Worsening Heart Failure Events Research Articles

Finerenone in patients with heart failure with mildly reduced or preserved ejection fraction: Rationale and design of the FINEARTS-HF trial.

Steroidal mineralocorticoid receptor antagonists (MRAs), spironolactone and eplerenone, are strongly recommended in the treatment of patients with chronic heart failure (HF) with reduced left ventricular ejection fraction (LVEF), but the balance of efficacy and safety in those with higher LVEF has not been well established. Broad use of steroidal MRAs has further been limited in part due to safety concerns around risks of hyperkalaemia, gynecomastia, and kidney dysfunction. These risks may be mitigated by the unique pharmacological properties of the non-steroidal MRA finerenone. The FINEARTS-HF trial is designed to evaluate the long-term efficacy and safety of the selective non-steroidal MRA finerenone among patients with HF with mildly reduced or preserved ejection fraction. FINEARTS-HF is a global, multicentre, event-driven randomized trial evaluating oral finerenone versus matching placebo in symptomatic patients with HF with LVEF ≥40%. Adults (≥40 years) with HF with New York Heart Association class II-IV symptoms, LVEF ≥40%, evidence of structural heart disease, and diuretic use for at least the previous 30 days were eligible. All patients required elevated natriuretic peptide levels: for patients in sinus rhythm, N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml (or B-type natriuretic peptide [BNP] ≥100 pg/ml) were required, measured within 30 days (in those without a recent worsening HF event) or within 90 days (in those with a recent worsening HF event). Qualifying levels of NT-proBNP or BNP were tripled if a patient was in atrial fibrillation at screening. Estimated glomerular filtration rate <25 ml/min/1.73 m2 or serum potassium >5.0 mmol/L were key exclusion criteria. Patients were enrolled irrespective of clinical care setting (whether hospitalized, recently hospitalized, or ambulatory). The primary endpoint is the composite of cardiovascular death and total (first and recurrent) HF events. The trial started on 14 September 2020 and has validly randomized 6001 participants across 37 countries. Approximately 2375 total primary composite events are targeted. The FINEARTS-HF trial will determine the efficacy and safety of the non-steroidal MRA finerenone in a broad population of hospitalized and ambulatory patients with HF with mildly reduced or preserved ejection fraction. ClinicalTrials.gov NCT04435626 and EudraCT 2020-000306-29.

Applying natural language processing to identify emergency department and observation encounters for worsening heart failure.

Worsening heart failure (WHF) events occurring in non-inpatient settings are becoming increasingly recognized, with implications for prognostication. We evaluate the performance of a natural language processing (NLP)-based approach compared with traditional diagnostic coding for non-inpatient clinical encounters and left ventricular ejection fraction (LVEF). We compared characteristics for encounters that did vs. did not meet WHF criteria, stratified by care setting [i.e. emergency department (ED) and observation stay]. Overall, 8407 (22%) encounters met NLP-based criteria for WHF (3909 ED visits and 4498 observation stays). The use of an NLP-derived definition adjudicated 3983 (12%) of non-primary HF diagnoses as meeting consensus definitions for WHF. The most common diagnosis indicated in these encounters was dyspnoea. Results were primarily driven by observation stays, in which 2205 (23%) encounters with a secondary HF diagnosis met the WHF definition by NLP. The use of standard claims-based adjudication for primary diagnosis in the non-inpatient setting may lead to misclassification of WHF events in the ED and overestimate observation stays. Primary diagnoses alone may underestimate the burden of WHF in non-hospitalized settings.

Baseline characteristics of patients with heart failure with mildly reduced or preserved ejection fraction: The FINEARTS-HF trial.

To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF. Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m2, elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials. FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population.

Initiation and continuation of pharmacological therapies in patients hospitalized for heart failure in Japan.

