coronary composite occurred less frequently in the sacubitril/valsartan group, compared with the enalapril group, only CV death was reduced significantly.Compared with enalapril, sacubitril/valsartan reduced the risk of both the primary endpoint and a coronary composite outcome in PARADIGM-HF. Additional studies on the effect of sacubitril/valsartan on atherothrombotic outcomes in high-risk patients are merited.

We agree with Dr. Canepa and colleagues that interrogation of cardiac implantable electronic devices may represent an opportunity for earlier detection of atrial fibrillation, as well as for prevention of thromboembolic (and other) events in these high-risk patients. However, this attractive idea

BACKGROUND: Heart failure (HF) complicating acute myocardial infarction (MI) is an ominous prognostic sign frequently caused by left ventricular (LV) systolic dysfunction. However, many patients develop HF despite preserved LV ejection fractions. The aim of this study was to test the hypothesis that LV longitudinal function is a stronger marker of in-hospital HF than traditional echocardiographic indices.METHODS: A total of 548 patients with acute MIs were evaluated (mean age, 63.2 ± 11.7 years; 71.6% men). Within 48 hours of admission, comprehensive echocardiography with assessment of global longitudinal strain (GLS) was performed, along with measurements of N-terminal pro-brain natriuretic peptide.RESULTS: A total 89 patients (16.2%) had in-hospital HF assessed by Killip class > 1 in whom GLS was significantly impaired compared with patients without in-hospital HF (Killip class 1) (-14.6 ± 3.3% vs -10.1 ± 3.5%, P < .0001). In stepwise multiple logistic regression analysis including age, known HF, three-vessel disease, involvement of the left anterior descending coronary artery, episodes of atrial fibrillation, renal function, N-terminal pro-brain natriuretic peptide, troponin T level, LV ejection fraction, wall motion score index, and diastolic dysfunction indices, GLS emerged as the strongest marker of clinical HF (odds ratio, 1.47; 95% confidence interval [CI], 1.33-1.62; P < .0001). GLS remained independently associated with in-hospital HF in patients with LV ejection fractions > 40% (odds ratio, 1.33; 95% CI, 1.14-1.54; P < .05) and improved the C-statistic over other important covariates significantly (0.87 [95% CI, 0.82-0.91] vs 0.82 [95% CI, 0.76-0.89], P = .02).CONCLUSIONS: Global longitudinal function assessed by GLS is significantly impaired in patients with MIs with in-hospital HF, and multivariate analysis suggests that reduced GLS is the single most powerful marker of manifest LV hemodynamic deterioration in the acute phase of MI.

Background: In patients with heart failure and preserved ejection fraction, little is known about the characteristics of, and outcomes in, those with and without diabetes mellitus. Methods: We examined clinical and echocardiographic characteristics and outcomes in the I-Preserve trial (Irbesartan in Heart Failure With Preserved Ejection Fraction) according to history of diabetes mellitus. Cox regression models were used to estimate hazard ratios for cardiovascular outcomes adjusted for known predictors, including age, sex, natriuretic peptides, and comorbidity. Echocardiographic data were available in 745 patients and were additionally adjusted for in supplementary analyses. Results: Overall, 1134 of 4128 patients (27%) had diabetes mellitus. Compared with those without diabetes mellitus, they were more likely to have a history of myocardial infarction (28% versus 22%), higher body mass index (31 versus 29 kg/m 2 ), worse Minnesota Living With Heart Failure score (48 versus 40), higher median N-terminal pro-B-type natriuretic peptide concentration (403 versus 320 pg/mL; all P P P =0.010) were higher in patients with diabetes mellitus. Over a median follow-up of 4.1 years, cardiovascular death or heart failure hospitalization occurred in 34% of patients with diabetes mellitus versus 22% of those without diabetes mellitus (adjusted hazard ratio, 1.75; 95% confidence interval, 1.49–2.05), and 28% versus 19% of patients with and without diabetes mellitus died (adjusted hazard ratio, 1.59; confidence interval, 1.33–1.91). Conclusions: In heart failure with preserved ejection fraction, patients with diabetes mellitus have more signs of congestion, worse quality of life, higher N-terminal pro-B-type natriuretic peptide levels, and a poorer prognosis. They also display greater structural and functional echocardiographic abnormalities. Further investigation is needed to determine the mediators of the adverse impact of diabetes mellitus on outcomes in heart failure with preserved ejection fraction and whether they are modifiable. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00095238.

PURPOSE: β2-Agonists are widely used for relief of respiratory symptoms. Studies so far have reported conflicting results regarding use of β2-agonists and risk of myocardial infarction (MI). Yet, coronary angiographical data and longitudinal outcomes data are sparse and could help explain if there is an association between use of β2-agonists and MI.METHODS: Using a novel data-linkage of the Eastern Danish Heart Registry and nationwide administrative registries we identified a cohort of patients referred for acute coronary angiography due to ST-elevation MI (STEMI). Clinical and angiographical findings were compared between β2-agonist users and non-users.RESULTS: Among 66,234 patients undergoing coronary angiography, 9857 patients had STEMI. Of these, 933 (9%) patients used β2-agonists. β2-Agonist users were more often without significant coronary stenosis (15% in β2-agonist users vs 9% in non-users; pCONCLUSION: Among patients referred to urgent coronary angiography for STEMI, use of β2-agonists was associated with a lower frequency of significant coronary stenosis and a higher mortality compared with non-users.