Background: Sodium-glucose cotransporter 2 inhibitors improve outcomes in patients with heart failure with reduced ejection fraction, but additional information is needed about whether glycemic status influences the magnitude of their benefits on heart failure and renal events. Methods: Patients with Class II–IV heart failure and a left ventricular ejection fraction ≤40% were randomized to receive empagliflozin (10 mg daily) or placebo in addition to recommended therapy. We prespecified a comparison of the effect of empagliflozin in patients with and without diabetes. Results: Of the 3730 patients enrolled, 1856 (50%) had diabetes, 1268 (34%) had prediabetes (hemoglobin A1c [HbA1c] 5.7–6.4%), and 606 (16%) had normoglycemia (HbA1c <5.7%). The risks of the primary outcome (cardiovascular death or hospitalization for heart failure), total hospitalizations for heart failure, and adverse renal outcomes were higher in patients with diabetes, but were similar between patients with prediabetes and normoglycemia. Empagliflozin reduced the risk of the primary outcome in patients with and without diabetes (hazard ratio, 0.72 [95% CI, 0.60–0.87] and 0.78 [95% CI, 0.64–0.97], respectively, P -interaction=0.57). Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total hospitalizations for heart failure, on the decline in estimated glomerular filtration rate over time, and on the risk of serious adverse renal outcomes. Among these end points, the effects of the drug did not differ in patients with prediabetes or normoglycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome ( P -interaction=0.40). Empagliflozin did not lower HbA1c in patients with prediabetes or normoglycemia and was not associated with increased risk of hypoglycemia. Conclusions: In EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin significantly improved cardiovascular and renal outcomes in patients with heart failure and a reduced ejection fraction, independent of baseline diabetes status and across the continuum of HbA1c. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03057977.

Background: The impact of hospital readmission reduction program (HRRP) on heart failure (HF) outcomes has been debated. Limited data exist regarding trends of HF readmission rates beyond 30 days from all-payer sources. The aim of this study was to investigate temporal trends of 30- and 90-day HF readmissions rates from 2010 to 2017 in patients from all-payer sources. Methods: The National Readmission Database was utilized to identify HF hospitalizations between 2010 and 2017. In the primary analysis, a linear trend in 30-day and 90-day readmissions from 2010 to 2017 was assessed. While in the secondary analysis, a change in aggregated 30- and 90-day all-cause and HF-specific readmissions pre-HRRP penalty phase (2010–2012) and post-HRRP penalties (2013–2017) was compared. Subgroup analyses were performed based on (1) Medicare versus non-Medicare insurance, (2) low versus high HF volume, and (3) HF with reduced versus preserved ejection fraction (heart failure with reduced ejection fraction and heart failure with preserved ejection fraction). Multiple logistic and adjusted linear regression analyses were performed for annual trends. Results: A total of 6 669 313 index HF hospitalizations for 30-day, and 5 077 949 index HF hospitalizations for 90-day readmission, were included. Of these, 1 213 402 (18.2%) encounters had a readmission within 30 days, and 1 585 445 (31.2%) encounters had a readmission within 90 days. Between 2010 and 2017, both 30 and 90 days adjusted HF-specific and all-cause readmissions increased (8.1% to 8.7%, P trend 0.04, and 18.3% to 19.9%, P trend <0.001 for 30-day and 14.8% to 16.0% and 30.9% to 34.6% for 90-day, P trend <0.001 for both, respectively). Readmission rates were higher during the post-HRRP penalty period compared with pre-HRRP penalty phase (all-cause readmission 30 days: 18.6% versus 17.5%, P <0.001, all-cause readmission 90 days: 32.0% versus 29.9%, P <0.001) across all subgroups except among the low-volume hospitals. Conclusions: The rates of adjusted HF-specific and all-cause 30- and 90-day readmissions have increased from 2010 to 2017. Readmissions rates were higher during the HRRP phase across all subgroups except the low-volume hospitals.

