Spectrum Of Left Ventricular Ejection Fraction Research Articles

Cost-effectiveness of dapagliflozin for patients with heart failure across the spectrum of ejection fraction: A pooled analysis of DAPA-HF and DELIVER data.

To assess the cost-effectiveness of dapagliflozin in addition to usual care, compared with usual care alone, in a large population of patients with heart failure (HF), spanning the full range of left ventricular ejection fraction (LVEF). Patient-level data were pooled from HF trials (DAPA-HF, DELIVER) to generate a population including HF with reduced, mildly reduced and preserved LVEF, to increase statistical power and enable exploration of interactions among LVEF, renal function and N-terminal pro-B-type natriuretic peptide levels, as they are relevant determinants of health status in this population. Survival and HF recurrent event risk equations were derived and applied to a lifetime horizon Markov model with health states defined by Kansas City Cardiomyopathy Questionnaire total symptom score quartiles; costs and utilities were in the UK setting. The base case incremental cost-effectiveness ratio (ICER) was £6470 per quality-adjusted life year (QALY) gained, well below the UK willingness-to-pay (WTP) threshold of £20 000/QALY gained. In interaction sensitivity analyses, the highest ICER was observed for elderly patients with preserved LVEF (£16 624/QALY gained), and ranged to a region of dominance (increased QALYs, decreased costs) for patients with poorer renal function and reduced/mildly reduced LVEF. Results across the patient characteristic interaction plane were mostly between £5000 and £10 000/QALY gained. Dapagliflozin plus usual care, versus usual care alone, yielded results well below the WTP threshold for the UK across a heterogeneous population of patients with HF including the full spectrum of LVEF, and is likely a cost-effective intervention.

Dapagliflozin in patients with heart failure and previous myocardial infarction: A participant-level pooled analysis of DAPA-HF and DELIVER.

Patients with heart failure (HF) and history of myocardial infarction (MI) face a higher risk of disease progression and clinical events. Whether sodium-glucose cotransporter 2 inhibitors may modify clinical trajectory in such individuals remains incompletely understood. The DAPA-HF and DELIVER trials compared dapagliflozin with placebo in patients with symptomatic HF with left ventricular ejection fraction (LVEF) ≤40% and > 40%, respectively. In this pooled participant-level analysis, we assessed efficacy and safety outcomes by history of MI. The primary outcome in both trials was the composite of cardiovascular death or worsening HF. Of the total of 11 007 patients, 3731 (34%) had a previous MI and were at higher risk of the primary outcome across the spectrum of LVEF in covariate-adjusted models (hazard ratio [HR] 1.12, 95% confidence interval [CI] 1.02-1.24). Dapagliflozin reduced the risk of the primary outcome to a similar extent in patients with (HR 0.83, 95% CI 0.72-0.96) and without previous MI (HR 0.76, 95% CI 0.68-0.85; pinteraction = 0.36), with consistent benefits on key secondary outcomes as well. Serious adverse events did not occur more frequently with dapagliflozin, irrespective of previous MI. History of MI confers increased risks of adverse cardiovascular outcomes in patients with HF across the LVEF spectrum, even among those with preserved ejection fraction. Dapagliflozin consistently and safely reduces the risk of cardiovascular death or worsening HF, regardless of previous MI.

The role of multimorbidity in patients with heart failure across the left ventricular ejection fraction spectrum: Data from the Swedish Heart Failure Registry.

The aim of this analysis was to provide data on the overall comorbidity burden, both cardiovascular (CV) and non-CV, in a large real-world heart failure (HF) population across the ejection fraction (EF). Patients with HF from the Swedish HF Registry between 2000 and 2021 were included. Of 91 463 patients (median age 76 years [interquartile range 67-82]), 98% had at least one among the 17 explored comorbidities (94% at least one CV and 85% at least one non-CV comorbidity). All comorbidities, except for coronary artery disease (CAD), were more frequent in HF with preserved EF (HFpEF). Patients with multiple comorbidities were older, more likely female, inpatients, with HFpEF, worse New York Heart Association class and higher N-terminal pro-B-type natriuretic peptide levels. In a multivariable Cox model, 12 comorbidities were independently associated with a higher risk of death from any cause. The highest risk was associated with dementia (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.45-1.65), chronic kidney disease (HR 1.37, 95% CI 1.34-1.41), chronic obstructive pulmonary disease (HR 1.32, 95% CI 1.28-1.35). Obesity was associated with a lower risk of all-cause death (HR 0.81, 95% CI 0.79-0.84). CAD and valvular heart disease were associated with a higher risk of all-cause and CV mortality, but not non-CV mortality, whereas cancer and musculo-skeletal disease increased the risk of non-CV mortality. A significant interaction with EF was observed for several comorbidities. Occurrence of CV and non-CV outcomes was related to the number of CV and non-CV comorbidities, respectively. The burden of both CV and non-CV comorbidities was high in HF regardless of EF, but overall higher in HFpEF. Multimorbidity was associated with a high risk of death with a different burden on CV or non-CV outcomes.

