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Aims: The importance of intra-ventricular conduction delay (IVCD), the incidence of new IVCD and its relationship to outcomes in heart failure and reduced ejection fraction (HFrEF) are not well studied. We addressed these questions in the PARADIGM-HF and ATMOSPHERE trials. Methods and results: The risk of the primary composite outcome of cardiovascular death or heart failure hospitalization and all-cause mortality were estimated by use of Cox regression according to baseline QRS duration and morphology in 11 861 patients without an intracardiac device. At baseline, 1789 (15.1%) patients had left bundle branch block (LBBB), 524 (4.4%) right bundle branch block (RBBB), 454 (3.8%) non-specific IVCD, 2588 (21.8%) ‘mildly abnormal’ QRS (110–129 ms) and 6506 (54.9%) QRS

Aim: To examine the rates of all‐cause mortality and heart failure (HF) readmission in patients hospitalized with decompensated HF according to HF duration – new‐onset HF and worsening of chronic HF. Methods and results: In this nationwide observational cohort study, 17 176 patients were included at first hospital admission for HF in the period 2013–2015 using data from Danish nationwide registries. In total, 8860 (51.6%) patients were admitted with new‐onset HF and 8316 (48.4%) with worsening of chronic HF. Patients with worsening of chronic HF were characterized by a greater comorbidity burden compared with patients with new‐onset HF. The rates of outcomes were examined by multivariable Cox regression models, adjusted for age, sex, and comorbidity. Worsening of chronic HF was associated with a higher rate of the composite endpoint of all‐cause mortality or HF readmission [hazard ratio (HR) 1.37, 95% confidence interval (CI) 1.31–1.43], all‐cause mortality (HR 1.22, 95% CI 1.16–1.28), and HF readmission (HR 1.81, 95% CI 1.69–1.93) compared with new‐onset HF. There was an interaction between atrial fibrillation (AF), HF duration, and outcome: in worsening of chronic HF, the rate of the composite endpoint was higher in patients with AF compared with those without (HR 1.12, 95% CI 1.07–1.19), whereas in new‐onset HF, the rate of the composite endpoint was lower in patients with AF compared with those without (HR 0.91, 95% CI 0.85–0.96) (P‐value for interaction

Aims: The role of microvascular complications in the risk conferred by diabetes in heart failure with reduced ejection fraction (HFrEF) is unknown. Methods and results: We studied 2707 HFrEF patients in the Beta‐blocker Evaluation of Survival Trial (BEST), stratified into three groups: no diabetes and diabetes without or with microvascular complications (neuropathy, nephropathy, or retinopathy). The risks of the composite of cardiovascular death or heart failure hospitalization, and all‐cause death, were studied using Cox regression analyses adjusted for other prognostic variables. Overall, 964 (36%) patients had diabetes, of which 313 (32%) had microvascular complications. Patients with microvascular complications had more severe symptoms (New York Heart Association class IV 12% vs. 9% diabetes with no complications and 7% no diabetes), and worse quality of life (Minnesota Living with Heart Failure median score 60 vs. 54 and 51 points). In patients with diabetes and complications, the rate of the composite outcome was 50 per 100 person‐years of follow‐up (compared with 34 and 29 in those with diabetes and no microvascular complications and participants without diabetes, respectively). Compared to patients without diabetes, the adjusted hazard ratio (HR) for the composite outcome was 1.44 [95% confidence interval (CI) 1.22–1.70] and 1.18 (95% CI 1.03–1.35) for patients with diabetes with and without complications, respectively. The risk of all‐cause mortality was similarly elevated: adjusted HR 1.42 (95% CI 1.16–1.74) and 1.20 (95% CI 1.01–1.42), respectively. Conclusion: In HFrEF, diabetes with microvascular complications is associated with worse symptoms and outcomes than diabetes without microvascular complications. Prevention of microvascular complications has the potential to improve HFrEF outcomes.

AIMS: The landmark STICH trial found that surgical revascularization compared to medical therapy alone improved survival in patients with heart failure (HF) of ischemic etiology and an ejection fraction (EF) ≤35%. However, the interaction between the burden of medical comorbidities and the benefit from surgical revascularization has not been previously described in patients with ischemic cardiomyopathy. METHODS: The STICH trial (ClinicalTrials.gov Number: NCT00023595) enrolled patients ≥18 years of age with coronary artery disease amenable to coronary artery bypass grafting (CABG) and an EF ≤35%. Eligible participants were randomly assigned 1:1 to receive medical therapy (MED) (602 patients) or MED/CABG (610 patient). A modified Charlson Comorbidity Index (CCI) based on the availability of data and study definitions was calculated by summing the weighted points for all comorbid conditions. Patients were divided into mild/moderate (CCI 1–4) and severe (CCI ≥5) comorbidity. Cox proportional hazards models were used to evaluate the association between CCI and outcomes. The interaction between severity of comorbidity and treatment effect was assessed with the log-rank test. RESULTS: The study population included 349 patients (29%) with a mild/moderate CCI score and 863 patients (71%) with a severe CCI score. Patients with a severe CCI score had greater functional limitations based on 6-minute walk test and impairments in health-related quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire. A total of 161 patients (Kaplan-Meier [KM] rate = 50%) with a mild/moderate CCI score and 579 patients (KM rate = 69%) with a severe CCI score died over a median follow-up of 9.8 years. After adjusting for baseline confounders, patients with a severe CCI score were at higher risk for all-cause mortality (Hazard Ratio [HR] 1.44, 95% confidence interval [CI] 1.19–1.74; p-value

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:\ud \ud The prevalence and consequences of prediabetic dysglycemia and undiagnosed diabetes is unknown in patients with heart failure (HF) and preserved ejection fraction (HFpEF) and has not been compared to heart failure and reduced ejection fraction (HFrEF).\ud \ud Methods:\ud \ud We examined the prevalence and outcomes associated with normoglycemia, prediabetic dysglycemia and diabetes (diagnosed and undiagnosed) among individuals with a baseline glycated hemoglobin (hemoglobin A1c, HbA1c) measurement stratified by HFrEF or HFpEF in the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity programme (CHARM). We studied the primary outcome of HF hospitalization or cardiovascular (CV) death, and all-cause death, and estimated hazard ratios (HR) by use of multivariable Cox regression models.\ud \ud Results:\ud \ud HbA1c was measured at baseline in CHARM patients enrolled in the USA and Canada and was available in 1072/3023 (35%) of patients with HFpEF and 1578/4576 (34%) patients with HFrEF. 18 and 16% had normoglycemia (HbA1c < 6.0), 20 and 22% had prediabetes (HbA1c 6.0–6.4), respectively. Finally among patients with HFpEF 22% had undiagnosed diabetes (HbA1c > 6.4), and 40% had known diabetes (any HbA1c), with corresponding prevalence among HFrEF patients being 26 and 35%. The rates of both clinical outcomes of interest were higher in patients with undiagnosed diabetes and prediabetes, compared to normoglycemic patients, irrespective of HF subtype, and in general higher among HFrEF patients. For the primary composite outcome among HFpEF patients, the HRs were 1.02 (95% CI 0.63–1.65) for prediabetes, HR 1.18 (0.75–1.86) for undiagnosed diabetes and 2.75 (1.83–4.11) for known diabetes, respectively, p value for trend across groups < 0.001. Dysglycemia was also associated with worse outcomes in HFrEF.\ud \ud Conclusions:\ud \ud These findings confirm the remarkably high prevalence of dysglycemia in heart failure irrespective of ejection fraction phenotype, and demonstrate that dysglycemia is associated with a higher risk of adverse clinical outcomes, even before the diagnosis of diabetes and institution of glucose lowering therapy in patients with HFpEF as well as HFrEF.

