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Background: Even on optimal therapy, many patients with heart failure and atrial fibrillation experience cardiovascular complications. Additional treatments are needed to reduce these events, especially in patients with heart failure and preserved left ventricular ejection fraction (HFpEF). Methods: This prespecified subanalysis of the randomized EAST - AFNET 4 trial assessed the effect of systematic, early rhythm control therapy (ERC; using antiarrhythmic drugs or catheter ablation) compared to usual care (UC, allowing rhythm control therapy to improve symptoms) on the two primary outcomes of the trial and on selected secondary outcomes in patients with heart failure, defined as heart failure symptoms NYHA II-III or left ventricular ejection fraction [LVEF] <50%. Results: This analysis included 798 patients (300 (37.6%) female, median age 71.0 [64.0, 76.0] years, 785 with known LVEF). The majority of patients (n=442) had HFpEF (LVEF≥50%; mean LVEF 61% ± 6.3%), the others had heart failure with mid-range ejection fraction (n=211; LVEF40-49%; mean LVEF 44% ± 2.9%) or heart failure with reduced ejection fraction (n=132; LVEF<40%; mean LVEF 31% ± 5.5%). Over the 5.1-year median follow-up, the composite primary outcome of cardiovascular death, stroke or hospitalization for worsening of heart failure or for acute coronary syndrome occurred less often in patients randomized to ERC (94/396; 5.7 per 100 patient-years) compared with patients randomized to UC (130/402; 7.9 per 100 patient-years; hazard ratio 0.74 [0.56-0.97], p=0.03), not altered by heart failure status (interaction p-value=0.63). The primary safety outcome (death, stroke, or serious adverse events related to rhythm control therapy) occurred in 71/396 (17.9%) heart failure patients randomized to ERC and in 87/402 (21.6%) heart failure patients randomized to UC (hazard ratio 0.85 [0.62-1.17], p=0.33). LV ejection fraction improved in both groups (LVEF change at two years: ERC 5.3%±11.6%, UC 4.9%±11.6%, p=0.43). ERC also improved the composite outcome of death or hospitalization for worsening of heart failure. Conclusions: Rhythm control therapy conveys clinical benefit when initiated within one year of diagnosing atrial fibrillation in patients with signs or symptoms of heart failure. Clinical Trial Registration: Unique Identifiers: ISRCTN04708680, NCT01288352, EudraCT2010-021258-20, Study web site www.easttrial.org; URLs: www.controlled-trials.com; https://clinicaltrials.gov; https://www.clinicaltrialsregister.eu

Background Despite advances in the management of bloodstream infections (BSI) caused by Candida spp., the mortality still remains high in critically ill patients. The worldwide epidemiology of yeast-related BSI is subject to changing species distribution and resistance patterns, challenging antifungal treatment strategies. The aim of this single-center study was to identify predictors of mortality after 28 and 180 days in a cohort of mixed surgical and medical critically ill patients with candidemia. Methods Patients, who had been treated for laboratory-confirmed BSI caused by Candida spp. in one of 12 intensive care units (ICU) at a University hospital between 2008 and 2017, were retrospectively identified. We retrieved data including clinical characteristics, Candida species distribution, and antifungal management from electronic health records to identify risk factors for mortality at 28 and 180 days using a Cox regression model. Results A total of 391 patients had blood cultures positive for Candida spp. (incidence 4.8/1000 ICU admissions). The mortality rate after 28 days was 47% (n = 185) and increased to 60% (n = 234) after 180 days. Age (HR 1.02 [95% CI 1.01–1.03]), a history of liver cirrhosis (HR 1.54 [95% CI 1.07–2.20]), septic shock (HR 2.41 [95% CI 1.73–3.37]), the Sepsis-related Organ Failure Assessment score (HR 1.12 [95% CI 1.07–1.17]), Candida score (HR 1.25 [95% CI 1.11–1.40]), and the length of ICU stay at culture positivity (HR 1.01 [95% CI 1.00–1.01]) were significant risk factors for death at 180 days. Patients, who had abdominal surgery (HR 0.66 [95% CI 0.48–0.91]) and patients, who received adequate (HR 0.36 [95% CI 0.24–0.52]) or non-adequate (HR 0.31 [95% CI 0.16–0.62]) antifungal treatment, had a reduced mortality risk compared to medical admission and no antifungal treatment, respectively. Conclusions The mortality of critically ill patients with Candida BSI is high and is mainly determined by disease severity, multiorgan dysfunction, and antifungal management rather than species distribution and susceptibility. Our results underline the importance of timely treatment of candidemia. However, controversies remain on the optimal definition of adequate antifungal management.