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Aim: Randomized clinical trials (RCTs) allocating type 2 diabetes patients to treatment with sodium‐glucose transport protein 2 (SGLT‐2) inhibitors or placebo have found significant effects on the risk of heart failure and modest effects on mortality. In the wake of the first trials, a number of observational studies have been conducted, some of these reporting a mortality reduction of 50% compared to active comparators. In this review, we systematically assess and compare the results on all‐cause mortality, cardiovascular mortality and heart failure hospitalization observed in RCTs with the results obtained in observational studies. Method: We performed a systematic bibliographical search including cardiovascular outcome trials and observational studies assessing the effect of SGLT‐2 inhibitors on mortality and heart failure. Results: Seven RCTs and 23 observational studies were included in the current review. The observed heterogeneity between study results for all‐cause mortality (p‐interaction < 0.001) and cardiovascular mortality (p‐interaction < 0.001) was explained by study type, whereas this was not the case for heart failure (p‐interaction = 0.18). Conclusion: Methodological considerations such as the omission of important confounders, immortal‐time bias and residual confounding such as unmeasured social economic inequality may be the cause of the inflated results observed in observational studies and that calls for caution when observational studies are used to guide treatment of patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

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 bemale (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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 <40 years (incidence rate ratio, 1.48; 95% CI, 1.37-1.59), cardiovascular disease (1.20; 95% CI, 1.06-1.36), depression (1.72; 95% CI, 1.55-1.90), and low educational level (2.61; 95% CI, 2.34-2.91).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. [ABSTRACT FROM AUTHOR]

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/m2), 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<0.01), more signs of congestion, but no significant difference in left ventricular ejection fraction. Patients with diabetes mellitus had a greater left ventricular mass and left atrial area than patients without diabetes mellitus. Doppler E-wave velocity (86 versus 76 cm/s; P<0.0001) and the E/e' ratio (11.7 versus 10.4; 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Return to work is important financially, as a marker of functional status and for self-esteem in patients developing chronic illness. We examined return to work after first heart failure (HF) hospitalization.Methods: By individual-level linkage of nationwide Danish registries, we identified 21 455 patients of working age (18-60 years) with a first HF hospitalization in the period from 1997 to 2012. Of these patients, 11 880 (55%) were in the workforce before HF hospitalization and comprised the study population. We applied logistic regression to estimate odds ratios for associations between age, sex, length of hospital stay, level of education, income, comorbidity, and return to work.Results: One year after first HF hospitalization, 8040 (67.7%) returned to the workforce, 2981 (25.1%) did not, 805 (6.7%) died, and 54 (0.5%) emigrated. Predictors of return to work included younger age (18-30 versus 51-60 years; odds ratio [OR], 3.12; 95% confidence interval [CI], 2.42-4.03), male sex (OR, 1.22; 95% CI, 1.12-1.34), and level of education (long-higher versus basic school; OR, 2.06; 95% CI, 1.63-2.60). Conversely, hospital stay >7 days (OR, 0.56; 95% CI, 0.51-0.62) and comorbidity including history of stroke (OR, 0.55; 95% CI, 0.45-0.69), chronic kidney disease (OR, 0.46; 95% CI, 0.36-0.59), chronic obstructive pulmonary disease (OR, 0.62; 95% CI, 0.52-0.75), diabetes mellitus (OR 0.76; 95% CI, 0.68-0.85), and cancer (OR, 0.49; 95% CI, 0.40-0.61) were all significantly associated with lower chance of return to work.Conclusions: Patients in the workforce before HF hospitalization had low mortality but high risk of detachment from the workforce 1 year later. Young age, male sex, and a higher level of education were predictors of return to work. [ABSTRACT FROM AUTHOR]