AIMS: To evaluate the risk of heart failure (HF) in patients with type 2 diabetes (T2D) complicated by development of intercurrent ischaemic heart disease (IHD), end-stage renal disease (ESRD), or both, compared to patients with T2D and no IHD and ESRD.METHODS AND RESULTS: From Danish nationwide registries, we identified all patients with new-onset T2D with no history of HF between 1998 and 2015. Landmark analyses were used to estimate the 5-year absolute risk of HF at several follow-up times, and accounted for the occurrence of IHD and ESRD, identified before HF. The Aalen-Johansen estimator was used to account for censoring and the competing risk of death. A total of 285 024 patients with new-onset T2D were included. During follow-up, 19 960 developed incident HF. Among patients with T2D free of HF 5 years after T2D diagnosis, patients without IHD and ESRD had the lowest 5-year risk of HF [4.02%; 95% confidence interval (CI) 3.90-4.15), those with T2D complicated by IHD [11.51%; relative risk (RR) 2.86; 95% CI 2.72-3.02; P CONCLUSION: Patients with T2D complicated by development of intercurrent IHD, ESRD, or both, showed a significantly higher risk of HF compared to those who did not develop IHD and ESRD. An effective way to delay or prevent the development of HF in patients with T2D may be to prevent IHD and ESRD.

Background Cardiac resynchronization therapy (CRT) improves survival in patients with heart failure, reduced ejection fraction (HFrEF) and left bundle branch block (LBBB). However, little is known about the incidence of LBBB in HFrEF and the risk factors for developing this. We addressed these questions in the PARADIGM-HF and ATMOSPHERE trials. Methods We identified 7703 patients with a non-paced rhythm on their baseline ECG, a QRS Results Overall, 313 of 7703 patients (4%) developed LBBB during a mean follow-up of 2.7 years, yielding an incidence rate of 1.5 per 100 py. The rate ranged from 0.9 in those with QRS ≤100 ms to 4.0 per 100 py in patients with QRS 116–129 ms. Other predictors of incident LBBB included male sex, age, lower LVEF, HF duration and absence of AF. The risk of the primary composite endpoint was higher among those who developed incident LBBB vs no incident LBBB; event rates 13.5 vs 10.0 per 100 py, yielding an adjusted HR of 1.43 (1.05–1.96). For all-cause mortality the corresponding rates were 12.6 vs 7.3 per 100 py; HR 1.55 (1.16–2.07) (Table 1). Table 1. Risk of outcomes according to incident LBBB during follow-up No. events Crude rate per 100py Adjusted* HR (95% CI) HF hospitalization or CV death No incident LBBB 2145 10.0 (9.6–10.4) 1.00 (ref.) Incident LBBB 43 13.5 (10.0–18.2) 1.43 (1.05–1.96) All-cause mortality No incident LBBB 1662 7.3 (6.9–7.6) 1.00 (ref.) Incident LBBB 48 12.6 (9.5–16.7) 1.55 (1.16–2.07) Conclusion Among patients with HFrEF, the annual incidence of new-onset LBBB (and a potential indication for CRT), was around 1.5%, ranging from 1% in those with QRS duration below 100 ms to 4% in those with QRS 116–129 ms. Incident LBBB was associated with a much higher risk of adverse outcomes, highlighting the importance of repeat ECG monitoring in patients with HFrEF. Acknowledgement/Funding Novartis

Background Estimated plasma volume (ePV) can be calculated from haematocrit and body weight, and has been shown to correlate with PV measured using 125Iodine labelled human serum albumin. Comparing a patient's ePV to ideal PV (iPV), an estimate of a patient's relative congestion, called PV status (PVS), is possible. Higher PVS is associated with increased mortality in patients with heart failure (HF), and has been proposed as a simple, cheap, and non-invasive way of assessing congestion. Purpose Whether PVS is associated with invasively measured markers of congestion is unknown. We calculated PVS in patients with HF who had right heart catheterisation (RHC), and assessed any correlation between PVS and invasive measures of congestion. Methods We calculated PVS in consecutive patients who had RHC performed as part of transplant assessment. iPV was calculated as: iPV = c × weight (kg) where c=39 in males and c=40 in females. ePV was calculated using subjects' haematocrit and weight as follows: ePV = (1 − haematocrit) × [a + (b × weight in kg)], where haematocrit is a fraction, a=1530 in males and a=864 in females, and b=41 in males and b=47.9 in females. PVS was calculated as: PVS = PVS = (ePV − iPV) /iPV × 100%. Correlation between PVS and invasive wedge pressure, mean right atrial (RA) pressure, and NTproBNP were made using Pearson correlation. Results PV indices and RHC data were available for 61 patients, 43 (71%) were male. Median age was 55 [IQR 48, 58] years. 20 (33%), 24 (39%), and 15 (25%) were NYHA association class II, III, and IV respectively. The median NTproBNP was 1390 [IQR 512, 3612] pg/ml and median ejection fraction was 29 [IQR 20, 35] %. The median PVS was −5.9% (IQR −12.5, −1.6]. Median wedge and mean-RA pressures were 14 [7, 21] and 4 [1, 8] mmHg, respectively. Correlation between mean RA pressure and PVS is shown in the figure. There was no correlation between PVS and mean RA pressure (r=0.12, p=0.34) or wedge pressure (r=0.01, p=0.92). There was a weak correlation between NTproBNP and PVS (r=0.31, p=0.01) Correlation mean RA pressure and PVS Conclusion PVS did not correlate with the invasive measures of congestion, mean RA and wedge pressure, but was weakly correlated with NTproBNP. Although there were limited number of patients in this study, we question the conclusion that PVS is a marker of congestion, and whether it can be used clinically for this purpose.

