Worsening Heart Failure Events Research Articles

Dapagliflozin and New York Heart Association functional class in heart failure with mildly reduced or preserved ejection fraction: the DELIVER trial.

This pre-specified analysis of the DELIVER trial examined whether clinical benefits of dapagliflozin in heart failure (HF) with left ventricular ejection fraction (LVEF) >40% varied by baseline New York Heart Association (NYHA) class and examined the treatment effects on NYHA class over time. Treatment effects of dapagliflozin by baseline NYHA class II (n=4713) versus III/IV (n=1549) were examined on the primary endpoint (cardiovascular death or worsening HF event) and key secondary endpoints. Effects of dapagliflozin on change in NYHA class at 4, 16, and 32 weeks were also evaluated. Higher baseline NYHA class was associated with older age, female sex, greater comorbidity burden, lower LVEF, and higher natriuretic peptide levels. Participants with baseline NYHA class III/IV, as compared with II, were independently more likely to experience the primary endpoint (adjusted hazard ratio [HR] 1.16 [95% confidence interval, 1.02-1.33]) and all-cause death (adjusted HR 1.22 [1.06-1.40]). Dapagliflozin consistently reduced the risk of the primary endpoint compared with placebo, irrespective of baseline NYHA class (HR 0.81 [0.70-0.94] for NYHA class II vs. HR 0.80 [0.65-0.98] for NYHA class III/IV; pinteraction =0.921). Participants with NYHA class III/IV had greater improvement in Kansas City Cardiomyopathy Questionnaire total symptom scores between baseline and 32 weeks (+4.8 [2.5-7.1]) versus NYHA class II (+1.8 [0.7-2.9]; pinteraction =0.011). Dapagliflozin was associated with higher odds of any improvement in NYHA class (odds ratio [OR] 1.32 [1.16-1.51]), as well as improvement to NYHA class I (OR 1.43 [1.17-1.75]), versus placebo at 32 weeks, with benefits seen as early as 4 weeks. Among symptomatic patients with HF and LVEF >40%, treatment with dapagliflozin provided clinical benefit irrespective of baseline NYHA class and was associated with early and sustained improvements in NYHA class over time.

Dapagliflozin in Patients Recently Hospitalized With Heart Failure and Mildly Reduced or Preserved Ejection Fraction

BackgroundPatients recently hospitalized for heart failure (HF) are at high risk for rehospitalization and death. ObjectivesThe purpose of this study was to investigate clinical outcomes and response to dapagliflozin in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF) who were enrolled during or following hospitalization. MethodsThe DELIVER (Dapagliflozin Evaluation to Improve the LIVES of Patients With PReserved Ejection Fraction Heart Failure) trial randomized patients with HF and LVEF >40% to dapagliflozin or placebo. DELIVER permitted randomization during or shortly after hospitalization for HF in clinically stable patients off intravenous HF therapies. This prespecified analysis investigated whether recent HF hospitalization modified risk of clinical events or response to dapagliflozin. The primary outcome was worsening HF event or cardiovascular death. ResultsOf 6,263 patients in DELIVER, 654 (10.4%) were randomized during HF hospitalization or within 30 days of discharge. Recent HF hospitalization was associated with greater risk of the primary outcome after multivariable adjustment (HR: 1.88; 95% CI: 1.60-2.21; P < 0.001). Dapagliflozin reduced the primary outcome by 22% in recently hospitalized patients (HR: 0.78; 95% CI: 0.60-1.03) and 18% in patients without recent hospitalization (HR: 0.82; 95% CI: 0.72-0.94; Pinteraction = 0.71). Rates of adverse events, including volume depletion, diabetic ketoacidosis, or renal events, were similar with dapagliflozin and placebo in recently hospitalized patients. ConclusionsDapagliflozin safely reduced risk of worsening HF or cardiovascular death similarly in patients with and without history of recent HF hospitalization. Starting dapagliflozin during or shortly after HF hospitalization in patients with mildly reduced or preserved LVEF appears safe and effective. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)

Efficacy and Safety of Dapagliflozin According to Frailty in Patients With Heart Failure: A Prespecified Analysis of the DELIVER Trial.

