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Aim: There is an association between heart failure with preserved ejection fraction (HFpEF) and insulin resistance, but less is known about the diabetic continuum, and in particular about pre-diabetes, in HFpEF. We examined characteristics and outcomes of participants with diabetes or pre-diabetes in PARAGON-HF.Methods and results: Patients aged ≥50 years with left ventricular ejection fraction ≥45%, structural heart disease and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) were eligible. Patients were classified according to glycated haemoglobin (HbA1c): (i) normal HbA1c, Conclusion: Pre-diabetes is common in patients with HFpEF and is associated with worse clinical status and greater risk of HFH. Clinical Trial Registration: ClinicalTrials.gov Identifier NCT01920711.

Aims: We examined the prognostic importance of N‐terminal pro B‐type natriuretic peptide (NT‐proBNP) and troponin T (TnT) in heart failure patients with and without diabetes. Methods and results: We measured NT‐proBNP and TnT in the biomarker substudy of the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM‐HF). Of 1907 patients, 759 (40%) had diabetes. Median TnT in patients with diabetes was 18 (interquartile range 11–27) ng/L and 13 (9–21) ng/L in those without (P

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.

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.

Psoriasis is a common inflammatory disease that is associated with increased risk of cardiovascular disease, including myocardial infarction. Heart failure (HF) is independently associated with several cardiovascular risk factors and is a major cause of cardiovascular morbidity and mortality. The association between psoriasis and HF is unclear and we therefore investigated the risk of new-onset HF in a nationwide cohort of psoriasis patients compared with the background population.The study included the entire Danish population aged ≥18 years followed from 1 January 1997 until HF, death or 31 December 2011. Information on comorbidity and concomitant medication was identified by individual-level linkage of administrative registers. New-onset HF was defined as first hospital admission for HF. Incidence rates of new-onset HF were calculated and adjusted hazard ratios were estimated by multivariable Cox regression models adjusted for age, gender, comorbidity and cardiovascular medications.A total of 5 485 856 subjects were eligible for analysis. In the study period 66 389 patients with new-onset psoriasis, including 11 242 patients with severe psoriasis, were identified. The overall incidence rates of new-onset HF were 2.82, 4.22 and 4.70 per 1000 person-years for the reference population, mild psoriasis and severe psoriasis, respectively. Compared with the reference population, the fully adjusted hazard ratios for new-onset HF were increased in patients with psoriasis with a hazard ratio 1.22 (95% confidence interval 1.16-1.29) and hazard ratio of 1.53 (95% confidence interval 1.34-1.74) for those with mild and severe disease, respectively.In this nationwide cohort, psoriasis was associated with a disease severity-dependent increased risk of new-onset HF.