Background Data on stroke severity and prognosis in patients with AF are lacking and contemporary knowledge thereon could help identify preventive strategies. Purpose To investigate stroke severity among patients with and without AF, and secondly determine in-hospital and 1-year mortality in the two groups. Methods Using the nationwide Danish Stroke Registry we identified patients with first-time stroke (1 January 2005–31 December 2016). Patients with prior or new AF were matched 1:1 by sex, age, and calendar-year with patients with no history of AF. Stroke severity on admission was determined by the Scandinavian Stroke Scale (SSS) (0–29 points indicates very severe to severe stroke, 30–58 points indicates moderate to mild stroke) based on eye movements, paralysis and level of consciousness. The Kaplan-Meier estimator was used to calculate cumulative risk of death in AF patients versus non-AF patients. Risk of 1-year mortality was evaluated in an adjusted multivariable Cox-proportional hazard model. Results We identified 90,042 patients with first-time stroke; 16,186 (18.0%) had prior or new AF, and were included in the study, and matched with patients without AF. The median age was 80 years (p25-p75: 72–86 years) and 52.2% were females. AF patients had a higher comorbidity burden and more severe strokes compared with non-AF patients (median SSS 44 (p25-p75: 25–54) vs. 49 (p25-p75: 36–56), P value Conclusion In a nationwide contemporary stroke registry cohort, AF was associated with adverse stroke severity compared with stroke patients without AF. In-hospital mortality and 1-year mortality was higher among AF patients compared with non-AF patients. Acknowledgement/Funding This study was supported by an internal grant from Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Denmark

Background Mortality is increased following a hospitalization for heart failure (HF). It is not clear whether outpatient intensification of diuretic confers the same increased risk in the general population with heart failure Purpose This study sought to assess 1-year mortality risk after worsening HF, defined either as hospitalization due to HF or as intensified diuretic therapy in an outpatient setting, in a complete nationwide cohort of patients with HF on angiotensin converting enzyme inhibitors/ angiotensin receptor blocker and beta blockers. Methods From nationwide administrative registers, we identified all patients in Denmark diagnosed with HF in 2001–2016 and prescribed angiotensin converting enzyme inhibitor/ angiotensin receptor blocker and beta blocker within 120 days. During follow-up we defined worsening HF by the following events: Inpatient worsening (HF readmission) and outpatient worsening (intensified diuretic therapy, defined as the first event of new addition or doubled dosage of loop diuretic therapy or new onset addition of thiazide to loop diuretic therapy). Patients with a worsening event were risk set matched to two HF controls each at time of the event – based on age, sex and calendar year. One-year mortality risk was estimated with Kaplan-Meier and multivariable Cox regression models. Results We included 74,990 patients, median age 71 years (interquartile range: 62–79), 36% women. During five years of follow up, 8,727 patients had an inpatient worsening event, and 12,290 had an outpatient worsening event as first event. Absolute risk of 1-year mortality was 22.6% (95%-confidence interval (95%-CI): 21.7%-23.5%) after inpatient worsening, 18.0% (95%-CI: 17.3%-18.7%) after outpatient worsening compared to 9.8% (95%-CI: 9.5%-10.1%) for the matched controls. In a multivariable Cox model adjusted ischemic heart disease, atrial fibrillation, chronic obstructive pulmonary disease and diabetes, the hazard ratio for mortality among patients experiencing inpatient worsening was 2.46 (95%-CI: 2.33–2.60) and for outpatient worsening was 1.87 (95%-CI: 1.77–1.97), compared with the matched HF controls as reference (figure 1). Among patients who had an outpatient worsening as first event, 1,245 (10.1%) had a subsequent HF readmission within one year. Conclusion In a nationwide cohort of patients with HF, outpatient worsening defined by a diuretic intensification was associated with almost 2-fold risk of mortality during the next year. Although HF hospitalization is associated with a higher risk, the need to intensify diuretics in the outpatient setting is a signal to review and intensify efforts to improve HF outcomes. Acknowledgement/Funding The Danish Heart Foundation, (grant number 17-R116-A7610-22048)

Background Pericarditis accounts for 5% of all chest pain referrals to the emergency department and is generally considered a benign condition. However, recent studies suggested that pericarditis can be an early predictor of malignant disease, but data on mortality and other morbidity after incident pericarditis is lacking. Purpose To assess mortality risk and hospitalization patterns in patients with incident pericarditis. Methods In nationwide Danish registries we identified patients discharged from hospital with a first-time diagnosis of pericarditis from 1996 to 2016. Patients with prior myocarditis, heart failure, myocardial infarction and recent thoracic surgery were excluded. The patients were risk set matched with 8 controls each from the general population on sex and year of birth. We assessed 1-year mortality risk using Kaplan Meier and logistic regression adjusted for baseline comorbidities; cerebrovascular disease, chronic obstructive lung disease, cardiac dysrhythmias, ischaemic heart disease and malignancy. We identified subsequent hospital admissions due to new onset cardiovascular-, respiratory- or malignant disease. Differences in frequencies between the pericarditis group and controls were calculated with Chi squared test. Results We identified 8,077 patients with pericarditis, median age 45 years (IQR: 32–59) and 75.6% were men. The absolute 1-year mortality was 2.9% in patients with pericarditis compared to 0.8% in the control group (p The adjusted odds ratio (OR) of 1-year mortality was 2.79 (95%-CI: 2.14–3.65, p0.001, respiratory disease: 3.4% vs. 0.7%, p>0.001) and malignant disease: 1.4% vs. 0.5%, p>0.001). Figure 1 Conclusion In a nationwide cohort of patients discharged from hospital with incident pericarditis, we observed more than a triple 1-year mortality compared to age- and sex matched controls. Further, we observed a higher frequency of both cardiovascular and non-cardiovascular hospital admissions, highlighting the need for more focus on underlying morbidity in patients presenting with pericarditis.

Background Systematic echocardiographic screening is currently recommended for patients with hyperprolactinemic disorders treated with dopamine agonists, due to a perceived risk of cardiac valve regurgitation as observed in patients with Parkinson's disease. The dopamine agonist bromocriptine is used frequently in hyperprolactinemia patients, but its relation to cardiac valve disease remain uncertain. Purpose To determine the incidence of valvular heart disease in bromocriptine-treated women with hyperprolactinaemic disorders compared with matched controls from background population. Methods In nationwide Danish registries, we identified patients with hyperprolactinaemic disorders treated with bromocriptine between 1995–2017. Patients were matched 1:5 with population controls based on age and sex using incidence density sampling. We estimated the risk of valvular heart disease defined as admission and/or outpatient clinic visits. Incidence rates, cumulative incidence curve and adjusted cox-proportional hazard models were used to assess outcomes. Results A total of 23883 female bromocriptine users and 119415 controls were included. Median age was 29.9 years (Q1-Q3 26.4–33.8). Both groups had few comorbidities, 218 (0.9%) patients and 787 (0.7%) controls with hypertension, 160 (0.7%) patients and 629 (0.5%) controls with diabetes, 408 (1.7%) patients and 1305 (1.1%) controls were beta-blocker users. During a mean follow-up of 19 years 106 (0.44%) patients and 416 (0.35%) controls were diagnosed with valvular heart disease. Incidence rates were 0.254 per 1000 patient years (PY) in bromocriptine users (95% CI 0.21–0.31) and 0.198 per 1000 PY in the control cohort (95% CI 0.18–0.22). Overall, the cumulative incidence of valvular heart disease was 0.6% (95% CI 0.48–0.73) among patients and 0.5% (95% CI 0.4–0.51) among controls; P=0.03 (figure 1a). In adjusted analysis bromocriptine users still had a significant higher risk of valvular heart disease (hazard ratio=1.32, 95% CI 1.06–1.64, P=0.01). Incidence of valvular heart disease Conclusion The use of bromocriptine in younger and otherwise healthy women with hyperprolactinaemic disorders, were associated with a low absolute risk of cardiac valve disease. Still risk was approximately 30% higher compared with age- and sex matched controls. Our study suggests a low clinical yield of echocardiographic screening in this patient population. Acknowledgement/Funding Internal grant, Copenhagen University Hospital Rigshospitalet