Frailty is increasing in prevalence. Because patients with frailty are often perceived to have a less favorable risk/benefit profile, they may be less likely to receive new pharmacologic treatments. We investigated the efficacy and tolerability of dapagliflozin according to frailty status in patients with heart failure with mildly reduced or preserved ejection fraction randomized in DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure). Frailty was measured using the Rockwood cumulative deficit approach. The primary end point was time to a first worsening heart failure event or cardiovascular death. Of the 6263 patients randomized, a frailty index (FI) was calculable in 6258. In total, 2354 (37.6%) patients had class 1 frailty (FI ≤0.210; ie, not frail), 2413 (38.6%) had class 2 frailty (FI 0.211-0.310; ie, more frail), and 1491 (23.8%) had class 3 frailty (FI ≥0.311; ie, most frail). Greater frailty was associated with a higher rate of the primary end point (per 100 person-years): FI class 1, 6.3 (95% CI 5.7-7.1); class 2, 8.3 (7.5-9.1); and class 3, 13.4 (12.1-14.7; P<0.001). The effect of dapagliflozin (as a hazard ratio) on the primary end point from FI class 1 to 3 was 0.85 (95% CI, 0.68-1.06), 0.89 (0.74-1.08), and 0.74 (0.61-0.91), respectively (Pinteraction=0.40). Although patients with a greater degree of frailty had worse Kansas City Cardiomyopathy Questionnaire scores at baseline, their improvement with dapagliflozin was greater than it was in patients with less frailty: placebo-corrected improvement in Kansas City Cardiomyopathy Questionnaire Overall Summary Score at 4 months in FI class 1 was 0.3 (95% CI, -0.9 to 1.4); in class 2, 1.5 (0.3-2.7); and in class 3, 3.4 (1.7-5.1; Pinteraction=0.021). Adverse reactions and treatment discontinuation, although more frequent in patients with a greater degree of frailty, were not more common with dapagliflozin than with placebo irrespective of frailty class. In DELIVER, frailty was common and associated with worse outcomes. The benefit of dapagliflozin was consistent across the range of frailty studied. The improvement in health-related quality of life with dapagliflozin occurred early and was greater in patients with a higher level of frailty. URL: https://www. gov; Unique identifier: NCT03619213.

Analysis of Worsening Heart Failure Events in an Integrated Health Care System

BackgroundThere is growing interest to disentangle worsening heart failure (WHF) from location of care and move away from hospitalization as a surrogate for acuity. ObjectivesThe purpose of this study was to describe the incidence of WHF events across the care continuum from ambulatory encounters to hospitalizations. MethodsWe studied calendar year cohorts of adults with diagnosed heart failure (HF) from 2010-2019 within a large, integrated health care delivery system. Electronic health record (EHR) data were accessed for outpatient encounters, emergency department (ED) visits/observation stays, and hospitalizations. WHF was defined as ≥1 symptom, ≥2 objective findings including ≥1 sign, and ≥1 change in HF-related therapy. Symptoms and signs were ascertained using natural language processing. ResultsWe identified 103,138 eligible individuals with mean age 73.6 ± 13.7 years, 47.5% women, and mean left ventricular ejection fraction of 51.4% ± 13.7%. There were 1,136,750 unique encounters including 743,039 (65.4%) outpatient encounters, 224,670 (19.8%) ED visits/observation stays, and 169,041 (14.9%) hospitalizations. A total of 126,008 WHF episodes were identified, including 34,758 (27.6%) outpatient encounters, 28,301 (22.5%) ED visits/observation stays, and 62,949 (50.0%) hospitalizations. The annual incidence (events per 100 person-years) of WHF increased from 25 to 33 during the study period primarily caused by outpatient encounters (7 to 10) and ED visits/observation stays (4 to 7). The 30-day rate of hospitalizations for WHF ranged from 8.2% for outpatient encounters to 12.4% for hospitalizations. ConclusionsED visits/observation stays and outpatient encounters account for approximately one-half of WHF events, are driving the underlying growth in HF morbidity, and portend a poor short-term prognosis.

CO16 Association between Adherence and Worsening Heart Failure Events in an Employed Population

Heart failure (HF) is an important concern for employers because of its increasing prevalence, morbidity, mortality and cost. The purpose of this study is to describe the heart failure population in an employed population and the association between pharmacotherapy adherence and developing worsening heart failure events (WHFEs).

MO634: Effects of Dapagliflozin in Patients with Heart Failure

Abstract BACKGROUND AND AIMS In patients with type 2 diabetes, inhibitors of sodium–glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes. METHOD A multicenter prospective cohort study, where 225 patients with heart failure (III and IV by NYHA) and an ejection fraction of 45% or less to receive either dapagliflozin (10 mg once daily) or placebo, in addition to basic therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death. RESULTS After 12 months, the primary outcome occurred in 17 of 111 patients (15.31%) in the dapagliflozin group and in 24 of 114 patients (21.05%) in the placebo group {HR 0.74 [95% confidence interval (CI), 0.65–0.85]; P &amp;lt; 0.001}. A first worsening heart failure event occurred in 10 patients (9.0%) in the dapagliflozin group and in 16 patients (14.0%) in the placebo group [HR 0.70 (95% CI 0.59–0.85)]. Death from cardiovascular reasons occurred in six patients (5.4%) in the dapagliflozin group and in 11 patients (9.6%) in the placebo group [HR 0.80 (95% CI 0.69–0.95)]; 12 patients (10.8%) and 15 patients (13.1%), respectively, died from other causes [HR 0.83 (95% CI 0.71–0.96)]. Findings in patients with diabetes were not significantly pronounced than in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction and hypo/hyperglycemia did not differ between treatment groups. CONCLUSION Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular events was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.