Abstract 16586: Differences in Medical Care Across the Left Ventricular Ejection Fraction Spectrum Following New Heart Failure Diagnosis in a US Healthcare System

Introduction: Heart failure (HF) is a major public health concern with increasing prevalence and burden on healthcare systems. HF is aggravated by type 2 diabetes (T2D) and chronic kidney disease (CKD). Research Question: Understanding how HF is treated after new diagnosis could improve care. Aim: Describe treatment of patients with newly diagnosed HF. Methods: Observational, longitudinal study using electronic medical record data from 24,340 adults (≥18 years) in the US between 2005-2019 with new diagnosis of HF, defined as no HF identified at least 12 months prior to index diagnosis. Outcomes were stratified by HF type (reduced ejection fraction [HFrEF; LVEF ≤40%], preserved ejection fraction [HFpEF; LVEF ≥50%]) and presence of CKD and T2D. Results: For the 24,340 incident HF cases, mean age was 72.1±13.4 years. 51.1% had HFpEF and 10.0% HFrEF; 38.6% also had CKD, 39.7% had T2D and 40.3% had neither. Most patients were diagnosed in hospital (41.7%), Emergency Department (23.3%) or Primary Care (16.9%). First visit after HF diagnosis was most commonly with Primary Care (34.0%) or other specialties (39.6%), with only 10.7% with a cardiologist, regardless of comorbid CKD or T2D. Within the first year, those with HFpEF vs HFrEF were less likely to be seen by a cardiologist (51.7% vs 79.6%). Hospitalization rates within the first year were higher in patients with HF and both comorbidities (49.6%). All-cause mortality was slightly higher in HFpEF (15.3%) compared to HFrEF (13.9%), particularly in those with HFpEF and CKD (19.2%). At time of diagnosis, patients were likely to use any HF medication. Patients with HFpEF were more likely than those with HFrEF to be treated with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB; 46.1% vs 40.7%), β-blockers (BB; 53.2% vs 41.3%) and diuretics (41.0% vs 26.5%). Within 90 days of diagnosis, fewer patients with HFpEF vs HFrEF initiated ACEi/ARB (42.8% vs 70.4%), BB (35.4% vs 56.2%) and diuretics (47.8% vs 65.2%). Conclusion: Primary care plays a major role in early HF care. Comorbid CKD and T2D increased hospitalization and mortality rates but not cardiology care. However, patients with HFpEF were less likely to be seen by a cardiologist or initiate medication following diagnosis vs those with HFrEF.

Abstract 14120: Characteristics, Outcomes and Treatment Response With Dapagliflozin Across the Range of Ejection Fraction in People With HF and a History of CABG Surgery: A Pooled Analysis From DAPA-HF and DELIVER

Introduction: There is a paucity of data on contemporary outcomes of patients with a history of CABG who have heart failure (HF) with either reduced or preserved left ventricular ejection fraction (LVEF). We aimed to compare the baseline characteristics and outcomes by history of CABG, as well the efficacy and safety of the SGLT2 inhibitor, dapagliflozin, across the full range of LVEF in patients with heart failure. Methods: We conducted a patient-level pooled analysis of two trials testing dapagliflozin in 11,007 participants with HF and LVEF ≤40% (DAPA-HF trial) and >40% (DELIVER trial). The primary outcome was the composite of a worsening HF event or death from CV causes; other outcomes examined included total hospital admissions for HF, MACE, all-cause mortality and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores. Outcomes were compared by history of CABG. Results: Among 11,007 patients, 1576 had a prior history of CABG (~14%). Patients with CABG were characterised by a higher proportion of men, lower eGFR and LVEF, and higher rates of prior MI, PCTA, type 2 diabetes, antiplatelet and statin therapy. CABG patients were more likely to experience primary outcome (adjusted hazard ratio [aHR] 1.21, 95% CI 1.08-1.36), CV death (aHR 1.22, 95% CI 1.04-1.42), all-cause death (aHR 1.22, 95% CI 1.07-1.38), HF hospitalization (aHR 1.31, 95% CI 1.14-1.51), total HF events (adjusted rate ratio 1.38, 95% CI 1.20-1.59), and MACE (aHR 1.34 (1.17-1.52). Dapagliflozin consistently reduced the primary and key secondary endpoints in both people with and without a history of CABG across the entire spectrum of LVEF (P-interaction for all > 0.48) (Table). Adverse events and tolerability were similar between groups. Conclusions: In patients with HF, a prior history of CABG is associated with higher rates of CV outcomes and mortality compared to those without a history of CABG. The efficacy and safety of dapagliflozin was similar in patients with and without a history of CABG.

Developing Clinical Risk Prediction Models for Worsening Heart Failure Events and Death by Left Ventricular Ejection Fraction.

