The addition of neprilysin inhibition to standard therapy, including a renin-angiotensin system blocker, has been demonstrated to improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF) compared with standard therapy alone. The long-term absolute risk reduction from angiotensin receptor-neprilysin inhibitor (ARNI) therapy, and whether it merits widespread use among diverse subpopulations, has not been well described. OBJECTIVE To calculate estimated 5-year number needed to treat (NNT) values overall and for different subpopulations for the Prospective Comparison of ARNI with Angiotensin-Converting Enzyme Inhibitor (ACEI) to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) cohort. DESIGN, SETTING, AND PARTICIPANTS Overall and subpopulation 5-year NNT values were estimated for different end points using data from PARADIGM-HF, a double-blind, randomized trial of sacubitril-valsartan vs enalapril. This multicenter, international study included 8399 men and women with HFrEF (ejection fraction, Յ40%). The study began in December 2009 and ended in March 2014. Analyses began in March 2018. INTERVENTIONS Random assignment to sacubitril-valsartan or enalapril. MAIN OUTCOMES AND MEASURES Cardiovascular death or HF hospitalization, cardiovascular death, and all-cause mortality. RESULTS The final cohort of 8399 individuals included 1832 women (21.8%) and 5544 white individuals (66.0%), with a mean (SD) age of 63.8 (11.4) years. The 5-year estimated NNT for the primary outcome of cardiovascular death or HF hospitalization with ARNI therapy incremental to ACEI therapy in the overall cohort was 14. The 5-year estimated NNT values were calculated for different clinically relevant subpopulations and ranged from 12 to 19. The 5-year estimated NNT for all-cause mortality in the overall cohort with ARNI incremental to ACEI was 21, with values ranging from 16 to 31 among different subgroups. Compared with imputed placebo, the 5-year estimated NNT for all-cause mortality with ARNI was 11. The 5-year estimated NNT values were also calculated for other HFrEF therapies compared with controls from landmark trials for all-cause mortality and were found to be 18 for ACEI, 24 for angiotensin receptor blockers, 8 for β-blockers, 15 for mineralocorticoid antagonists, 14 for implantable cardioverter defibrillator, and 14 for cardiac resynchronization therapy. CONCLUSIONS AND RELEVANCE The 5-year estimated NNT with ARNI therapy incremental to ACEI therapy overall and for clinically relevant subpopulations of patients with HFrEF are comparable with those for well-established HF therapeutics. These data further support guideline recommendations for use of ARNI therapy among eligible patients with HFrEF.

Background and Purpose: Studies suggest an increased risk of adverse outcomes among patients with acute ischemic stroke (AIS) and coronavirus disease 2019 (COVID-19). Methods: Using Get With The Guidelines–Stroke, we identified 41 971 patients (AIS/COVID-19: 1143; AIS/no COVID-19: 40 828) with AIS hospitalized between February 4, 2020 and June 29, 2020, from 458 Get With The Guidelines–Stroke hospitals with at least one COVID-19 case and evaluated clinical characteristics, treatment patterns, and outcomes. Results: Compared with patients with AIS/no COVID-19, those with AIS/COVID-19 were younger, more likely to be non-Hispanic Black, Hispanic, or Asian, more likely to present with higher National Institutes of Health Stroke Scale scores, and had greater proportions of large vessel occlusions. Rates of thrombolysis and thrombectomy were similar between the groups. Door to computed tomography (median 55 [18–207] versus 35 [14–99] minutes, P <0.001), door to needle (59 [40–82] versus 46 [33–64] minutes, P <0.001), and door to endovascular therapy (114 [74–169] versus 90 [54–133] minutes, P =0.002) times were longer in the AIS/COVID-19 cohort. In adjusted models, patients with AIS/COVID-19 had decreased odds of discharge with modified Rankin Scale score of ≤2 (odds ratio, 0.65 [95% CI, 0.52–0.81], P <0.001) and increased odds of in-hospital mortality (odds ratio, 4.34 [95% CI, 3.48–5.40], P <0.001). ConclusionS: This analysis demonstrates younger age, greater stroke severity, longer times to evaluation and treatment, and worse morbidity and mortality in patients with AIS/COVID-19 compared with those with AIS/no COVID-19.

Purpose of Review To describe the epidemiology, pathophysiology, management, and prognosis of patients with heart failure with mid-range ejection fraction (HFmrEF). Recent Findings In 2013, The American Heart Association (AHA)/American College of Cardiology (ACC) assigned an ejection fraction (EF) range to heart failure with reduced ejection fraction (HFrEF, EF ≤ 40%) and heart failure with preserved ejection fraction (HFpEF, EF ≥50%). This classification created a "gray zone" of patients with EFs between 41% and 49% that ultimately came to be known as heart failure with borderline or mid-range ejection fraction. HFmrEF patients represent a group with heterogeneous clinical characteristics that at times resembles HFrEF, at others HFpEF, and at others still a unique phenotype altogether. No randomized controlled trials exist in those with HFmrEF, though HFrEF and HFpEF studies that include overlap suggest some potential benefit of beta blockers, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and angiotensin receptor-neprilysin inhibitors. Mortality rates among the HFmrEF population are significant, and are similar to those in patients with HFrEF and HFpEF. Summary HFmrEF is a complex disorder that remains poorly understood. Future research is needed to better elucidate the pathophysiology, management, and prognosis of this condition.

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