Currently, the utilization patterns of medications for heart failure (HF) after worsening HF events remain unelucidated in Japan. Here, we conducted a retrospective cohort study evaluating the changes in HF drug utilization patterns in 6 months before and after hospitalizations for HF. The adherence to newly initiated HF medications was evaluated based on the proportion of days covered (PDC) and persistence as continuous treatment episodes among new users. The study included 9091 patients hospitalized for HF between January 2016 and September 2019, including 2735 (30.1%) patients who were newly prescribed at least one HF medication after hospitalization. Despite increases in the use of foundational HF therapy (beta-blockers, angiotensin-converting-enzyme inhibitors/angiotensin receptor blockers, or mineralocorticoid receptor antagonists), 35.6% and 7.6% of patients were treated with the HF foundational monotherapy or diuretics alone after hospitalization, respectively. The mean PDC of newly initiated HF medications ranged from 0.57 for thiazide diuretics to 0.77 for sodium-glucose cotransporter-2 inhibitors. Continuous use of HF medications during the first year after initiation was observed in 30-60% of patients. The mean PDC and one-year continuous HF medication use were consistently lower in patients aged ≥ 75years and in patients with a history of HF hospitalization for all HF medication classes except for tolvaptan and digoxin. Despite the guideline recommendations of HF pharmacotherapy, both treatment and adherence were suboptimal after HF hospitalization, especially in vulnerable populations such as older patients and those with prior HF hospitalizations.

Cost-Utility Analysis of Vericiguat in Heart Failure with Reduced Ejection Fraction After Worsening Heart Failure Events in China.

Vericiguat is a new medication to demonstrate clinical efficacy in heart failure with reduced ejection fraction (HFrEF) after worsening heart failure (WHF) events, but its cost-utility was unknown. We aimed to assess the cost-utility of combining the application of vericiguat with standard treatment in HFrEF patients who had WHF events. A multistate Markov model was implemented to mimic the economic results of HFrEF patients who had WHF events in China after receiving vericiguat or placebo. An analysis of cost-utility was conducted; most parameters were set according to the published studies and related databases. All the utilities and costs were decreased at a rate of 5% annually. The incremental cost-effectiveness ratios (ICERs) were the primary outcome measure. We also conducted sensitivity analyses. Over a 20 year lifetime horizon, additional use of vericiguat led to an elevated cost from US$9725.03 to US$20,660.76 at the current vericiguat costs. This was related to increased quality-adjusted life years (QALYs) from 2.50 to 2.66, along with an ICER of US$65,057.24 per QALY, which was over the willingness-to-pay (WTP) threshold of US$36,096.30 per QALY. If the vericiguat costs were discounted at 80%, it contributed to an ICER of US$12,226.77 per QALY. Additional use of vericiguat for patients with plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) of ≤ 5314 pg per ml produced an ICER of US$23,688.46 per QALY. The outcomes of the one-way sensitivity analysis showed the risk of death from cardiovascular disease in both groups was variable with the highest sensitivity. The probabilistic sensitivity analysis showed that 41.6% of the mimicked population receiving vericiguat combined with standard therapy was cost-effective at the WTP threshold of US$36,096.30 per QALY. From the perspective of Chinese public healthcare system, the combined use of vericiguat and standard treatment in patients with HFrEF following WHF events did not generate advantages in cost-utility in China but was a cost-effective therapeutic strategy for those who with plasma NT-proBNP of ≤ 5314 pg per ml.

Treatment effects of empagliflozin in hospitalized heart failure patients across the range of left ventricular ejection fraction-Results from the EMPULSE trial.

The EMPULSE (EMPagliflozin in patients hospitalised with acUte heart faiLure who have been StabilizEd) trial showed that, compared to placebo, the sodium-glucose cotransporter 2 inhibitor empagliflozin (10 mg/day) improved clinical outcomes of patients hospitalized for acute heart failure (HF). We investigated whether efficacy and safety of empagliflozin were consistent across the spectrum of left ventricular ejection fraction (LVEF). A total of 530 patients hospitalized for acute de novo or decompensated HF were included irrespective of LVEF. For the present analysis, patients were classified as HF with reduced (HFrEF, LVEF ≤40%), mildly reduced (HFmrEF, LVEF 41-49%) or preserved (HFpEF, LVEF ≥50%) ejection fraction at baseline. The primary endpoint was a hierarchical outcome of death, worsening HF events (HFE) and quality of life over 90 days, assessed by the win ratio. Secondary endpoints included individual components of the primary endpoint and safety. Out of 523 patients with baseline data, 354 (67.7%) had HFrEF, 54 (10.3%) had HFmrEF and 115 (22.0%) had HFpEF. The clinical benefit (hierarchical composite of all-cause death, HFE and Kansas City Cardiomyopathy Questionnaire total symptom score) of empagliflozin at 90 days compared to placebo was consistent across LVEF categories (≤40%: win ratio 1.35 [95% confidence interval 1.04, 1.75]; 41-49%: win ratio 1.25 [0.66, 2.37)] and ≥50%: win ratio 1.40 [0.87, 2.23], pinteraction = 0.96) with a favourable safety profile. Results were consistent across individual components of the hierarchical primary endpoint. The clinical benefit of empagliflozin proved consistent across LVEF categories in the EMPULSE trial. These results support early in-hospital initiation of empagliflozin regardless of LVEF.