Background There is a need to develop electronic health record-based predictive models for worsening heart failure (WHF) events across clinical settings and across the spectrum of left ventricular ejection fraction (LVEF). Methods and Results We studied adults with heart failure (HF) from 2011 to 2019 within an integrated health care delivery system. WHF encounters were ascertained using natural language processing and structured data. We conducted boosted decision tree ensemble models to predict 1-year hospitalizations, emergency department visits/observation stays, and outpatient encounters for WHF and all-cause death within each LVEF category: HF with reduced ejection fraction (EF) (LVEF <40%), HF with mildly reduced EF (LVEF 40%-49%), and HF with preserved EF (LVEF ≥50%). Model discrimination was evaluated using area under the curve and calibration using mean squared error. We identified 338 426 adults with HF: 61 045 (18.0%) had HF with reduced EF, 49 618 (14.7%) had HF with mildly reduced EF, and 227 763 (67.3%) had HF with preserved EF. The 1-year risks of any WHF event and death were, respectively, 22.3% and 13.0% for HF with reduced EF, 17.0% and 10.1% for HF with mildly reduced EF, and 16.3% and 10.3% for HF with preserved EF. The WHF model displayed an area under the curve of 0.76 and mean squared error of 0.13, whereas the model for death displayed an area under the curve of 0.83 and mean squared error of 0.076. Performance and predictors were similar across WHF encounter types and LVEF categories. Conclusions We developed risk prediction models for 1-year WHF events and death across the LVEF spectrum using structured and unstructured electronic health record data and observed no substantial differences in model performance or predictors except for death, despite differences in underlying HF cause.

Remote patient management of heart failure across the ejection fraction spectrum: a pre-specified analysis of the TIM-HF2 trial.

The benefit of non-invasive remote patient management (RPM) for patients with heart failure (HF) has been demonstrated. We evaluated the effect of left ventricular ejection fraction (LVEF) on treatment outcomes in the TIM-HF2 (Telemedical Interventional Management in Heart Failure II; NCT01878630) randomized trial. TIM-HF2 was a prospective, randomized, multicentre trial investigating the effect of a structured RPM intervention versus usual care in patients who had been hospitalized for HF within 12 months before randomization. The primary endpoint was the percentage of days lost due to all-cause death or unplanned cardiovascular hospitalization. Key secondary endpoints were all-cause and cardiovascular mortality. Outcomes were assessed by LVEF in guideline-defined subgroups of ≤40% (HF with reduced EF [HFrEF]), 41-49% (HF with mildly reduced EF [HFmrEF]), and ≥50% (HF with preserved EF [HFpEF]). Out of 1538 participants, 818 (53%) had HFrEF, 224 (15%) had HFmrEF, and 496 (32%) had HFpEF. Within each LVEF subgroup, the primary endpoint was lower in the treatment group, i.e. the incidence rate ratio [IRR] remained below 1.0. Comparing intervention and control group, the percentage of days lost was 5.4% versus 7.6% for HFrEF (IRR 0.72, 95% confidence interval [CI] 0.54-0.97), 3.3% versus 5.9% for HFmrEF (IRR 0.85, 95% CI 0.48-1.50) and 4.7% versus 5.4% for HFpEF (IRR 0.93, 95% CI 0.64-1.36). No interaction between LVEF and the randomized group became apparent. All-cause and cardiovascular mortality were also reduced by RPM in each subgroup with hazard ratios <1.0 across the LVEF spectrum for both endpoints. In the clinical set-up deployed in the TIM-HF2 trial, RPM appeared effective irrespective of the LVEF-based HF phenotype.

Uptitrating Treatment After Heart Failure Hospitalization Across the Spectrum of Left Ventricular Ejection Fraction

BackgroundAcute heart failure (AHF) is associated with a poor prognosis regardless of left ventricular ejection fraction (LVEF). STRONG-HF showed the efficacy and safety of a strategy of rapid uptitration of oral treatment for heart failure (HF) and close follow-up (high-intensity care), compared with usual care, in patients recently hospitalized for AHF and enrolled independently from their LVEF. ObjectivesIn this study, we sought to assess the impact of baseline LVEF on the effects of high-intensity care vs usual care in STRONG-HF. MethodsThe STRONG-HF trial enrolled patients hospitalized for AHF with any LVEF and not treated with full doses of renin-angiotensin inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. High-intensity care with uptitration of oral medications was performed independently from LVEF. The primary endpoint was the composite of HF rehospitalization or all-cause death at day 180. ResultsAmong the 1,078 patients randomized, 731 (68%) had LVEF ≤40% and 347 (32%) had LVEF >40%. The treatment benefit of high-intensity care vs usual care on the primary endpoint was consistent across the whole LVEF spectrum (interaction P with LVEF as a continuous variable = 0.372). Mean difference in the EQ-5D visual analog scale change from baseline to day 90 between treatment arms was slightly greater at higher LVEF values, but with no interaction between LVEF as a continuous variable and the treatment strategy (interaction P = 0.358). Serious adverse events were also independent from LVEF. ConclusionsRapid uptitration of oral medications for HF and close follow-up reduce 180-day death and HF rehospitalization after AHF hospitalization independently from LVEF. (Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-ProBNP Testing, of Heart Failure Therapies [STRONG-HF]; NCT03412201)