Effect Of Saxagliptin On LV Structure And Function In Patients With Type 2 Diabetes And Heart Failure: Results Of Measure-HF

Introduction Further investigation was suggested by the SAVOR-TIMI 53 results regarding the risk of hospitalisation for heart failure (HF) and the dipeptidyl-peptidase 4 inhibitor saxagliptin (SAXA), especially for high-risk patients with type 2 diabetes (T2D) and established HF with reduced ejection fraction (HFrEF). The Measure-HF Trial investigated the effect of SAXA on left ventricular (LV) structure, function and N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with T2D and established symptomatic heart failure with LV ejection fraction (LVEF) &lt 45% (HFrEF) and NT-proBNP &gt 300 pg/mL. Methods Patients were randomised to SAXA (n=112), sitagliptin (SITA, n=115) or placebo (PBO, n=121) plus usual care for 24 weeks. Primary endpoint was change from baseline in LV end diastolic volume index (LVEDVi) measured by MRI (core laboratory). Secondary endpoints included changes in LV end systolic volume index (LVESVi), LVEF, LV mass, and NT-proBNP levels. Worsening HF events were adjudicated. Exploratory analyses also evaluated the same endpoints for SITA vs PBO. Results Mean age was 65.4 years, 68.9% male, mean LVEF 37.3%, and median NT-proBNP 941 pg/mL. Primary and secondary endpoints demonstrated no difference between SAXA vs PBO (Table). There was no significant difference in the change in NT-proBNP levels between SAXA and PBO groups. The changes in endpoints for SITA were consistent with those of SAXA. Adjudicated HF events were balanced: SAXA (5), SITA (3) and PBO (6). Conclusions In patients with T2D and HFrEF, SAXA compared with PBO produced no unfavorable effects on LV structure, function or natriuretic peptide levels. Further investigation was suggested by the SAVOR-TIMI 53 results regarding the risk of hospitalisation for heart failure (HF) and the dipeptidyl-peptidase 4 inhibitor saxagliptin (SAXA), especially for high-risk patients with type 2 diabetes (T2D) and established HF with reduced ejection fraction (HFrEF). The Measure-HF Trial investigated the effect of SAXA on left ventricular (LV) structure, function and N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with T2D and established symptomatic heart failure with LV ejection fraction (LVEF) &lt 45% (HFrEF) and NT-proBNP &gt 300 pg/mL. Patients were randomised to SAXA (n=112), sitagliptin (SITA, n=115) or placebo (PBO, n=121) plus usual care for 24 weeks. Primary endpoint was change from baseline in LV end diastolic volume index (LVEDVi) measured by MRI (core laboratory). Secondary endpoints included changes in LV end systolic volume index (LVESVi), LVEF, LV mass, and NT-proBNP levels. Worsening HF events were adjudicated. Exploratory analyses also evaluated the same endpoints for SITA vs PBO. Mean age was 65.4 years, 68.9% male, mean LVEF 37.3%, and median NT-proBNP 941 pg/mL. Primary and secondary endpoints demonstrated no difference between SAXA vs PBO (Table). There was no significant difference in the change in NT-proBNP levels between SAXA and PBO groups. The changes in endpoints for SITA were consistent with those of SAXA. Adjudicated HF events were balanced: SAXA (5), SITA (3) and PBO (6). In patients with T2D and HFrEF, SAXA compared with PBO produced no unfavorable effects on LV structure, function or natriuretic peptide levels.

Healthcare Disparities In Heart Failure Patients And Use Of Sodium Glucose Co-Transport Inhibitors (SGLT2-i)