Background Patients with infective endocarditis (IE) are at high risk of cerebral embolization, however little is known about the risk of stroke subsequent to IE in patients with stroke during IE admission. Purpose To investigate the risk of stroke after discharge of IE in patients with stroke during IE admission compared with patients without stroke during IE admission. Methods Using Danish nationwide registries we identified non-surgically treated patients with IE discharged alive, in the period 1996–2016. The study population was grouped in 1) patients with stroke during IE admission and 2) patients without stroke during IE admission. Crude cumulative risk of stoke were calculated using the Aalen-Johansen estimator accounting for death as a competing risk. Multivariable adjusted Cox proportional hazard analysis was used to compare the associated risk of stroke between groups. We identified differentials in the associated risk of stroke during follow-up between groups (p=0.006 for interaction with time), and follow-up was split into 0–1 year and 1–5 years time periods. Results We identified 4,284 patients with IE, 239 patients (5.6%) with stroke during IE admission (median age: 71.9 years, 58.2% males), and 4,045 patients (94.4%) without stroke during IE admission (median age 69.7 years, 64.8% males). The crude cumulative risk of stroke within 1 year of follow-up is shown in Figure Panel A, and with 1 to 5 years of follow-up in Figure Panel B. In multivariable adjusted analyses, the associated risk of stroke was higher in patients with stroke during IE admission within a follow-up period of 1 year, HR 3.21 (95% CI: 1.66–6.20) compared with patients without stroke during IE admission. From 1 to 5 years of follow-up, we identified no difference in the associated risk of stroke between groups, HR 0.91 (95% CI: 0.33–2.50). Cumulative incidence of stroke Conclusion Non-surgically treated patients with IE who had a stroke during IE admission were at significantly higher associated risk of subsequent stroke – although not significant beyond 1 year after discharge from IE. These findings underline the need for identification of causes and mechanisms of recurrent strokes after IE to develop preventive means.

Background Glucagon-like peptide-1 (GLP-1) receptor agonists differ in their structure and duration of action and have been studied in trials of varying sizes and with different patient populations, with inconsistent effects on cardiovascular outcomes reported. We aimed to synthesise the available evidence by doing a systematic review and meta-analysis of cardiovascular outcome trials of these drugs. Methods We searched MEDLINE (via PubMed) and the Cochrane Central Register of Controlled Trials for eligible placebo-controlled trials reporting major adverse cardiovascular events (MACE; ie, cardiovascular death, stroke, or myocardial infarction) up to June 15, 2019. We did a meta-analysis using a random-effects model to estimate overall hazard ratios (HRs) for MACE, its components, death from any cause, hospital admission for heart failure, kidney outcomes, and key safety outcomes (severe hypoglycaemia, pancreatitis, and pancreatic cancer). We also examined MACE in several subgroups based on patient characteristics (history of cardiovascular disease, BMI, age, baseline HbA1c, and baseline estimated glomerular filtration rate), trial duration, treatment dosing interval, and structural homology. Findings Of 27 publications screened, seven trials, with a combined total of 56 004 participants, were included: ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide), Harmony Outcomes (albiglutide), REWIND (dulaglutide), and PIONEER 6 (oral semaglutide). Overall, GLP-1 receptor agonist treatment reduced MACE by 12% (HR 0·88, 95% CI 0·82–0·94; p Interpretation Treatment with GLP-1 receptor agonists has beneficial effects on cardiovascular, mortality, and kidney outcomes in patients with type 2 diabetes. Funding None.

Aims Implantable cardioverter-defibrillator (ICD) implantation reduce the risk of sudden cardiac death, but not all-cause death in patients with non-ischaemic systolic heart failure (HF). Whether co-existence of diabetes affects ICD treatment effects is unclear. Methods and results We examined the effect of ICD implantation on risk of all-cause death, cardiovascular death, and sudden cardiac death (SCD) according to diabetes status at baseline in the Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischaemic Systolic Heart Failure on Mortality (DANISH) trial. Outcomes were analysed by use of cumulative incidence curves and Cox regressions models. Of the 1116 patients enrolled, 211 (19%) had diabetes at baseline. Patients with diabetes were more obese, had worse kidney function and more were in New York Heart Association Class III/IV. The risk of device infections and other complications in the ICD group was similar among patients with and without diabetes (6.1% vs. 4.6% P = 0.54). Irrespective of treatment group, diabetes was associated with higher risk of all-cause death, cardiovascular death, and SCD. The treatment effect of ICD in patients with diabetes vs. patients without diabetes was hazard ratio (HR) = 0.92 (0.57–1.50) vs. HR = 0.85 (0.63–1.13); Pinteraction = 0.60 for all-cause mortality, HR = 0.99 (0.58–1.70) vs. HR = 0.70 (0.48–1.01); Pinteraction = 0.25 for cardiovascular death, and HR = 0.81 (0.35–1.88) vs. HR = 0.40 (0.22–0.76); Pinteraction = 0.16 for sudden cardiac death. Conclusion Among patients with non-ischaemic systolic HF, diabetes was associated with higher incidence of all-cause mortality, primarily driven by cardiovascular mortality including SCD. Treatment effect of ICD therapy was not significantly modified by diabetes which might be due to lack of power.

Background The effect of implantable cardioverter-defibrillator (ICD) therapy in patients with heart failure with reduced ejection fraction (HFrEF) and diabetes is not fully elucidated. Methods We examined the effect of ICD therapy on sudden cardiac death, cardiovascular death and all-cause mortality, according to diabetes status at baseline in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). The outcomes were analyzed by use of cumulative incidence curves and Cox regressions models. Results Of the 1676 patients randomized to an ICD or placebo, 540 (32%) had diabetes at baseline. Patients with diabetes were slightly older (61 vs 58 years) and were more often in NYHA class III (37% vs 28%). ICD therapy did not reduce the risk of sudden cardiac death in HFrEF patients with diabetes (HR = 0.85; 95% CI 0.52–1.40); even though these patients had a higher risk of sudden cardiac death compared to patients without diabetes (HR = 1.73 95% CI 1.22–2.47). By contrast, ICD therapy did reduce sudden cardiac death in HFrEF patients without diabetes (HR = 0.26; 95% CI 0.15–0.46); Pinteraction=0.002. The findings for cardiovascular and all-cause death were similar. Conclusion ICD therapy did not reduce the risk of sudden cardiac death (or, as a consequence, all-cause death) in HFrEF patients with diabetes. Conversely, an ICD reduced the risk of sudden death in patients without diabetes, irrespective of etiology. Electronic supplementary material The online version of this article (10.1007/s00392-019-01415-z) contains supplementary material, which is available to authorized users.