Multi-organ sonographic assessment of congestion has incremental prognostic value in outpatients with heart failure irrespective of left ventricular ejection fraction

Abstract Funding Acknowledgements Type of funding sources: None. Background Congestion is a key driver of symptoms, disease progression and prognosis for patients with heart failure (HF), irrespective of left ventricular ejection fraction (LVEF). However, clinically overt congestion is often undiagnosed unless severe. Recent research has shown that ultrasonographic quantification of systemic venous (i.e. inferior vena cava), renal venous and lung (B-lines) congestion is feasible and identifies HF patients with a worse prognosis. Purpose Whether a simultaneous multi-organ evaluation of congestion by ultrasound may improve risk stratification in HF is unknown. In the present study, we assessed signs of ultrasonographic congestion in the inferior vena cava, lungs and kidneys in HF patients across the LVEF spectrum and investigated their association with pathophysiology, clinical characteristics and prognosis. Methods We prospectively enrolled 326 patients with a prior clinical diagnosis of HF attending a routine follow-up visit. We also enrolled 102 consecutive patients with cardiovascular risk factors (including hypertension, type II diabetes mellitus or chronic ischaemic heart disease) and no history of HF; these latter patients had NT-proBNP levels &amp;lt;125 ng/L, LVEF &amp;gt;50%, and were not taking loop diuretics. All patients underwent a complete clinical assessment, blood and urine tests, and an ultrasound evaluation. Ultrasound congestion was defined as inferior vena cava ≥21 mm, highest tertile of lung B-lines or discontinuous renal venous flow. Results The final population consisted of 310 HF patients (median age 77 years, median NT-proBNP 1037 ng/L, 51% with LVEF &amp;lt;50%), and 101 subjects without HF. Among the 224 HF patients (72%) with no clinical signs of congestion, 95 (42%) had at least one sign of congestion by ultrasound (p&amp;lt;0.0001). HF patients with ≥2 ultrasound signs were older, had greater neurohormonal activation (i.e., higher NT-proBNP; Figure 1), lower urinary sodium concentration, and larger left atria despite similar LVEF. During a median follow-up of 13 (interquartile range 6–15) months, 77 HF patients (19%) died or were hospitalized for HF. HF patients without ultrasonographic evidence of congestion had a similar outcome to subjects without HF (reference; HR 1.02, 95% CI 0.86 – 1.35), while those with ≥2 ultrasound signs had the worst outcome (HR 26.7, 95% CI 12.4–63.6), even after adjusting for multiple clinical variables and NT-proBNP (Figure 2). Adding multi-organ assessment of congestion by ultrasound to a clinical model, including NT-proBNP, provided a 28% net reclassification improvement (p=0.03). Conclusion Simultaneous assessment of pulmonary, systemic venous and kidney congestion by ultrasound identifies a high prevalence of sub-clinical congestion associated with poor outcomes in HF, irrespective of LVEF. The speed of investigation, along with the widespread availability and relatively low cost of ultrasound, makes this protocol easy to implement for real-time assessment of congestion.

Impact of left ventricular ejection fraction phenotypes on healthcare resource utilization in hospitalized heart failure: a secondary analysis of REPORT-HF.

Evidence on healthcare resource utilization (HCRU) for hospitalized patients with heart failure (HF) and reduced (HFrEF), mildly reduced (HFmrEF) and preserved (HFpEF) ejection fraction is limited. We analysed HCRU in relation to left ventricular ejection fraction (LVEF) phenotypes, clinical features and in-hospital and 12-month outcomes in 16 943 patients hospitalized for HF in a worldwide registry. HFrEF was more prevalent (53%) than HFmrEF (17%) or HFpEF (30%). Patients with HFmrEF and HFpEF were older, more often women, with milder symptoms and more comorbidities, but differences were not pronounced. HCRU was high in all three groups; two or more in- and out-of-hospital services were required by 51%, 49% and 52% of patients with HFrEF, HFmrEF and HFpEF, respectively, and intensive care unit by 41%, 41% and 37%, respectively. Hospitalization length was similar (median, 8 days). Discharge prescription of neurohormonal inhibitors was <80% for each agent in HFrEF and only slightly lower in HFmrEF and HFpEF (74% and 67%, respectively, for beta-blockers). Compared to HFrEF, 12-month all-cause and cardiovascular mortality were lower for HFmrEF (adjusted hazard ratios 0.78 [95% confidence interval 0.59-0.71] and 0.80 [0.70-0.92]) and HFpEF (0.64 [0.59-0.87] and 0.63 [0.56-0.71]); 12-month HF hospitalization was also lower for HFpEF and HFmrEF (21% and 20% vs. 25% for HFrEF). In-hospital mortality, 12-month non-cardiovascular mortality and 12-month all-cause hospitalization were similar among groups. In patients hospitalized for HF, overall HCRU was similarly high across LVEF spectrum, reflecting the subtle clinical differences among LVEF phenotypes during hospitalization. Discharge prescription of neurohormonal inhibitors was suboptimal in HFrEF and lower but significant in patients with HFpEF and HFmrEF, who had better long-term cardiovascular outcomes than HFrEF, but similar risk for non-cardiovascular events.

