Background: Comorbidities may differently affect treatment response and cause-specific outcomes in heart failure (HF) with preserved (HFpEF) vs. mid-range/mildly-reduced (HFmrEF) vs. reduced (HFrEF) ejection fraction (EF), complicating trial design. In patients with HF, we performed a comprehensive analysis of type 2 diabetes (T2DM), atrial fibrillation (AF) chronic kidney disease (CKD), and cause-specific outcomes. Methods and results: Of 42,583 patients from the Swedish HF registry (23% HFpEF, 21% HFmrEF, 56% HFrEF), 24% had T2DM, 51% CKD, 56% AF, and 8% all three comorbidities. HFpEF had higher prevalence of CKD and AF, HFmrEF had intermediate prevalence of AF, and prevalence of T2DM was similar across the EF spectrum. Patients with T2DM, AF and/or CKD were more likely to have also other comorbidities and more severe HF. Risk of cardiovascular (CV) events was highest in HFrEF vs. HFpEF and HFmrEF; non-CV risk was highest in HFpEF vs. HFmrEF vs. HFrEF. T2DM increased CV and non-CV events similarly but less so in HFpEF. CKD increased CV events somewhat more than non-CV events and less so in HFpEF. AF increased CV events considerably more than non-CV events and more so in HFpEF and HFmrEF. Conclusion: HFpEF is distinguished from HFmrEF and HFrEF by more comorbidities, non-CV events, but lower effect of T2DM and CKD on events. CV events are most frequent in HFrEF. To enrich for CV vs. non-CV events, trialists should not exclude patients with lower EF, AF and/or CKD, who report higher CV risk.

Background Comorbidities are associated with heart failure (HF) development, severity and outcomes, but may play different roles in HF with preserved (HFpEF) vs. mid-range (HFmrEF) vs. reduced ejection fraction (HFrEF). A detailed characterization of HF patients according to EF and comorbidities may improve prognostication and facilitate trial design. Purpose To investigate characteristics and outcomes in a large and unselected cohort of HF patients according to EF strata and presence/absence of concomitant type 2 diabetes (T2DM), atrial fibrillation (AF) and chronic kidney disease (CKD). Methods Patients enrolled in the Swedish HF registry between 2000–2012 were considered. Kaplan Meier curves and multivariable Cox regression models were fitted to assess risk and predictors of outcomes (HF and all-cause hospitalization; composite of cardiovascular (CV) death and HF hospitalization). Results Of 42,583 patients (23% HFpEF, 21% HFmrEF, 56% HFrEF), 24% had T2DM, 49% CKD defined as eGFR<60 ml/min/1.73m2, and 56% AF. T2DM, AF and CKD coexisted in 8% of the population with similar distribution across all EF strata. AF and CKD were the most likely to coexist. Prevalence of AF and/or CKD was highest in HFpEF and lowest in HFrEF, whereas prevalence of T2DM was similar across the EF spectrum (Figure). Compared to patients without T2DM and/or AF and/or CKD, those with any of them were more likely to suffer from other comorbidities (i.e. hypertension, anemia, COPD), to be inpatients, have more severe HF (higher NYHA class, NT-proBNP levels and use of diuretics, longer HF duration) but less likely to be followed-up in specialty vs. primary care. Concomitant history of ischemic heart disease was more likely in patients with vs. without CKD and/or T2DM but less likely in those with vs without AF. Patients with vs. without T2DM and/or CKD and/or AF had worse prognosis. In particular, risk of HF hospitalization and composite of HF hospitalization/CV death was highest in patients with HFrEF and concomitant comorbidities, whereas the risk of all-cause hospitalization was highest in those with HFpEF or HFmrEF and concomitant comorbidities. Prognostic predictors of CV death/HF hospitalization were consistent in patients with T2DM, CKD or AF, regardless of EF (e.g. male sex, older age, lower EF category, more severe HF, ischemic heart disease, anemia, COPD). Comorbidities burden Conclusion HF patients show a high burden of concomitant diseases, specifically T2DM, CKD and AF. CKD and AF are more prevalent in HFpEF vs. HFmrEF vs. HFrEF, whereas T2DM prevalence is consistent across the EF spectrum. Presence of comorbidities identifies patients with more severe HF regardless of EF category. Presence of comorbidities may identify patients at higher risk of CV outcomes in HFrEF and those at higher risk of non-CV events in HFpEF. Acknowledgement/Funding This study has been supported by funding from Boehringer Ingelheim