Introduction Co-existence of heart failure (HF) and diabetes presents myriad of challenges in patientcare which are further complicated by socioeconomic disparities that disproportionately affect patients of color. To understand and address the unique challenges faced by socioeconomically disadvantaged HF-patient population in the Bronx county of New York City, we sought to phenotype the burden of diabetes, and understand any disparities including the use of SGLT2-i. Methods Consecutive adult(18years and older) HF patients [reduced and preserved left-ventricular ejection fraction (LVEF)] seen in the advanced-HF clinics were included in the analysis. Patients were categorized based on race/ethnicity and compared for baseline characteristics and associated outcomes including worsening HF event, all-cause hospitalization in the previous 1-year, and medication adverse-events. Results Of the 1218 HF-patients [n=556 non-Hispanic-Black (nH-Black), n=485 Hispanic, n=177 non-Hispanic-White (nH-White)]; 541(44.4%) had type-2 diabetes-mellitus (44.1% nH-Black, 47.0% Hispanic, 38.4% nH-White, p=0.14). In the HF-DM cohort, substantial proportion (20.9%) had poorly controlled diabetes (HgA1c 9% or higher) that did not vary with race/ethnicity. The median-household-income based on residential address was significantly lower for nH-Black $41,500 (33,490-58,392) and Hispanic $37,804 (29,579-54,278) cohorts compared to nH-White $65,399 (52,091-92,232) cohort. Overall use of SGLT2-i was low (5.7% overall, 0.9% in HF-NoDM and 11.7% HF-DM). On further analysis of HF-DM patients based on SGLT2-i use, patients on SGLT2-i were younger [62(54-69)vs.66(58-75)years], more nH-White (22.2%vs.11.3%); but were also more likely to have HF with reduced ejection fraction (HFrEF)(69.8%vs.54.2%), more poorly controlled DM (31.8%vs.19.5%) and higher median HgA1c levels[7.9(6.9-9.2)vs.7.0(6.3-8.4)%], all p<0.05. Based on race/ethnicity, while the three groups had statistically similar rates of worsening HF events (30.9% nH-Black, 26.0% Hispanic, 24.3% nH-White, p=0.104), the rate of all-cause hospitalization was higher in nH-Black(38.9% nH-Black, 32.2% Hispanic, 31.2% nH-White, p=0.040) . Using logistic-regression model, nH-Black had higher Odds-ratio (OR)=1.46(1.01-2.11), p=0.043 when compared to nH-White for all-cause hospitalization adjusted for age, gender, DM, hypertension, ischemic-cardiomyopathy and LVEF. However, this association was substantially attenuated (p=0.14) when the model was adjusted for median-household-income. Conclusion These findings highlight the complex relationships between income inequality, social determinants of health (including language barriers) and observed racial/ethnic differences in HF and diabetes. Co-existence of heart failure (HF) and diabetes presents myriad of challenges in patientcare which are further complicated by socioeconomic disparities that disproportionately affect patients of color. To understand and address the unique challenges faced by socioeconomically disadvantaged HF-patient population in the Bronx county of New York City, we sought to phenotype the burden of diabetes, and understand any disparities including the use of SGLT2-i. Consecutive adult(18years and older) HF patients [reduced and preserved left-ventricular ejection fraction (LVEF)] seen in the advanced-HF clinics were included in the analysis. Patients were categorized based on race/ethnicity and compared for baseline characteristics and associated outcomes including worsening HF event, all-cause hospitalization in the previous 1-year, and medication adverse-events. Of the 1218 HF-patients [n=556 non-Hispanic-Black (nH-Black), n=485 Hispanic, n=177 non-Hispanic-White (nH-White)]; 541(44.4%) had type-2 diabetes-mellitus (44.1% nH-Black, 47.0% Hispanic, 38.4% nH-White, p=0.14). In the HF-DM cohort, substantial proportion (20.9%) had poorly controlled diabetes (HgA1c 9% or higher) that did not vary with race/ethnicity. The median-household-income based on residential address was significantly lower for nH-Black $41,500 (33,490-58,392) and Hispanic $37,804 (29,579-54,278) cohorts compared to nH-White $65,399 (52,091-92,232) cohort. Overall use of SGLT2-i was low (5.7% overall, 0.9% in HF-NoDM and 11.7% HF-DM). On further analysis of HF-DM patients based on SGLT2-i use, patients on SGLT2-i were younger [62(54-69)vs.66(58-75)years], more nH-White (22.2%vs.11.3%); but were also more likely to have HF with reduced ejection fraction (HFrEF)(69.8%vs.54.2%), more poorly controlled DM (31.8%vs.19.5%) and higher median HgA1c levels[7.9(6.9-9.2)vs.7.0(6.3-8.4)%], all p<0.05. Based on race/ethnicity, while the three groups had statistically similar rates of worsening HF events (30.9% nH-Black, 26.0% Hispanic, 24.3% nH-White, p=0.104), the rate of all-cause hospitalization was higher in nH-Black(38.9% nH-Black, 32.2% Hispanic, 31.2% nH-White, p=0.040) . Using logistic-regression model, nH-Black had higher Odds-ratio (OR)=1.46(1.01-2.11), p=0.043 when compared to nH-White for all-cause hospitalization adjusted for age, gender, DM, hypertension, ischemic-cardiomyopathy and LVEF. However, this association was substantially attenuated (p=0.14) when the model was adjusted for median-household-income. These findings highlight the complex relationships between income inequality, social determinants of health (including language barriers) and observed racial/ethnic differences in HF and diabetes.

Medication Trajectory and Treatment Patterns in Medicare Patients With Heart Failure and Reduced Ejection Fraction

Although a worsening heart failure event (WHFE) is associated with poor outcomes in patients with heart failure with reduced ejection fraction (HFrEF), it is unclear how guideline-directed medical therapy (GDMT) is used in this population compared to those without WHFEs. This study evaluated treatment patterns in patients with HFrEF, both with and without WHFEs. A retrospective study using 100% Medicare Fee-For-Service claims identified beneficiaries with HFrEF, stratified by those with and without WHFEs (defined as hospitalization due to HF or outpatient intravenous diuretic use). The use of GDMT for HFrEF before and after WHFEs and adherence were assessed in patients who were prescribed and initiated GDMT. Logistic regression identified patients' characteristics associated with medication nonadherence. Of 353,642 patients with HFrEF, 31.4% had a WHFE. Although there was no overall change in the treatment trajectory of patients without WHFEs, GDMT use in patients with WHFEs intensified within the first 3 months of a WHFE, but the intensification was not sustained in subsequent months. From 0-3 months pre-WHFE to 0-3 months post-WHFE, the proportion of patients receiving dual (41%-48%) and triple-therapy (4%-12%) increased, followed by a decline to pre-WHFE rates. The 1-year adherence rates for those with and without WHFEs were 67.9% vs 73.3% for beta-blockers; 59.1% vs 70.9% for angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor-neprilysin inhibitors, beta-blockers, and mineralocorticoid receptor antagonists; 53.9% vs 61.3% for angiotensin receptor-neprilysin inhibitors; and 49.2% vs 59.3% for mineralocorticoid receptor antagonists. WHFE, age < 65 years, Black race, asthma, chronic kidney disease, and depression were associated with nonadherence to medications. Asians and Hispanics were less adherent to some medication classes. This study demonstrated underuse of GDMT for patients with HFrEF with or without WHFEs. Although there was a treatment escalation within 3 months following WHFE, it was not sustained thereafter.