MRI Investigation of the Differential Impact of Left Ventricular Ejection Fraction After Myocardial Infarction in Elderly vs. Nonelderly Patients to Predict Readmission for Heart Failure.

Patients with ST-segment elevation myocardial infarction (STEMI), especially elderly individuals, have an increased risk of readmission for acute heart failure (AHF). To study the impact of left ventricular ejection fraction (LVEF) by MRI to predict AHF in elderly (>70 years) and nonelderly patients after STEMI. Prospective. Multicenter registry of 759 reperfused STEMI patients (23.3% elderly). 1.5-T. Balanced steady-state free precession (cine imaging) and segmented inversion recovery steady-state free precession (late gadolinium enhancement) sequences. One-week MRI-derived LVEF (%) was quantified. Sequential MRI data were recorded in 579 patients. Patients were categorized according to their MRI-derived LVEF as preserved (p-LVEF, ≥50%), mildly reduced (mr-LVEF, 41%-49%), or reduced (r-LVEF, ≤40%). Median follow-up was 5 [2.33-7.54] years. Univariable (Student's t, Mann-Whitney U, chi-square, and Fisher's exact tests) and multivariable (Cox proportional hazard regression) comparisons and continuous-time multistate Markov model to analyze transitions between LVEF categories and to AHF. Hazard ratios (HR) with 95% confidence intervals (CIs) were computed. P < 0.05 was considered statistically significant. Over the follow-up period, 79 (10.4%) patients presented AHF. MRI-LVEF was the most robust predictor in nonelderly (HR 0.94 [0.91-0.98]) and elderly patients (HR 0.94 [0.91-0.97]). Elderly patients had an increased AHF risk across the LVEF spectrum. An excess of risk (compared to p-LVEF) was noted in patients with r-LVEF both in nonelderly (HR 11.25 [5.67-22.32]) and elderly patients (HR 7.55 [3.29-17.34]). However, the mr-LVEF category was associated with increased AHF risk only in elderly patients (HR 3.66 [1.54-8.68]). Less transitions to higher LVEF states (n=19, 30.2% vs. n=98, 53%) and more transitions to AHF state (n=34, 53.9% vs. n=45, 24.3%) were observed in elderly than nonelderly patients. MRI-derived p-LVEF confers a favorable prognosis and r-LVEF identifies individuals at the highest risk of AHF in both elderly and nonelderly patients. Nevertheless, an excess of risk was also found in the mr-LVEF category in the elderly group. 2. Stage 2.

The four pillars of HFrEF therapy: is it time to treat heart failure regardless of ejection fraction?

The syndrome of heart failure (HF) has historically been dichotomized based on clinical trial inclusion criteria into patients with a reduced or preserved left ventricular ejection fraction (LVEF) using a cut-off of above or below 40%. The majority of trial evidence for the benefits of disease-modifying pharmacological therapy has been in patients with HF with reduced ejection fraction (HFrEF), i.e. those with an LVEF ≤40%. Recently, the sodium-glucose co-transporter 2 inhibitors empagliflozin and dapagliflozin have been shown to be the first drugs to improve outcomes in HF across the full spectrum of LVEF. There is, however, growing evidence that the benefits of many of the neurohumoral modulators shown to be beneficial in patients with HFrEF may extend to those with a higher LVEF above 40% but still below the normal range, i.e. HF with mildly reduced ejection fraction (HFmrEF). Whether the benefits of some of these medications also extend to patients with HF and preserved ejection fraction (HFpEF) is an area of ongoing debate. This article will review the evidence for HF treatments across the full spectrum of LVEF, provide an overview of recently updated clinical practice guidelines, and address the question whether it may now be time to treat HF with some therapies regardless of ejection fraction.