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.

Recent studies have suggested that transthyretin amyloidosis (ATTR) is a more common cause of heart failure (HF) than previously appreciated, and novel treatments for amyloidosis are emerging. About one-half of patients with ATTR cardiac amyloidosis have a history of carpal tunnel syndrome (CTS).This study examined the risk of amyloidosis, HF, and other adverse cardiovascular outcomes associated with CTS relative to control subjects without CTS.Using Danish nationwide registries from 1996 to 2012, 56,032 patients were identified who underwent surgical treatment for CTS, and they were compared with a sex- and age-matched cohort (ratio 1:1) from the general population to examine their risk of amyloidosis, HF, and other adverse cardiovascular outcomes. Cumulative incidence curves and Cox proportional hazard models were used to assess differences.As expected, CTS was associated with a future diagnosis of amyloidosis (hazard ratio: 12.12 [95% confidence interval: 4.37 to 33.60]). CTS was associated with a higher incidence of HF, and this held true in the adjusted analysis yielding a hazard ratio of 1.54 (95% confidence interval: 1.45 to 1.64). No significant interaction with sex was found (p = 0.5). Risk of other adverse outcomes was also associated with CTS (p 0.0001 for atrial fibrillation, atrioventricular heart block, and pacemaker implantation).Patients who undergo surgical treatment for CTS are associated with a higher risk of amyloidosis and HF relative to matched control subjects from the general population. Other cardiovascular outcomes were also increased with CTS.

Background: Infective endocarditis (IE) may cause debilitating physical and mental changes that can interfere with activities of daily living. Admission to a nursing home and need for domiciliary care following hospitalization for IE represent such relevant outcomes, yet no such data have been reported.Methods: Using Danish nationwide registries, we identified all patients discharged alive after a first-time IE hospitalization in the period 1996 to 2014. These were matched by age, sex, calendar year, and relevant comorbidities with the background population in a 1:1 ratio. The 1-year rate of nursing home admission and initiation of domiciliary care, respectively, were assessed by multivariable Cox regression analyses.Results: In total, 4,493 IE patients were matched with 4,493 control subjects from the background population (median age: 66.8 years; interquartile range: 54.1, 76.7; 67.8% men). The 1-year incidence of nursing home admission was significantly higher among IE patients compared with the matched population (3.4% vs. 1.0%; hazard ratio: 7.95; 95% confidence interval: 4.00–15.77). Furthermore, IE patients had an increased use of domiciliary care compared with the matched population (6.6% vs. 2.1%; hazard ratio: 4.39; 95% confidence interval: 2.74–7.05). Factors associated with an increased risk of nursing home admission and domiciliary care among IE patients included older age, living alone, longer length of hospital stay, cardiovascular comorbidities, and stroke during admission.Conclusions: Patients who survived IE had an 8× higher incidence of nursing home admission and a 4× higher incidence of initiation of domiciliary care than their counterparts from the matched population.HighlightsWe found that patients who survive IE have an 8× higher incidence of nursing home admission and a 4× higher incidence of initiation of domiciliary care than their counterparts from the matched population.We show that IE is associated with debilitating physical and mental changes that are necessary to consider assessing the severity of IE and the follow-up on patients surviving IE.We believe that this paper contributes important research findings emphasizing the importance of the follow-up on patients surviving IE.

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.

This study aims to identify patients with nonischemic heart failure who are more likely to benefit from implantable cardioverter-defibrillator (ICD) implantation by use of established risk prediction models.It has been debated whether an ICD for primary prevention reduces mortality in patients with nonischemic heart failure.The Seattle Heart Failure Model (SHFM) predicts all-cause mortality whereas the Seattle Proportional Risk Model (SPRM) predicts the proportion of sudden cardiac death (SCD) versus nonsudden death, with a higher score indicating a greater proportion of SCD. We report the effect of ICD implantation on all-cause mortality and SCD, according to median SPRM and SHFM scores in all 1,116 patients enrolled in the DANISH (Danish study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on mortality) trial.Among patients with an SPRM score above the median (n = 558), ICD implantation reduced all-cause mortality (hazard ratio [HR]: 0.63; 95% confidence interval [CI]: 0.43 to 0.94), whereas patients with lower SPRM scores (n = 558) had no effect (HR: 1.08; 95% CI: 0.78 to 1.49, p for interaction = 0.04). The corresponding numbers for SHFM score above and below the median were HR: 0.84; 95% CI: 0.62 to 1.13 and HR: 0.82; 95% CI: 0.53 to 1.28, respectively (p for interaction = 0.980). In 177 patients with upper SPRM/upper SHFM, ICD implantation reduced all-cause mortality (HR: 0.45; 95% CI: 0.25 to 0.80) when compared to 381 patients with lower SPRM/upper SHFM (HR: 1.09; 95% CI: 0.76 to 1.55) (p for interaction 0.001).Nonischemic heart failure patients with high predicted relative likelihood of SCD, as estimated by higher SPRM score, seemed to benefit from ICD implantation. (DANISH [Danish ICD Study in Patients With Ditaled Cardiomyopathy]; NCT00542945).

BackgroundRecent randomised clinical trials have suggested prognostic benefits of catheter ablation in highly selected patients with atrial fibrillation (AF) and heart failure (HF).ObjectivesThis study sought to identify the treatment effect associated with catheter ablation in a broad population of patients with AF and HF.MethodsThrough nationwide administrative registers in Denmark, we estimated the 2-year average treatment effect (ATE) of catheter ablation for AF on a composite endpoint of HF readmission, stroke and all-cause mortality at 1-year and 5-year landmark analyses. The primary cohort was patients with AF before HF, and the second cohort of patients with HF before AF.ResultsA total of 13 756 patients were included with 9904 patients in the primary cohort, and 3852 in the secondary. An ATE (95% CI) reduction of the composite endpoint of 7.0% (4.5% to 9.5%) was observed in the primary cohort and 11.8% (6.0% to 17.6%) in the secondary in the 1-year landmark analysis with a reduction in all-cause mortality of 5.8% (3.7%–7.8%) and 6.3% (0.9%–11.7%), respectively. At the 5-year landmark, catheter ablation was associated with reductions in the composite endpoint and all-cause mortality in the primary (4.7% (2.3% to 7.2%), and 3.6% (1.0% to 6.3%), respectively), but not in the secondary cohort.ConclusionsAblation was associated with decreased risk of HF readmission, stroke and all-cause mortality in patients with AF and HF. The effect is most substantial in patients with AF before HF and with catheter ablation after 1 year from the diagnosis of both conditions.

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.