Clinical trajectory of patients with a worsening heart failure event and reduced ventricular ejection fraction

Recent data suggest that patients with heart failure with reduced ejection fraction (HFrEF) and worsening heart failure (WHF) have potential for greater benefit from newer HF therapies. We investigated characteristics and outcomes of patients with HFrEF and WHF by severity of left ventricular dysfunction. We identified patients with chronic symptomatic HFrEF (left ventricular ejection fraction [LVEF] ≤35%) and evidence of WHF (emergency department visit or hospitalization for acute HF within 12 months of index echocardiogram) treated at Duke University between 1/2009 and 12/2018. Patients were stratified by LVEF≤25% or 26% to35%. Cox models were used to estimate cause-specific hazard ratios and 5-year event incidence of death and hospitalization across the range of LVEF. Of 2823 patients with HFrEF and WHF, 1620 (57.4%) had an LVEF≤25% and 1203 (42.6%) had an LVEF 26% to35%. Compared to patients with LVEF 26% to35%, those with LVEF≤25% were younger and more commonly men with a lower cardiovascular comorbidity burden. Patients with LVEF≤25% were less commonly on beta blockers (85.9% vs 90.5%) but more commonly treated with mineralocorticoid receptor antagonists (49.3% vs 41.1%) and implantable defibrillators (41.3% vs 28.2%). Patients with LVEF≤25% had significantly higher hazards for death (HR 1.24 [95% CI 1.11 - 1.38]), all-cause hospitalization (HR 1.21 [95% CI 1.10 - 1.33]), and HF hospitalization (HR 1.25 [95% CI 1.1 - 1.38]) through 5-years. More than half of patients with chronic HFrEF and WHF have severe LV dysfunction. Important differences in comorbidities, HF therapies, and outcomes exist between those with LVEF≤25% and those with LVEF 26% to35%.

N-terminal pro-B-type natriuretic peptide testing patterns in patients with heart failure with reduced ejection fraction.

AimsThe N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) is a commonly used biomarker in heart failure for diagnosis and prognostication. We aimed to determine the prevalence of NT‐proBNP testing, distribution of NT‐proBNP concentrations, and factors associated with receiving an NT‐proBNP test in patients with heart failure with reduced ejection fraction (HFrEF), including the subset with a worsening heart failure event (WHFE).Methods and resultsThis was a retrospective cohort study using two US databases: (i) the de‐identified Humana Research Database between January 2015 and December 2018 and (ii) the Veradigm PINNACLE Registry® between July 2013 and September 2017. We included adult patients with a confirmed diagnosis of HFrEF. In each data source, a subgroup of patients with a WHFE was identified, where a WHFE was defined as a heart failure‐related hospitalization or receipt of intravenous diuretics. Bivariate and multivariate analyses were conducted to assess factors associated with receiving NT‐proBNP testing. In Cohort 1 (n = 249 238), 9.2% of patients with HFrEF and 10.8% of patients with a WHFE received NT‐proBNP testing. When restricted to patients with at least one laboratory claim, 11.3% of patients with HFrEF and 13.2% of those with a WHFE received NT‐proBNP testing. In Cohort 2 (n = 91 444), 2.3% of patients with HFrEF were tested. Median (inter‐quartile range) NT‐proBNP concentrations among patients with HFrEF were 1399 (423–4087) pg/mL in Cohort 1 and 394 (142–688) pg/mL in Cohort 2. Median (inter‐quartile range) NT‐proBNP concentrations in the subset of patients with a WHFE in each cohort were 2209 (740–5894) and 464 (174–783) pg/mL, respectively. In Cohort 1, 13.4% of all HFrEF patients receiving NT‐proBNP testing and 18.9% of patients with a WHFE had NT‐proBNP values >8000 pg/mL; in Cohort 2, these percentages were 1.0% and 2.5%, respectively.ConclusionsIn US clinical practice, NT‐proBNP testing was not frequently performed in patients with HFrEF. NT‐proBNP concentrations varied across data sources and subpopulations within HFrEF.

Comparison of Pharmacological Treatment Effects on Long-Time Outcomes in Heart Failure With Preserved Ejection Fraction: A Network Meta-analysis of Randomized Controlled Trials.