260 EFFICACY OF SGLT2 INHIBITORS IN PATIENTS WITH AND WITHOUT HEART FAILURE AND ACROSS THE SPECTRUM OF LEFT VENTRICULAR EJECTION FRACTION: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Abstract Background Sodium-glucose cotransporter 2 (SGLT-2) inhibitors have demonstrated to reduce heart failure (HF) and renal outcomes irrespective of diabetes status. The cardiovascular efficacy and the mortality benefit of these agents in patients without HF and across the spectrum of left ventricular ejection fraction (EF) are a matter of debate. Methods This study-level meta-analysis included 11 controlled randomized trials and 76,520 patients randomized to a SGLT-2 inhibitor (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin and sotagliflozin) or placebo in different clinical settings including diabetes, HF with reduced or preserved EF and chronic kidney disease. Data were stratified by history of HF, HF with reduced EF (≤40%), mid-range EF (40-49%) and preserved EF (≥50%). The incidence of the following outcomes, when available, was evaluated: HF composite outcome, defined as cardiovascular death or hospitalization/urgent visit for HF, its individual components and all-cause mortality. An additional sensitivity analysis tested the efficacy of SGLT-2 inhibitors in patients with extremely reduced EF (≤30%). Results Overall, there were 22,653 patients with HF (33.8%) and 44,304 patients without HF (66.2%). In patients without history of HF, SGLT-2 inhibitors significantly reduced the risk of HF outcomes (HR 0.76, 95% CI 0.68-0.86) and all-cause mortality (HR 0.84, 95% CI 0.73-0.95). In patients with HF, a significant reduction in the composite of cardiovascular death and HF events was consistently observed in those with reduced EF (HR 0.71, 95% CI 0.65-0.78), mid-range EF (HR 0.68, 95% CI 0.57-0.81) and preserved EF (HR 0.78, 95% CI 0.69-0.89; Figure). There was a significant reduction in all-cause mortality also in patients with HF treated with SGLT-2 inhibitors (HR 0.87, 95% CI 0.80-0.95). Conclusions SGLT-2 inhibitors demonstrated cardiovascular and mortality benefits irrespective from history of HF and across the spectrum of left ventricular EF.

1153 SODIUM GLUCOSE COTRANSPORTER-2 INHIBITORS ELIGIBILITY IN PATIENTS WITH HEART FAILURE ACROSS THE SPECTRUM OF EJECTION FRACTION

Abstract Background Large randomized clinical trials demonstrated that sodium–glucose co-transporter-2 (SGLT2) inhibitors reduced adverse cardiovascular outcomes in patients with heart failure (HF) with both reduced (HFrEF) and preserved (HFpEF) ejection fraction. Despite the high potential to change clinical practice, the strict trial selection criteria might reduce external validity of these findings. Purpose The aim of the study was to evaluate the proportion of outpatients with HF that would be eligible for SGLT2 inhibitors across the spectrum of left ventricular ejection fraction (LVEF) in a contemporary real-world population. Methods We retrospectively evaluated patients with chronic stable HF followed-up at the outpatient clinic of our institution. HFrEF (LVEF &amp;lt;40%) patients’ eligibility was assessed according to the entry criteria of DAPA-HF (dapagliflozin) and EMPEROR-Reduced (empagliflozin) trials and to US Food and Drug Administration (FDA) label criteria (only dapagliflozin). In HFpEF group (LVEF&amp;gt;40%), Eligibility to SGLT2 inhibitors was based both strict and pragmatic (most likely influencing treatment decisions in clinical practice) EMPEROR- Preserved inclusion/exclusion criteria (empagliflozin). Results A total of 642 HF patients (441 HFrEF; 201 HFpEF) was studied. Among HFrEF patients, according to the major inclusion and exclusion criteria from DAPA-HF and EMPEROR-Reduced trials, 198 (45%) patients would be candidates for initiation of both dapagliflozin and empagliflozin, 61 (14%) would be eligible only to dapagliflozin and 23 (5%) only to empagliflozin, On the other hand, in HFpEF patients, 125 (62%) patients would be candidates for initiation of empagliflozin based on the EMPEROR-Preserved trial selection criteria. No significant differences were found between diabetic and non-diabetic patients in both HFrEF (p=0.23) and HFpEF (p=0.37). In patients not suitable for gliflozins treatment the major determinant of ineligibility was the failure to achieve the predefined NTproBNP inclusion threshold. Excluding NTproBNP as per FDA label criteria, dapagliflozin eligibility increased to 86%. Similarly, applying EMPEROR-Preserved criteria most likely influencing treatment decisions in clinical practice (symptomatic HF; eGFR &amp;lt;20 mL/min/1.73 m2; symptomatic hypotension; history of ketoacidosis) the proportion of HFpEF patients potentially eligible to empagliflozin rose to 85%. Conclusions In our real-world analysis the proportion of HF patients potentially candidate for initiation of SGLT2 inhibitors is consistent across the entire spectrum of LVEF. Our findings might herald an extensive use of gliflozins in HF treatment, with a consequent strong beneficial impact on cardiovascular outcomes in eligible patients.