Sex-Based Differences in the Epidemiology, Clinical Characteristics, and Outcomes Associated with Worsening Heart Failure Events in a Learning Health System

BackgroundDifferences in demographics, risk factors, and clinical characteristics may contribute to variations in men and women in terms of the prevalence, clinical setting, and outcomes associated with worsening heart failure (WHF) events. We sought to describe sex-based differences in the epidemiology, clinical characteristics, and outcomes associated with WHF events across clinical settings. Methods and ResultsWe examined adults diagnosed with HF from 2010 to 2019 within a large, integrated health care delivery system. Electronic health record data were accessed for hospitalizations, emergency department (ED) visits and observation stays, and outpatient encounters. WHF was identified using validated natural language processing algorithms and defined as ≥1 symptom, ≥2 objective findings (including ≥1 sign), and ≥1 change in HF-related therapy. Incidence rates and associated outcomes for WHF were compared across care setting by sex. We identified 1,122,368 unique clinical encounters with a diagnosis code for HF, with 124,479 meeting WHF criteria. These WHF encounters existed among 102,116 patients, of whom 48,543 (47.5%) were women and 53,573 (52.5%) were men. Women experiencing WHF were older and more likely to have HF with preserved ejection fraction compared with men. The clinical settings of WHF were similar among women and men: hospitalizations (36.8% vs 37.7%), ED visits or observation stays (11.8% vs 13.4%), and outpatient encounters (4.4% vs 4.9%). Women had lower odds of 30-day mortality after an index hospitalization (adjusted odds ratio 0.88, 95% confidence interval 0.83–0.93) or ED visit or observation stay (adjusted odds ratio 0.86, 95% confidence interval 0.75–0.98) for WHF. ConclusionsWomen and men contribute similarly to WHF events across diverse clinical settings despite marked differences in age and left ventricular ejection fraction.

Prevalence and clinical outcomes of isolated or combined moderate to severe mitral and tricuspid regurgitation in patients with cardiac amyloidosis.

Evidence on the epidemiology and prognostic significance of mitral regurgitation (MR) and tricuspid regurgitation (TR) in patients with cardiac amyloidosis (CA) is scarce. Overall, 538 patients with either transthyretin (ATTR, n = 359) or immunoglobulin light-chain (AL, n = 179) CA were included at three Italian referral centres. Patients were stratified according to isolated or combined moderate/severe MR and TR. Overall, 240 patients (44.6%) had no significant MR/TR, 112 (20.8%) isolated MR, 66 (12.3%) isolated TR, and 120 (22.3%) combined MR/TR. The most common aetiologies were atrial functional MR, followed by primary infiltrative MR, and secondary TR due to right ventricular (RV) overload followed by atrial functional TR. Patients with isolated or combined MR/TR had a more frequent history of heart failure (HF) hospitalization and atrial fibrillation, worse symptoms, and higher levels of NT-proBNP as compared to those without MR/TR. They also presented more severe atrial enlargement, atrial peak longitudinal strain impairment, left ventricular (LV) and RV systolic dysfunction, and higher pulmonary artery systolic pressures. TR carried the most advanced features. After adjustment for age, sex, CA subtypes, laboratory, and echocardiographic markers of CA severity, isolated TR and combined MR/TR were independently associated with an increased risk of all-cause death or worsening HF events, compared to no significant MR/TR [adjusted HR 2.75 (1.78-4.24) and 2.31 (1.44-3.70), respectively]. In a large cohort of patients with CA, MR, and TR were common. Isolated TR and combined MR/TR were associated with worse prognosis regardless of CA aetiology, LV, and RV function, with TR carrying the highest risk.