Beneficial effects of therapeutic drugs are controversial for heart failure with preserved ejection fraction (HFpEF). This meta-analysis aimed to evaluate and compare the interactive effects of different therapeutic drugs and placebo in patients with HFpEF. A comprehensive search was conducted using PubMed, Google Scholar, and Cochrane Central Register to identify related articles published before March 2021. The primary outcome was all-cause mortality. Secondary outcomes were cardiovascular mortality, heart failure (HF) hospitalization, and worsening HF events. A total of 14 randomized controlled trials, comprising 19,573 patients (intervention group, n = 9,954; control group, n = 9,619) were included in this network meta-analysis. All-cause mortality, cardiovascular mortality, and worsening HF events among therapeutic drugs and placebo with follow-up of 0.5–4 years were not found to be significantly correlated. The angiotensin receptor neprilysin inhibitor (ARNI) and angiotensin-converting enzyme inhibitor (ACEI) significantly reduced the HF hospitalizations compared with placebo (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.60–0.87 and HR 0.64, 95% CI 0.43–0.96, respectively), without heterogeneity among studies. The ARNI was superior to angiotensin receptor blocker (ARB) in reducing HF hospitalizations (HR 0.80, 95% CI 0.71–0.91), and vericiguat 10 mg ranked worse than beta-blockers for reducing all-cause mortality in patients with HFpEF (HR 3.76, 95% CI 1.06–13.32). No therapeutic drugs can significantly reduce mortality, but the ARNI or ACEI is associated with the low risk of HF hospitalizations for patients with HFpEF. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021247034

Dapagliflozin and atrial fibrillation in heart failure with reduced ejection fraction: insights from DAPA-HF.

Among patients with heart failure (HF) and reduced ejection fraction (HFrEF), those with atrial fibrillation (AF) may respond differently to certain treatments than patients without AF. We investigated the efficacy and safety of dapagliflozin in patients with HFrEF with and without AF in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF). We also examined the effect of dapagliflozin on new-onset AF. The primary outcome was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death. Of the 4744 patients randomized, 1910 (40.3%) had 'any AF' (history of AF or AF on enrolment electrocardiogram). Compared with placebo, dapagliflozin reduced the risk of worsening HF or cardiovascular death to a similar extent in patients with and without any AF [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.62-0.92 and 0.74, 95% CI 0.62-0.88, respectively; p for interaction=0.88]. Consistent benefits were observed for the components of the primary outcome, all-cause mortality, and improvement of Kansas City Cardiomyopathy Questionnaire total symptom score. Among patients without AF at baseline, dapagliflozin did not significantly reduce the risk of new-onset AF compared with placebo (HR 0.86, 95% CI 0.60-1.22). However, patients with new-onset AF had a 5 to 6-fold higher risk of adverse outcomes when compared to those without incident AF. Dapagliflozin, compared with placebo, reduced the risk of worsening HF events, cardiovascular death, and all-cause death, and improved symptoms, in patients with and without AF. Dapagliflozin did not reduce the risk of new-onset AF.

Abstract 9958: Calcium-Phosphorus Product is Associated with Adverse Prognosis in Hospitalized Patients with Heart Failure and Chronic Kidney Disease

Introduction: It has been reported that calcium-phosphorus (Ca-P) product &amp;gt 55 mg 2 /dl 2 is an independent predictor for coronary calcifications, and Ca-P product &amp;gt 80 or &amp;lt 40 is a mortality risk in patients undergoing chronic hemodialysis. However, the association between Ca-P product and prognosis in patients with heart failure (HF) and chronic kidney disease (CKD) remains unclear. We aimed to evaluate the significance of the Ca-P product to predict prognosis of patients with HF and CKD. Methods: We conducted a prospective observational study of 793 patients with decompensated HF and CKD, who had been discharged from our hospital. According to the receiver operating characteristic curve analysis, the accurate cut-off value of Ca-P product in predicting post-discharge all-cause mortality and/or worsening HF was 28 mg 2 /dl 2 . These patients were divided into two groups: the high group (Ca-P product &amp;gt 28, n=594) and the low group (Ca-P product &amp;lt 28, n=199). We compared the patient baseline characteristics and their post-discharge prognosis between the two groups. Results: Age was significantly higher, and the prevalence of male, ischemic etiology and anemia was significantly higher in the low group than in the high group. In contrast, there was no difference in echocardiographic parameters between two groups. Ca-P product was correlated with cardio-ankle vascular index (a marker of arterial stiffness), but not with left ventricular ejection fraction. In the Kaplan-Meier analysis (mean follow-up 1089 days), all-cause mortality and/or worsening HF event rates were higher in the low group than in the high group (Figure, log-rank P=0.001). In the multivariable Cox proportional hazard analysis, the low group was found to be an independent predictor of all-cause mortality and/or worsening HF (hazard ratio 1.218, P=0.048). Conclusions: Lower Ca-P product is associated with arterial stiffness, and predicts adverse prognosis in patients with HF and CKD.

Efficacy of Dapagliflozin in Black Versus White Patients With Heart Failure and Reduced Ejection Fraction