Background Returning to the workforce after coronary artery bypass grafting (CABG) holds important socioeconomic consequences not only for patients, but the society as well. Yet data on this issue are limited. We examined return to the workforce and associated factors in patients of working age undergoing CABG. Methods and results Using Danish nationwide administrative registries, we identified 6031 patients of working age (18–60years) undergoing isolated CABG (1998–2011) who were part of the workforce 30days prior to admission and alive at discharge. One year after discharge for CABG, 4827 (80.0%) patients had returned to the workforce, 614 (10.2%) were on paid sick leave, 267 (4.4%) received disability pension, 250 (4.1%) were on early retirement, 57 (0.9%) had died, and 16 (0.3%) had emigrated. Factors associated with return to the workforce were identified using multivariable logistic regression. Younger age (18–45 versus 56–60years; odds ratio, 1.89; 95% confidence interval, 1.48–2.42), male sex (1.51, 1.24–1.84), and higher level of education (higher educational level versus basic school; 1.53, 1.05–2.23) and income (highest quartile versus lowest; 3.01, 2.42–3.75) were associated with return to the workforce. Urgency of surgery (emergency versus elective; 0.65, 0.49–0.88), cardiovascular comorbidity, a history of chronic kidney disease (0.49, 0.29–0.84) and liver disease (0.47, 0.28–0.80), as well as additional hospital admissions within the first year post-discharge (>2 versus none; 0.25, 0.19–0.32) were associated with a lower likelihood of returning to the workforce. Conclusion One year after discharge for CABG, four out of five patients were part of the workforce and mortality was low. Younger age, male sex, higher socioeconomic status, and absence of major comorbidities were associated with return to the workforce.

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

Background— International geographic differences in outcomes may exist for clinical trials of heart failure and reduced ejection fraction (HF-REF), but there are few data for those with preserved ejection fraction (HF-PEF). Methods and Results— We analyzed outcomes by international geographic region in the Irbesartan in Heart Failure with Preserved systolic function trial (I-Preserve), the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved trial, the CHARM-Alternative and CHARM–Added HF-REF trials, and the Controlled Rosuvastatin Multinational Trial in HF-REF (CORONA). Crude rates of heart failure hospitalization varied by geographic region, and more so for HF-PEF than for HF-REF. Rates in patients with HF-PEF were highest in the United States/Canada (HF hospitalization rate 7.6 per 100 patient-years in I-Preserve; 8.8 in CHARM-Preserved), intermediate in Western Europe (4.8/100 and 4.7/100), and lowest in Eastern Europe/Russia (3.3/100 and 2.8/100). The difference between the United States/Canada versus Eastern Europe/Russia persisted after adjustment for key prognostic variables: adjusted hazard ratios 1.34 (95% confidence interval, 1.01–1.74; P =0.04) in I-Preserve and 1.85 (95% confidence interval, 1.17–2.91; P =0.01) in CHARM-Preserved. In HF-REF, rates of HF hospitalization were slightly lower in Western Europe compared with other regions. For both HF-REF and HF-PEF, there were few regional differences in rates of all-cause or cardiovascular mortality. Conclusions— The differences in event rates observed suggest there is international geographic variation in 1 or more of the definition and diagnosis of HF-PEF, the risk profile of patients enrolled, and the threshold for hospitalization, which has implications for the conduct of future global trials.

Aims To investigate the prognostic significance of hospitalization for worsening heart failure (WHF), myocardial infarction (MI), and stroke in patients with chronic heart failure (HF). Methods and results We studied 5011 patients with HF and reduced EF (HF-REF) in the CORONA trial and 4128 patients with HF and preserved EF (HF-PEF) in the I-Preserve trial. Adjusted hazard ratios (HRs) for death were estimated for 0–30 days and ≥31 days after first post-randomization WHF, MI, or stroke used as a time-dependent variable, compared with patients with none of these events. In CORONA, 1616 patients (32%) had post-randomization first events (1223 WHF, 216 MI, 177 stroke), and the adjusted HR for mortality ≤30 days after an event was: WHF 7.21 [95% confidence interval (CI) 2.05–25.40], MI 23.08 (95% CI 6.44–82.71), and stroke 32.15 (95% CI 8.93–115.83). The HR for mortality at >30 days was: WHF 3.62 (95% CI 3.11–4.21), MI 4.41 (95% CI 3.23–6.02), and stroke 3.19 (95% CI 2.21–4.61). In I-Preserve, 896 patients (22%) experienced a post-randomization event (638 WHF, 111 MI, 147 stroke). The HR for mortality ≤30 days was WHF 31.77 (95% CI 7.60–132.81), MI 154.77 (95% CI 34.21–700.17), and stroke 223.30 (95% CI 51.42–969.78); for >30 days it was WHF 3.36 (95% CI 2.79–4.05), MI 3.29 (95% CI 2.14–5.06), and stroke 5.13 (95% CI 3.61–7.29). Conclusions In patients with both HF-REF and HF-PEF, hospitalization for WHF was associated with high early and late mortality. The early relative risk of death was not as great as following MI or stroke, but the longer term relative risk of death was similar following all three types of event. Numerically, more deaths occurred following WHF because it was a much more common event.

Background— First-time syncopal episodes usually occur in adults of working age, but their impact on occupational safety and employment remains unknown. We examined the associations of syncope with occupational accidents and termination of employment. Methods and Results— Through linkage of Danish population-based registers, we included all residents 18 to 64 years from 2008 to 2012. Among 3 410 148 eligible individuals, 21 729 with a first-time diagnosis of syncope were identified, with a median age 48.4 years (first to third quartiles, 33.0–59.5), and 10 757 (49.5%) employed at time of the syncope event. Over a median follow-up of 3.2 years (first to third quartiles, 2.0–4.5), 622 people with syncope had an occupational accident requiring hospitalization (2.1/100 person-years). In multiple Poisson regression analysis, the incidence rate ratio in the employed syncope population was higher than in the employed general population (1.44; 95% confidence interval [CI], 1.33–1.55) and more pronounced in people with recurrences (2.02; 95% CI, 1.47–2.78). The 2-year risk of termination of employment was 31.3% (95% CI, 30.4%–32.3%), which was twice the risk of the reference population (15.2%; 95% CI, 14.7%–15.7%), using the Aalen–Johansen estimator. Factors associated with termination of employment were age Conclusions— In this nationwide cohort, syncope was associated with a 1.4-fold higher risk of occupational accidents and a 2-fold higher risk of termination of employment compared with the employed general population.