Sacubitril/Valsartan in Patients Hospitalized With Decompensated Heart Failure

BackgroundThe efficacy and safety of sacubitril/valsartan in patients hospitalized with heart failure (HF) across the spectrum of left ventricular ejection fraction (EF) has not been described. ObjectivesData from randomized trials of sacubitril/valsartan in HF patients with EF ≤40% (PIONEER-HF [Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode] trial) and >40% (PARAGLIDE-HF [Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF] trial) following recent worsening heart failure (WHF) were pooled to examine treatment effect across the EF spectrum. MethodsThe PIONEER-HF and PARAGLIDE-HF trials were double-blind, randomized trials of sacubitril/valsartan vs control therapy (enalapril or valsartan, respectively). All participants in the PIONEER-HF trial and 69.5% in the PARAGLIDE-HF trial were enrolled during hospitalization for HF after stabilization. The remainder in the PARAGLIDE-HF trial were enrolled ≤30 days after a WHF event. The primary endpoint of both trials was time-averaged proportional change in N-terminal pro–B-type natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8. Adjudicated clinical endpoints were analyzed through the end of follow-up, adjusting for trial. ResultsThe pooled analysis included 1,347 patients (881 from PIONEER-HF, 466 from PARAGLIDE-HF). Baseline characteristics included median age 66 years, 36% women, 31% Black, 34% de novo HF, and median EF 30%. The reduction in NT-proBNP was 24% greater with sacubitril/valsartan vs control therapy (n = 1,130; ratio of change = 0.76; 95% CI: 0.69-0.83; P < 0.0001). Cardiovascular death or hospitalization for HF was reduced by 30% with sacubitril/valsartan vs control therapy (HR: 0.70; 95% CI: 0.54-0.91; P = 0.0077). This effect was consistent across the spectrum of EF ≤60%. Sacubitril/valsartan increased symptomatic hypotension (risk ratio: 1.35; 95% CI: 1.05-1.72). ConclusionsIn patients stabilized after WHF, sacubitril/valsartan led to a greater reduction in plasma NT-proBNP and improved clinical outcome compared with control therapy, in particular across the spectrum of EF ≤60%. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890; Changes in NT-proBNP, Safety, and Tolerability in HFpEF Patients With a WHF Event [HFpEF Decompensation] Who Have Been Stabilized and Initiated at the Time of or Within 30 Days Post-decompensation [PARAGLIDE-HF]; NCT03988634)

Effectiveness of Dapagliflozin in Reducing Incidence of Worsening Heart Failure Events among patients with Reduced Ejection Fraction

Background: Sodium–glucose co-transporter 2 (SGLT2) inhibitors are the groups of oral hypoglycemics that decreases the worse events among cardiac patients of chronic heart failure. Aim: To assess the effectiveness of Dapagliflozin in reducing the incidence of worsening heart failure events among chronic heart failure patients. Study design: Randomized controlled trial. Methodology: This study enrolled 480 cardiac patients with mildly reduced ejection fraction. This study was held at Punjab Institute of Cardiology. All patients received dapagliflozin 10mg once daily or matching placebo, in addition to usual therapy for four weeks. The data was entered and analyzed in SPSS 25. Independent sample t-test was used to compare the mean age and body mass index between two groups. Chi square test was used to compare gender and hypertension with primary composite. Results: There were 138(57.5%) males in Dapagliflozin group and 131(54.6%) males in placebo group. Dapagliflozin demonstrated significant benefits compared to placebo, as evidenced by lower rates of the primary composite outcome (15.8% vs. 23.3%, p = 0.038), hospitalization for heart failure or an urgent visit (10.4% vs. 20.0%, p = 0.003). Practical Implication: Chronic heart failure with mildly reduced ejection fraction is a major problem in modern era. Present study will highlight the effect of oral hypoglycemic, dapagliflozin, in reducing worse cardiovascular events among chronic heart failure patients. As there is a lack of local literature review on this health issue so this study added information to existing literature and add new dimensions in its treatment. Conclusion: It was concluded that dapagliflozin reduced worsening of cardiac events among heart failure patients with mildly reduced ejection fraction thus this drug is effective treatment option among cardiac failure patients in reducing hospitalization. Keywords: Heart Failure, Reduced Ejection Fraction, Effectiveness, Urgent Visits and Hospitalization

N-terminal pro-B-type natriuretic peptide concentrations, testing and associations with worsening heart failure events.