ObjectivesThis study sought to investigate the efficacy and safety of dapagliflozin in Black and White patients with heart failure (HF) with reduced ejection fraction (HFrEF) enrolled in DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure). BackgroundBlack patients may respond differently to certain treatments for HFrEF than White patients. MethodsPatients with New York Heart Association functional class II to IV with an ejection fraction of ≤40% and elevated N-terminal pro–B-type natriuretic peptide were eligible for DAPA-HF. Because >99% of Black patients were randomized in the Americas, this post hoc analysis considered Black and White patients enrolled only in North and South America. The primary outcome was the composite of a worsening HF event (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death. ResultsOf the 4,744 patients randomized in DAPA-HF, 1,494 (31.5%) were enrolled in the Americas. Of these, 1,181 (79.0%) were White, and 225 (15.1%) were Black. Black patients had a higher rate of worsening HF events, but not mortality, compared with White patients. Compared with placebo, dapagliflozin reduced the risk of the primary endpoint similarly in Black patients (HR: 0.62; 95% CI: 0.37-1.03) and White patients (HR: 0.68; 95% CI: 0.52-0.90; P-interaction = 0.70). Consistent benefits were observed for other prespecified outcomes, including the composite of total (first and repeat) HF hospitalizations and cardiovascular death (P-interaction = 0.43) and Kansas City Cardiomyopathy Questionnaire total symptom score. Study drug discontinuation and serious adverse events were not more frequent in the dapagliflozin group than in the placebo group in either Black or White patients. ConclusionsDapagliflozin reduced the risk of worsening HF and cardiovascular death, and it improved symptoms, similarly in Black and White patients without an increase in adverse events. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124)

Cost Effectiveness of Vericiguat for the Treatment of Chronic Heart Failure with Reduced Ejection Fraction Following a Worsening Heart Failure Event from a US Medicare Perspective.

ObjectiveGiven the high economic burden of disease among adult patients with chronic heart failure with reduced ejection fraction (HFrEF) following a worsening heart failure event in the US, this study aimed to estimate the cost effectiveness of vericiguat plus prior standard-of-care therapies (PSoCT) versus PSoCT alone from a US Medicare perspective.MethodsA four-state Markov model (alive prior to heart failure hospitalization, alive during heart failure hospitalization, alive post-heart failure hospitalization, and death) was developed to predict clinical and economic outcomes, based on the results of the VICTORIA trial, in which patients with chronic HFrEF following a worsening heart failure were randomized to placebo or vericiguat, in addition to PSoCT, which consisted of β-blockers, renin-angiotensin-aldosterone inhibitors, mineralocorticoid receptor antagonists, and the angiotensin receptor–neprilysin inhibitor sacubitril/valsartan. Risks of heart failure hospitalization and cardiovascular mortality were based on multivariable regression models derived from VICTORIA data. Utilities were derived from VICTORIA EQ-5D data and the literature. Costs included drug acquisition, heart failure hospitalization, routine care, and terminal care. Primary outcomes included heart failure hospitalization, cardiovascular mortality, life-years, quality-adjusted life-years (QALYs), and incremental costs per QALY gained over a 30-year lifetime horizon, discounted at 3.0% annually.ResultsFor the VICTORIA overall intent-to-treat population, compared with PSoCT, vericiguat plus PSoCT resulted in 19 fewer heart failure hospitalizations and 13 fewer cardiovascular deaths per 1000 patients, as well as 0.28 QALY gained per patient at an incremental cost of $23,322, leading to $82,448 per QALY gained.ConclusionsBased on the results of VICTORIA, patients treated with vericiguat had lower rates of heart failure hospitalization and cardiovascular death. The addition of vericiguat to PSoCT was estimated to increase QALYs and to be cost effective at a willingness-to-pay threshold of $100,000 per QALY gained.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40273-021-01091-w.

Sodium-glucose co-transporter-2 inhibitors in the non-diabetic heart failure patient.

Heart failure (HF) with reduced ejection fraction (HFrEF) is a global cause of morbidity and mortality with over 60 million estimated cases worldwide. The burden of HF care is expected to increase with an ageing population as evidenced by the fact that 80% of HF-related hospitalizations occur in those aged above 65. Given the significant morbidity and mortality associated with HFrEF, there is a need for new prognostic therapies that have an impact on morbidity and mortality. In February of 2021, the National institute for Health and Care Excellence (NICE) released new guidance on the utility of Dapagliflozin for the management of heart failure with reduced ejection fraction (HFrEF). NICE advocated that dapagliflozin is a viable treatment option in symptomatic HFrEF patients on optimal medical management. The current list price of dapagliflozin is around £36.59 per 28-tablet pack with an estimated annual cost of £476.98 equating to £6939 per quality-adjusted life year. The guidance was mainly based on evidence produced from the 2019 DAPA-HF trial. This demonstrated that in HFrEF population, the use of dapagliflozin led to a significant reduction in worsening HF events, cardiovascular, and all-cause death. In this article, we summarize the evidence base for sodium-glucose co-transporter-2 inhibitors in the non-diabetic heart failure patient.

Potential Implications of Expanded US Food and Drug Administration Labeling for Sacubitril/Valsartan in the US