Background:\ud \ud Data on young patients with heart failure (HF) are sparse. We examined the characteristics, healthcare utilization and survival of younger versus older patients with HF.\ud \ud Methods:\ud \ud Analysis of linked administrative databases in Alberta, Canada. 34,548 patients with first hospitalization for HF as principal diagnosis were identified from 2002 to 2014. Patients were stratified into four age groups: 20-44, 45-54, 55-64, and ≥65 years.\ud \ud Results:\ud \ud Of the 34548 patients, 496 (1.4%), 1319 (3.8%), 3359 (9.7%) and 29374 (85%) patients were aged 20-44, 45-54, 55-64 and ≥65 years, respectively. Incidence of HF hospitalization decreased over time among patients ≥65 years, and increased among men aged 20 – 64 years. In the year following the index HF hospitalization, younger compared to older patients were less likely to present to the emergency department (ED) (e.g. 67.2% of those aged 20-44 years vs. 74.8% of those aged ≥65 years) or be hospitalized: for any reason (48.5% vs. 61.2%), cardiovascular causes (28.6% vs. 34.4%), or HF (14.8% vs. 23.6%). Mortality rates were lower in younger patients aged 20-44 years, but still substantial: 3.9%, 12.4%, and 27.7% at 30 days, 1 year, and 5 years respectively.\ud \ud Conclusions:\ud \ud Although young patients, especially those

Background Venous thromboembolism (VTE) is a major public health concern. Lupus erythematosus (LE) is a chronic autoimmune disease ranging from localized cutaneous disease (CLE) to systemic involvement (SLE). Patients with SLE have an increased risk of venous thromboembolism (VTE), but little is known about the CLE-related risk of VTE. Methods To evaluate the risk of VTE in patients with SLE and CLE as compared to the general population, a retrospective cohort study was conducted. Incidence rates and hazard ratios (HRs) with 95% confidence intervals (CIs) from multivariable Cox regression models were used to evaluate and compare the risk of VTE. Registries of hospitalizations, outpatient visits, and prescription drug use were studied to determine the risk of VTE in patients with CLE and SLE and the general population between 1997 and 2011. Results A total of 3234 patients with CLE and 3627 patients with SLE were identified and compared to 5,590,070 individuals in the reference population. The incidence rates per 1000 year of VTE were higher in patients with LE, i.e. 1.20, 3.06, and 5.24 for the reference population, CLE, and SLE, respectively. In adjusted models, both CLE (HR 1.39; 95% CI 1.10–1.78) and SLE (HR 3.32; 95% CI 2.73–4.03) were associated with a statistically significant increased risk of VTE, compared to the reference population. Conclusion In this nationwide study, both CLE and SLE were significant risk factors for VTE. The results add to our understanding of comorbidities in patients with LE, and call for further studies and increased awareness of thromboembolic complications in patients with CLE.

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).

Aims:\ud \ud Inhibition of neprilysin, an enzyme degrading natriuretic and other vasoactive peptides, is beneficial in heart failure with reduced ejection fraction (HFrEF), as shown in PARADIGM-HF which compared the angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan with enalapril. As neprilysin is also one of many enzymes clearing amyloid-β peptides from the brain, there is a theoretical concern about the long-term effects of sacubitril/valsartan on cognition. Therefore, we have examined dementia-related adverse effects (AEs) in PARADIGM-HF and placed these findings in the context of other recently conducted HFrEF trials.\ud Methods and results:\ud \ud In PARADIGM-HF, patients with symptomatic HFrEF were randomized to sacubitril/valsartan 97/103 mg b.i.d. or enalapril 10 mg b.i.d. in a 1:1 ratio. We systematically searched AE reports, coded using the Medical Dictionary for Regulatory Activities (MedDRA), using Standardized MedDRA Queries (SMQs) with ‘broad’ and ‘narrow’ preferred terms related to dementia. In PARADIGM-HF, 8399 patients aged 18–96 years were randomized and followed for a median of 2.25 years (up to 4.3 years). The narrow SMQ search identified 27 dementia-related AEs: 15 (0.36%) on enalapril and 12 (0.29%) on sacubitril/valsartan [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.33–1.59]. The broad search identified 97 (2.30%) and 104 (2.48%) AEs (HR 1.01, 95% CI 0.75–1.37), respectively. The rates of dementia-related AEs in both treatment groups in PARADIGM-HF were similar to those in three other recent trials in HFrEF.\ud Conclusion:\ud \ud We found no evidence that sacubitril/valsartan, compared with enalapril, increased dementia-related AEs, although longer follow-up may be necessary to detect such a signal and more sensitive tools are needed to detect lesser degrees of cognitive impairment. Further studies to address this question are warranted.

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.

Background The prognostic significance of age and continuous positive airway pressure (CPAP) therapy on cardiovascular disease in patients with sleep apnoea has not been assessed previously. Methods Using nationwide databases, the entire Danish population was followed from 2000 until 2011. First-time sleep apnoea diagnoses and use of CPAP therapy were determined. Incidence rate ratios (IRRs) of ischaemic stroke and myocardial infarction (MI) were analysed using Poisson regression models. Results Amongst 4.5 million individuals included in the study, 33 274 developed sleep apnoea (mean age 53, 79% men) of whom 44% received persistent CPAP therapy. Median time to initiation of CPAP therapy was 88 days (interquartile range 34–346). Patients with sleep apnoea had more comorbidities compared to the general population. Crude rates of MI and ischaemic stroke were increased for sleep apnoea patients (5.4 and 3.6 events per 1000 person-years compared to 4.0 and 3.0 in the general population, respectively). Relative to the general population, risk of MI [IRR 1.71, 95% confidence interval (CI) 1.57–1.86] and ischaemic stroke (IRR 1.50, 95% CI 1.35–1.66) was significantly increased in patients with sleep apnoea, in particular in patients younger than 50 years (IRR 2.12, 95% CI 1.64–2.74 and IRR 2.34, 95% CI 1.77–3.10, respectively). Subsequent CPAP therapy was not associated with altered prognosis. Conclusions Sleep apnoea is associated with increased risk of ischaemic stroke and MI, particularly in patients younger than 50 years of age. CPAP therapy was not associated with a reduced rate of stroke or MI.

Purpose National reimbursement policies in Denmark were changed in November 2010 favouring a shift in angiotensin-II receptor blocker (ARB) treatment to generic losartan for heart failure (HF) patients. We examined how changes in reimbursement policies affected the fraction of HF patients up-titrated to optimal or suboptimal ARB dosage. Methods A historical cohort study was performed including HF patients with at least one prescription of ARB in the months of May–Jul 2010 (baseline). Patients were considered up-titrated at doses 100, 16 or 160 mg for losartan, valsartan and candesartan, respectively. Individual-level linkage of nationwide registries of hospitalization and drug dispensing in Denmark was used to describe patterns of ARB prescriptions and estimate dosage before and after November 2010. Logistic regression models were used to assess the probability for being up-titrated in the period. Results Of 6036 individuals included (mean age 73.5 [standard deviation 11.2] years; 51% males), 3346 (55.4%) used losartan, 541 (9.0%) valsartan and 2149 (35.6%) candesartan at inclusion, respectively. 2887 (47.8%) were up-titrated at baseline (May–Jul 2010), followed by 2878 (48.2%) in the three months before the policy change (Aug–Oct 2010), and 2492 (43.7%) in the first months after the policy change (Feb–Apr 2011). Odds ratios for being up-titrated according to time period were 1.02 [0.95–1.09] in Aug–Oct 2010 (before policy change) and 0.84 [0.78-0.90] in Feb–Apr 2011 (after policy change), compared with May–Jul 2010 (reference). Conclusion Probability of being up-titrated in ARB treatment was reduced 20% following changes in drug reimbursement policies. Copyright © 2014 John Wiley & Sons, Ltd.