Efficacy of empagliflozin in heart failure with preserved versus mid-range ejection fraction: a pre-specified analysis of EMPEROR-Preserved

The EMPEROR-Preserved trial showed that the sodium–glucose co-transporter 2 inhibitor empagliflozin significantly reduces the risk of cardiovascular death or hospitalization for heart failure (HHF) in heart failure patients with left ventricular ejection fraction (LVEF) > 40%. Here, we report the results of a pre-specified analysis that separately evaluates these patients stratified by LVEF: preserved (≥ 50%) (n = 4,005; 66.9%) or mid-range (41–49%). In patients with LVEF ≥ 50%, empagliflozin reduced the risk of cardiovascular death or HHF (the primary endpoint) by 17% versus placebo (hazard ratio (HR) 0.83; 95% confidence interval (CI): 0.71–0.98, P = 0.024). For the key secondary endpoint, the HR for total HHF was 0.83 (95%CI: 0.66–1.04, P = 0.11). For patients with an LVEF of 41–49%, the HR for empagliflozin versus placebo was 0.71 (95%CI: 0.57–0.88, P = 0.002) for the primary outcome (Pinteraction = 0.27), and 0.57 (95%CI: 0.42–0.79, P < 0.001) for total HHF (Pinteraction = 0.06). These results, together with those from the EMPEROR-Reduced trial in patients with LVEF < 40%, support the use of empagliflozin across the full spectrum of LVEF in heart failure.

Abstract 10399: Population-Level Implications of Empagliflozin for Heart Failure With Preserved Ejection Fraction in the United States

Introduction: The indication for empagliflozin has been expanded to patients with heart failure (HF) and left ventricular ejection fraction (LVEF) &gt;40% after findings of significant reduction in HF hospitalizations (HFH) and cardiovascular mortality (CVM) in the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction) trial. Objective: To quantify the estimated United States population-level impact of reducing worsening HF events with empagliflozin in LVEF &gt;40%. Methods: A projected adult HF population (age &gt;18) eligible for empagliflozin, obtained using weighted data from the National Health and Nutritional Examination Survey (2015-2018) was mapped onto newly eligible LVEF distributions, &gt;40% overall and those &gt;40% to 65% from the Get With The Guidelines Heart Failure registry. Number needed to treat (NNT) at 3 years for worsening HF events (urgent HF visits, total HFH and CVM) and total HFH, were calculated using rate difference from the EMPEROR program to estimate population-level treatment effects. Results: A projected 4,794,524 adults with HF are eligible for empagliflozin therapy. The population was predominantly male (57%) and white (67%), with a mean age of 66 years. Of this total population, 2,619,248 would be estimated as newly eligible with LVEF &gt;40% and 2,310,960 with LVEF &gt;40% to 65%. A projected 923,426 (95% CI, 769,893 – 1,076,959) worsening HF events would be prevented across the LVEF spectrum with empagliflozin over 3 years, out of which 301,738 (95%CI: 251,570, 351,906) and 295,341 (95%CI: 246,236 – 344,446) would be prevented in LVEF &gt;40% and LVEF &gt;40% to 65% subgroups, respectively. Moreover, an estimated 614,179 (95% CI, 512,063 – 716295) total HFH events would be prevented across the LVEF spectrum, out of which 201,159 (95%CI: 167,713 – 234,604) and 218,386 (95%CI: 182,076 – 254,696) total HFH events would be prevented in LVEF &gt;40% and LVEF &gt;40% to 65% subgroups, respectively. Conclusions: In addition to the proven benefit in HF with LVEF ≤40%, optimal implementation of empagliflozin in the US for treatment of HF with LVEF &gt;40% has the potential to prevent/postpone an additional 300,000 worsening HF events over 3 years.

Population-Level Implications of Sodium-Glucose Cotransporter-2 Inhibitors for Heart Failure With Preserved Ejection Fraction in the US