The US Food and Drug Administration (FDA) expanded labeling for sacubitril/valsartan for use in individuals with chronic heart failure (HF) with left ventricular ejection fraction (LVEF) lower than normal. The population-level implications of implementation of sacubitril/valsartan at higher LVEF ranges is unknown. While the Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction (PARAGON-HF) trial did not meet its primary end point, the trial may provide useful information in projecting expected clinical events among treated individuals. To quantify newly eligible treatment candidates for sacubitril/valsartan under the expanded FDA labeling and to apply treatment effects and the number needed to treat (NNT) to prevent 1 worsening HF event derived from subgroups of the PARAGON-HF trial who fall under the revised FDA label. Newly eligible treatment candidates were estimated by mapping the LVEF distribution from 559 520 adult patients hospitalized between 2014 and 2019 in the Get With The Guidelines-Heart Failure registry to adults self-identifying with HF in the National Health and Nutrition Examination Survey (2015 to 2018). The NNT with 3 years of treatment for 3 end points of interest (total HF hospitalizations, total HF hospitalizations and cardiovascular death, and total HF hospitalizations and urgent HF visits and cardiovascular death) were estimated from the PARAGON-HF trial. Data were analyzed from February to June 2021. Number of worsening HF events prevented or postponed if eligible patients were treated with sacubitril/valsartan for 3 years. Of an estimated 4 682 098 adults, the mean (SE) age was 66.3 (0.8) years, 1 995 037 (42.6%) were women, and 748 045 (16.0%) were Black. The potential number of adults projected to be newly eligible varied by the definition of FDA labeling of lower than normal LVEF from 643 161 (95% CI, 534 433-751 888; LVEF of 41% to 50%) to 1 838 756 (95% CI, 1 527 911-2 149 601; LVEF of 41% to 60%). In the PARAGON-HF trial, the NNT to prevent a worsening HF event (range, 7 to 12 patients) was consistent irrespective of specific LVEF range selected. Comprehensive implementation of sacubitril/valsartan among newly eligible patients was empirically estimated to prevent up to 69 268 (95% CI, 57 558-80 978) worsening HF events (LVEF of 41% to 50%) to 182 592 (95% CI, 151 725-213 460) worsening HF events (LVEF of 41% to 60%). The expanded FDA labeling is positioned to substantially increase the potential HF population eligible for sacubitril/valsartan by up to 1.8 million individuals and has the potential to prevent or postpone as many as 180 000 worsening HF events, depending on the definition of normal LVEF.

Characteristics and Outcomes of Patients With Heart Failure With Reduced Ejection Fraction After a Recent Worsening Heart Failure Event.

BackgroundContemporary trials of patients with heart failure with reduced ejection fraction (HFrEF) required a recent worsening heart failure (WHF) event for inclusion. We aimed to describe characteristics and outcomes of patients with HFrEF and a recent WHF event at a large tertiary referral center.Methods and ResultsWe identified adult patients with chronic symptomatic HFrEF (ejection fraction ≤35%) treated at Duke University between January 1, 2009, and December 31, 2018, and applied a set of exclusion criteria to generate a cohort similar to those enrolled in contemporary heart failure trials. Patients were stratified by presence or absence of a recent WHF event, defined as an emergency department visit for heart failure or hospitalization for heart failure in the prior 12 months. Characteristics and outcomes including death and hospitalization were assessed. Of 3867 patients with HFrEF meeting study criteria, 2823 (73.0%) had a WHF event in the prior 12 months. Compared with patients without a WHF event, those with a WHF event were more likely to be under‐represented racial and ethnic groups and had lower ejection fraction, a greater burden of comorbidities, and more echocardiographic evidence of cardiac dysfunction. Despite higher use of guideline‐directed therapies, patients with a WHF event had higher rates of death (hazard ratio, 2.30; 95% CI, 2.01–2.63), all‐cause hospitalization (hazard ratio, 1.56; 95% CI, 1.42–1.71), and heart failure hospitalization (hazard ratio, 1.59; 95% CI, 1.44–1.75) through 5 years compared with those without a recent WHF event.ConclusionsWHF events are common in patients with HFrEF and are associated with more advanced disease. Patients with recent WHF have high rates of death and hospitalization, underscoring the need for novel therapies in this large subgroup of patients with HFrEF.

Effect of Empagliflozin on Worsening Heart Failure Events in Patients With Heart Failure and Preserved Ejection Fraction: EMPEROR-Preserved Trial.

Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure with preserved ejection fraction, but additional data are needed about its effect on inpatient and outpatient heart failure events. We randomly assigned 5988 patients with class II through IV heart failure with an ejection fraction of >40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to usual therapy, for a median of 26 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite end points. Empagliflozin reduced the combined risk of cardiovascular death, hospitalization for heart failure, or an emergency or urgent heart failure visit requiring intravenous treatment (432 versus 546 patients [empagliflozin versus placebo, respectively]; hazard ratio, 0.77 [95% CI, 0.67-0.87]; P<0.0001). This benefit reached statistical significance at 18 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (hazard ratio, 0.71 [95% CI, 0.52-0.96]; P=0.028) and the total number of all hospitalizations that required a vasopressor or positive inotropic drug (hazard ratio, 0.73 [95% CI, 0.55-0.97]; P=0.033). Compared with patients in the placebo group, fewer patients in the empagliflozin group reported outpatient intensification of diuretics (482 versus 610; hazard ratio, 0.76 [95% CI, 0.67-0.86]; P<0.0001), and patients assigned to empagliflozin were 20% to 50% more likely to have a better New York Heart Association functional class, with significant effects at 12 weeks that were maintained for at least 2 years. The benefit on total heart failure hospitalizations was similar in patients with an ejection fraction of >40% to <50% and 50% to <60%, but was attenuated at higher ejection fractions. In patients with heart failure with preserved ejection fraction, empagliflozin produced a meaningful, early, and sustained reduction in the risk and severity of a broad range of inpatient and outpatient worsening heart failure events. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.