Background: Influenza infection causes considerable morbidity and mortality in patients with cardiovascular disease. We assessed the effects of the influenza vaccine on mortality and cardiovascular outcomes in patients with cardiovascular disease. Methods and Results: We searched PubMed, Embase, and the Cochrane Library through January 2020 for randomized controlled trials and observational studies assessing the effects of influenza vaccine on mortality and cardiovascular outcomes in patients with cardiovascular disease. Estimates were reported as random effects risk ratios (RRs) with 95% CIs. Analyses were stratified by study design into randomized controlled trials and observational studies. A total of 16 studies (n=237 058), including 4 randomized controlled trials (n=1667) and 12 observational studies (n=235 391), were identified. Participants' mean age was 69.2±7.01 years, 36.6% were women, 65.1% had hypertension, 31.1% had diabetes mellitus, and 23.4% were smokers. At a median follow‐up duration of 19.5 months, influenza vaccine was associated with a lower risk of all‐cause mortality (RR, 0.75; 95% CI, 0.60–0.93 [ P =0.01]), cardiovascular mortality (RR, 0.82; 95% CI, 0.80–0.84 [ P <0.001]), and major adverse cardiovascular events (RR, 0.87; 95% CI, 0.80–0.94 [ P <0.001]) compared with control. The use of the influenza vaccine was not associated with a statistically significant reduction of myocardial infarction (RR, 0.73; 95% CI, 0.49–1.09 [ P =0.12]) compared with control. Conclusions: Data from both randomized controlled trials and observational studies support the use of the influenza vaccine in adults with cardiovascular disease to reduce mortality and cardiovascular events, as currently supported by clinical guidelines. Clinicians and health systems should continue to promote the influenza vaccine as part of comprehensive secondary prevention.

At least half of all patients with heart failure (HF) are affected by frailty, a syndrome that limits an individual ability to recover from acute stressors. While frailty affects up to 90% of patients with HF with preserved ejection fraction, it is also seen in ~30–60% of patients with HF with reduced ejection fraction, with ~26% higher prevalence in women compared with men. The relationship between frailty and HF is bidirectional, with both conditions exacerbating the other. Frailty is further complicated by a higher prevalence of sarcopenia (by ~20%) in HF patients compared with patients without HF, which negatively affects outcomes. Several frailty assessment methods have been employed historically including the Fried frailty phenotype and Rockwood Clinical Frailty Scale to classify HF patients based on the severity of frailty; however, a validated HF‐specific frailty assessment tool does not currently exist. Frailty in HF is associated with a poor prognosis with a 1.5‐fold to 2‐fold higher risk of all‐cause death and hospitalizations compared to non‐frail patients. Frailty is also highly prevalent in patients with worsening HF, affecting >50% of patients hospitalized for HF. Such patients with multiple readmissions for decompensated HF have markedly poor outcomes compared to younger, non‐frail cohorts, and it is hypothesized that it may be due to major physical and functional limitations that limit recovery from an acute episode of worsening HF, a care aspect that has not been addressed in HF guidelines. Frail patients are thought to confer less benefit from therapeutic interventions due to an increased risk of perceived harm, resulting in lower adherence to HF interventions, which may worsen outcomes. Multiple studies report that <40% of frail patients are on guideline‐directed medical therapy for HF, of which most are on suboptimal doses of these medications. There is a lack of evidence generated from randomized trials in this incredibly vulnerable population, and most current practice is governed by post hoc analyses of trials, observational registry‐based data and providers' clinical judgement. The current body of evidence suggests that the treatment effect of most guideline‐based interventions, including medications, cardiac rehabilitation and device therapy, is consistent across all age groups and frailty subgroups and, in some cases, may be amplified in the older, more frail population. In this review, we discuss the characteristics, assessment tools, impact on prognosis and impact on therapeutic interventions of frailty in patients with HF.

Background: In 1993, the US Food and Drug Administration established guidelines to increase diversity by sex and race/ethnicity of participants in clinical trials supporting novel drug approvals. In this study we investigated the 10‐year trends of participation of women and minorities in pivotal trials supporting approval of new molecular entities in cardiometabolic drugs from January 2008 to December 2017. Methods and Results: A list of new molecular entities was abstracted from publicly available data at Drugs@Fda . Sex and race/ethnicity data were collected from trial publications. Linear regression analysis was performed to assess the relation between drug approval year and proportion of women and minorities enrolled. Thirty‐five novel cardiovascular (n=24) and diabetes mellitus (n=11) drugs were approved by the US Food and Drug Administration during the study period. The median number of participants supporting each drug was 5930 (interquartile range, 3175–10 942). Women represented 36% (n=108 052) of trial participants (n=296 163). Women were underrepresented compared with their proportion of the disease population in trials of coronary heart disease (participation‐to‐prevalence ratio, 0.52), heart failure (participation‐to‐prevalence ratio, 0.58), and acute coronary syndrome (participation‐to‐prevalence ratio, 0.68). Among trial participants, 81% were white, 4% black, 12% Asian, and 11% Hispanic/Latino. There was no significant association between enrollment of women ( P =0.29) or underrepresented minorities ( P =0.45) with the drug approval year. Conclusions: Over the past decade (2008–2017), women and minorities, particularly blacks, have continued to be inadequately represented in pivotal cardiometabolic clinical trials that support US Food and Drug Administration approval of new molecular entities. This may have major implications in determining efficacy of such therapies in these groups, and may impair generalizability of trial results to routine clinical practice.