The expansion of sodium-glucose cotransporter-2 (SGLT-2) inhibitor use in patients with heart failure (HF) and left ventricular ejection fraction (LVEF) more than 40% following the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction) and the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trials have major implications in the US. To quantify the estimated US population-level impact of reducing worsening HF events with SGLT-2 inhibitors in individuals with LVEF more than 40%. This decision analytical model study used self-reported HF data from the National Health and Nutritional Examination Survey from 2015 to 2018, which was weighted across the entire US population and subsequently mapped onto newly eligible LVEF distributions from the Get With The Guidelines-Heart Failure registry. All patients older than 18 years with HF from the National Health and Nutritional Examination Survey were grouped into the following categories: all LVEF and LVEF more than 40%. Numbers needed to treat estimations over 3 years were obtained for outcome measures from the EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction), EMPEROR-Preserved, DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), and DELIVER trials. Worsening HF events (unplanned HF hospitalizations, urgent HF visits requiring intravenous therapy, or cardiovascular death). A projected 4 794 524 (95% CI, 3 997 363-5 591 684) adults (57% male; 67% White; mean age, 66 years) with HF would be eligible for SGLT-2 inhibitors. Of this total population, 2 619 248 (95% CI, 2 183 759-3 054 737) would be estimated as newly eligible with LVEF more than 40%. Based on estimates from the EMPEROR-Reduced/EMPEROR-Preserved and DAPA-HF/DELIVER trials, a projected 624 247 (95% CI, 520 457-728 037) to 627 124 (95% CI, 522 855-731 392) worsening HF events could be prevented across the LVEF spectrum with SGLT-2 inhibitors over 3 years, of which 232 589 (95% CI, 193 918-271 260) to 282 879 (95% CI, 235 846-329 912) events could be prevented in individuals with LVEF more than 40%. Moreover, an estimated 468 904 (95% CI, 390 942-546 867) to 499 110 (95% CI, 416 125-582 094) total HF hospitalizations could be prevented across the LVEF spectrum, of which 172 870 (95% CI, 144 128-201 613) to 231 018 (95% CI, 192 608-269 428) could be prevented in individuals with LVEF more than 40%. In addition to the proven benefit in HF with LVEF of 40% and less, optimal implementation of SGLT-2 inhibitor therapy for HF with LVEF more than 40% can potentially prevent/postpone an additional approximately 250 000 worsening HF events over 3 years in the US.

Pharmacologic Therapy for Heart Failure with Preserved Ejection Fraction.

The management of heart failure with preserved ejection fraction (HFpEF) is rapidly evolving. The pharmacologic treatment of patients with HFpEF includes symptom management with diuretics and optimization of comorbidities, including hypertension, obesity, diabetes mellitus, and atrial fibrillation. Specific therapies, including angiotensin II receptor blockers, mineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitors, and sodium-glucose cotransporter-2 inhibitors, are well tolerated and can reduce the risk of HF hospitalization, particularly in those on the lower end of the HFpEF left ventricular ejection fraction spectrum. Ongoing trials should continue to inform optimal therapy in this evolving field.

Empagliflozin: A Review in Symptomatic Chronic Heart Failure.

Empagliflozin (Jardiance®), a sodium-glucose cotransporter 2 inhibitor (SGLT2i) initially developed to treat type 2 diabetes mellitus (T2DM), has also been approved in the EU and USA for the treatment of all adults with symptomatic chronic heart failure (CHF), regardless of their left ventricular ejection fraction (LVEF). In pivotal phase III trials in ambulant patients with symptomatic CHF and mildly-reduced or preserved ejection fraction (EMPEROR-Preserved; LVEF > 40%) or those with symptomatic CHF and reduced ejection fraction (EMPEROR-Reduced; LVEF ≤ 40%), the addition of oral empagliflozin 10 mg/day to standard of care significantly reduced the risk of cardiovascular (CV) death or hospitalization for HF (HHF), as well as that of a number of other outcomes indicative of worsening HF, compared with placebo. The beneficial effect of empagliflozin on CV death/HHF was seen irrespective of the presence or absence of T2DM and regardless of background HF therapies. In addition, empagliflozin significantly improved health-related quality of life (HRQOL) and was generally well tolerated, with an adverse event profile that was generally consistent with that seen in patients with T2DM. Thus, empagliflozin is a valuable treatment option for ambulant patients with symptomatic CHF across a broad LVEF spectrum.

Characteristics, prognosis, and treatment response in HFpEF patients with high vs. normal ejection fraction.

BackgroundHeart failure with preserved ejection fraction (HFpEF) patients varied by left ventricular ejection fraction (LVEF) have different clinical characteristics, prognosis, and treatment response. With data from our prospective HFpEF cohort, we assessed the possible relationship between clinical characteristics, outcome as well as treatment response and LVEF.MethodsWe compared differences in baseline characteristics and clinical outcomes across LVEF categories (50%≤LVEF <60% vs. LVEF≥60%) in 1,502 HFpEF patients, and determined whether LVEF modified the treatment response. During 5-year follow-up, all-cause mortality was used as the primary endpoints, and composite endpoints (all-cause mortality or HF hospitalization) were set as the secondary endpoint.ResultsPatients with higher LVEF were statistically older, more likely to be women and have a history of atrial fibrillation. Patients with lower LVEF category were more likely to have a history of coronary artery disease. The incidences of all-cause mortality and composite endpoints were higher in patients with higher LVEF. Also, LVEF modified the spironolactone treatment effect for the primary outcome and secondary endpoint with stronger estimated benefits at the lower LVEF category with respect to all-cause mortality (HR 0.734, 95% CI 0.541–0.997, P = 0.048) and all-cause mortality or HF hospitalization (HR 0.767, 95% CI 0.604–0.972, P = 0.029).ConclusionThe characteristics and outcomes of HFpEF patients varied substantially by LVEF. Patients with higher LVEF encountered more adverse events than those with lower LVEF. The potential efficacy of spironolactone was greatest at the lower category of LVEF spectrum in HFpEF.