Objectives The aim of this study was to investigate the impact of atrial fibrillation (AF) and antithrombotic treatment on the prognosis in patients with heart failure (HF) as well as vascular disease. Background HF, vascular disease, and AF are pathophysiologically related, and understanding antithrombotic treatment for these conditions is crucial. Methods In hospitalized patients with HF and coexisting vascular disease (coronary artery disease or peripheral arterial disease) followed from 1997 to 2009, AF status was categorized as prevalent AF, incident AF, or no AF. Risk of thromboembolism (TE), myocardial infarction (MI), and serious bleeding was assessed by Cox regression models (hazard ratio [HR] with 95% confidence interval [CI]) with antithrombotic therapy and AF as time-dependent variables. Results A total of 37,464 patients were included (age, 74.5 ± 10.7 years; 36.3% females) with a mean follow-up of 3 years during which 20.7% were categorized as prevalent AF and 17.2% as incident AF. Compared with vitamin K antagonist (VKA) in prevalent AF, VKA plus antiplatelet was not associated with a decreased risk of TE (HR: 0.91; 95% CI: 0.73 to 1.12) or MI (HR: 1.11; 95% CI: 0.96 to 1.28), whereas bleeding risk was significantly increased (HR: 1.31; 95% CI: 1.09 to 1.57). Corresponding estimates for incident AF were HRs of 0.77 (95% CI: 0.56 to 1.06), 1.07 (95% CI: 0.89 to 1.28), and 2.71 (95% CI: 1.33 to 2.21) for TE, MI, and bleeding, respectively. In no AF patients, no statistical differences were seen between antithrombotic therapies in TE or MI risk, whereas bleeding risk was significantly increased for VKA with and without single-antiplatelet therapy. Conclusions In AF patients with coexisting HF and vascular disease, adding single-antiplatelet therapy to VKA therapy is not associated with additional benefit in thromboembolic or coronary risk, but notably increased bleeding risk.

Despite improvement in treatment, heart failure (HF) is associated with a median survival of 5 years. However, HF is a heterogeneous disease, and more knowledge on mortality rates and HF progression is warranted in subgroups. We sought to assess risk of death and HF progression (HF hospitalization

OBJECTIVE Psoriasis is associated with increased risk of cardiovascular events and increased prevalence of cardiovascular risk factors. Diabetes mellitus (DM) is a major contributor to cardiovascular morbidity and mortality that may be associated with psoriasis, but conflicting results have been presented and nationwide data on the risk of new-onset DM in patients with psoriasis have not been reported. RESEARCH DESIGN AND METHODS The study comprised a Danish population ≥10 years of age on 1 January 1997 who were followed until new-onset DM, death, or 31 December 2009. Information on comorbidity, concomitant medication, and socioeconomic status was linked on an individual level. The primary study end point was DM requiring pharmacotherapy. Incidence rates for the development of DM events per 1,000 observational years were calculated and adjusted. Incidence rate ratios (IRRs) were estimated by Poisson regression. RESULTS A total of 4,614,807 subjects were eligible for analysis, with a maximum follow-up of 13 years. In the study period, 52,613 patients with psoriasis, including 6,784 patients with severe psoriasis, were identified. The overall incidence rates for new-onset DM were 3.67 (CI 3.65–3.69), 6.93 (6.63–7.25), and 9.65 (8.68–10.73) for the reference population, mild psoriasis, and severe psoriasis, respectively. Compared with the reference population, the IRR of new-onset DM was increased in all patients with psoriasis, i.e., IRR 1.49 (CI 1.43–1.56) and 2.13 (1.91–2.37) for those with mild and severe psoriasis. CONCLUSIONS In this nationwide cohort, psoriasis was associated with increased incidence rates of new-onset DM. The association remained statistically significant after adjustment for confounding factors.

Aims Administrative discharge codes are widely used in epidemiology, but the specificity and sensitivity of this coding is unknown and must be validated. We assessed the validity of the discharge diagnosis of syncope in administrative registers and reviewed the etiology of syncope after workup. Methods and results Two samples were investigated. One sample consisted of 5262 randomly selected medical patients. The other sample consisted of 750 patients admitted or seen in the emergency department (ED) for syncope (ICD-10: R55.9) in three hospitals in Denmark. All charts were reviewed for baseline characteristics and to confirm the presence/absence of syncope and to compare with the administrative coding. In a sample of 600 admitted patients 570 (95%) and of 150 patients from ED 140 (93%) had syncope representing the positive predictive values. Median age of the population was 69 years (IQR: ±14). In the second sample of 5262 randomly selected medical patients, 75 (1.4%) had syncope, of which 47 were coded as R55.9 yielding a sensitivity of 62.7%, a negative predictive value of 99.5%, and a specificity of 99.9%. Conclusion ED and hospital discharge diagnostic coding for syncope has a positive predictive value of 95% and a sensitivity of 63%.

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.

AIM: Although the relation between stroke risk factors and stroke in patients with atrial fibrillation (AF) has been extensively examined, only few studies have explored the association of AF and the risk of ischaemic stroke/systemic thromboembolism/transient ischaemic attack (stroke/TE/TIA) in the presence of concomitant stroke risk factors.METHODS AND RESULTS: From nationwide registries, all persons who turned 50, 60, 70, or 80 from 1997 to 2011 were identified. Persons receiving warfarin were excluded. The absolute risk of stroke/TE/TIA was reported for a 5-year period, as was the absolute risk ratios for AF vs. no AF according to prior stroke and the number of additional risk factors. The study cohort comprised of 3 076 355 persons without AF and 48 189 with AF. For men aged 50 years, with no risk factors, the 5-year risk of stroke was 1.1% (95% confidence interval 1.1-1.1); with AF alone 2.5% (1.8-3.2); with one risk factor and no prior stroke or AF 2.5% (2.3-2.7); and with one factor, no prior stroke and AF 2.9% (1.4-4.3). In men aged 50 years with prior stroke as the only risk factor, 5-year risk was 10.2% (9.1-11.3). In men aged 70 years, the corresponding risks were 4.8% (4.7-4.9), 6.8% (5.7-7.9), 6.6% (6.3-6.8), 8.7 (7.4-9.9), and 19.1% (18.1-20.1), respectively. In women aged 50 years, the risk was of 0.7% (0.7-0.7), 2.1% (0.9-3.2), 1.6% (1.4-1.8), 4.1% (0.6-7.6), and 7.2% (6.3-8.2), respectively, and in women aged 70 years 3.4% (3.3-3.5), 8.2% (7.0-9.5), 4.6% (4.4-4.8), 9.1% (7.5-10.6), and 15.4% (14.5-16.4), respectively.CONCLUSIONS: Stroke/TE/TIA risk was particularly increased when prior stroke/TE/TIA was present. Atrial fibrillation is associated with an increase in risk of stroke/TE/TIA in the absence of other risk factors but only a moderate increase in risk when other risk factors are present.