Background Anaemia is common in patients with HFrEF and is associated with poor clinical outcomes. Although they reduce rates of mortality and heart failure hospitalization, renin-angiotensin (RAS) blockers lower haemoglobin and may induce anaemia. Concomitant neprilysin inhibition might ameliorate this effect of RAS blockers. Purpose We investigated the effect of sacubitril/valsartan compared with enalapril on clinical outcomes, according to anaemia status, and on haemoglobin levels in PARADIGM-HF. Methods Patient characteristics and clinical outcomes were compared between patients with and without anaemia (defined as haemoglobin <120 g/L in women and <130 g/L in men) at baseline. We investigated the effect of randomized treatment (sacubitril/valsartan or enalapril) on clinical outcomes according to anaemia status at screening. We also examined the effect of treatment on change in haemoglobin from baseline and on the incidence of anaemia. The primary endpoint in PARADIGM-HF was the composite of heart failure hospitalization or cardiovascular death. Results Of 8239 participants with a baseline haemoglobin measurement, 1677 (20.4%) were anaemic. Compared to those without anaemia, patients with anaemia had a more severe heart failure profile, worse kidney function, greater neurohormonal derangement and worse clinical outcomes. Sacubitril/valsartan, compared to enalapril, reduced the risk of the primary endpoint similarly in patients with anaemia (HR 0.84, 95% CI 0.71–1.00) and without anaemia (HR 0.78, 95% CI 0.71–0.87), p-value for interaction=0.478. Between baseline and 12 months, haemoglobin decreased by 1.5 (95% CI 1.7 to 1.2) g/L with sacubitril/valsartan compared with 2.3 (2.6 to 2.0) g/L with enalapril group: mean difference 0.8 (95% CI 0.5 to 1.2) g/L, p<0.001. The between-treatment difference apparent by 12 months, persisted up to 36 months. Patients assigned to sacubitril/valsartan were less likely to develop new anaemia at 12 months [321 of 2806 (11.4%)] compared to patients randomized to enalapril [440 of 2384 (15.6%)], odds ratio 0.70 (95% CI 0.60–0.81), p<0.001. Conclusions Compared to enalapril, sacubitril/valsartan reduced mortality and hospitalization in HFrEF patients with and without anaemia. Haemoglobin decreased less with sacubitril/valsartan and the incidence of new anaemia was lower in the sacubitril/valsartan group compared with the enalapril group. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): PARADIGM-HF was funded by Novartis.

Background Stroke is an important but neglected comorbidity in patients with heart failure (HF). Little is known about the characteristics and outcomes of HF patients with a history of stroke. Purpose To examine the prevalence of prior stroke in patients with HF and reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), the clinical characteristics of patients with a history of stroke, and the clinical outcomes in patients with prior stroke compared to those without. Methods Individual patient data analysis using three recent HFrEF trials (ATMOSPHERE, PARADIGM-HF, and DAPA-HF) and HFpEF trials (CHARM-Preserved, I-Preserve, TOPCAT-Americas, and PARAGON-HF). Cox regression was used to analyze clinical outcomes. Results Among 20159 HFrEF patients enrolled, 1683 (8.3%) had a history of stroke and among the 13252 patients with HFpEF 1287 (9.7%) had a prior stroke. Compared to patients without stroke, those with stroke were slightly older and more likely to have a history of hypertension, myocardial infarction, atrial fibrillation, diabetes, carotid artery disease, and peripheral artery disease (for both HFrEF and HFpEF). Patients with a history of stroke had worse NYHA class and KCCQ scores, and a higher rate of fatigue; they also had a higher median NT-proBNP level and lower eGFR than those without prior stroke (whether HFrEF or HFpEF). Systolic BP, pulse pressure and LVEF did not differ susbtantialy between patients with and without a history of stroke. The table shows outcomes according to history of stroke or not, stratified by LVEF phenotype. During follow-up, all fatal and non-fatal outcomes were significantly more common in patients with a history of stroke. The augmentation of risk tended to be greater in patients with HFpEF than HFrEF, but was not statistically different. Conclusion Approximately 1 in 11 patients in recent HF trials had a history of stroke and these patients were at higher risk of fatal and non-fatal events than those without prior stroke. HF hospitalization as well as atherothrombotic events (myocardial infarction and stroke) were more common among patients with prior stroke – patients with prior stroke had at least 30% higher risk of all events examined, regardless of LVEF, and more than double incidence of repeat stroke. Funding Acknowledgement Type of funding sources: Other.