In patients with heart failure (HF), we aimed to assess (i) the time trends in N-terminal pro-B-type natriuretic peptide (NT-proBNP) testing; (ii) patient characteristics associated with NT-proBNP testing; (iii) distribution of NT-proBNP levels, focusing on the subgroups with (WHFE) vs. without (NWHFE) a worsening HF event, defined as an HF hospitalization; and (iv) changes of NT-proBNP levels over time. NT-proBNP testing and levels were investigated in HF patients enrolled in the Swedish Heart Failure Registry (SwedeHF) linked with the Stockholm CREAtinine Measurements project from January 2011 to December 2018. Index date was the first registration in SwedeHF. Patterns of change in NT-proBNP levels before (in the previous 6±3months) and after (in the following 6±3months) the index date were categorized as follows: (i) <3000ng/L at both measurements=stable low; (ii) <3000ng/L at the first measurement and ≥3000ng/L at the second measurement=increased; (iii) ≥3000ng/L at the first measurement and <3000ng/L at the second measurement=decreased; and (iv) ≥3000ng/L at both measurements=stable high. Univariable and multivariable logistic regression models, expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs), were performed to assess the associations between (i) clinical characteristics and NT-proBNP testing and (ii) changes in NT-proBNP from 6months prior to the index date and the index date and a WHFE. Consistency analyses were performed in HF with reduced ejection fraction (HFrEF) alone. A total of 4424 HF patients were included (median age 74years, women 34%, HFrEF 53%), 33% with a WHFE. NT-proBNP testing increased over time, up to 55% in 2018, and was almost two-fold as frequent, and time to testing was less than half, in patients with WHFE vs. NWHFE. Independent predictors of testing were WHFE, higher heart rate, diuretic use, and preserved ejection fraction. Median NT-proBNP was 3070ng/L (Q1-Q3: 1220-7395), approximately three-fold higher in WHFE vs. NWHFE. Compared with stable low NT-proBNP levels, increased (OR 4.27, 95% CI 2.47-7.37) and stable high levels (OR 2.48, 95% CI 1.58-3.88) were independently associated with a higher risk of WHFE. Results were consistent in the HFrEF population. NT-proBNP testing increased over time but still was only performed in half of the patients. Testing was associated with a WHFE, with features of more severe HF and for differential diagnosis purposes. Increased and stable high levels were associated with a WHFE. Overall, our data highlight the potential benefits of carrying further implementation of NT-proBNP testing in clinical practice.

Heart Failure, Investigator-Reported Sleep Apnea and Dapagliflozin: A Patient-Level Pooled Meta-Analysis of DAPA-HF and DELIVER

Sleep apnea is more common in patients with heart failure (HF) than in the general population, but little is known about its association with clinical outcomes in various HF phenotypes or how it might modify the effect of HF therapy. To examine the prevalence of sleep apnea, its association with outcomes and the effects of dapagliflozin in patients with HF with and without sleep apnea in a pooled analysis of 2 trials comparing dapagliflozin to placebo in HFrEF (DAPA-HF trial) and HFmrEF/HFpEF (DELIVER trial). A history of sleep apnea was investigator-reported. The primary outcome was a composite of worsening HF or cardiovascular death. The prevalence of sleep apnea was 5.7% and 7.8% in patients with HFrEF and HFmrEF/HFpEF, respectively. The primary outcome occurred at a rate of 16.0 in participants with sleep apnea compared to 10.6 per 100 person-years in those without (adjusted HR 1.29 [95%CI, 1.10-1.52]). Compared with placebo, dapagliflozin reduced the risk of the primary endpoint to the same extent in patients with (HR 0.78 [95% CI, 0.59-1.03]) and without sleep apnea (HR 0.79 [0.72-0.87]) [Pinteraction = 0.93]. The beneficial effects of dapagliflozin on other clinical outcomes and symptom burden, physical function, and quality of life were consistent in participants with and without sleep apnea. In DAPA-HF and DELIVER, the true prevalence of sleep apnea was likely underestimated. An investigator-reported history of sleep apnea was associated with higher rates of worsening HF events. The benefits of dapagliflozin on clinical outcomes were consistent in patients with and without sleep apnea. Unique identifiers: NCT01920711 CONDENSED ABSTRACT: In a pooled analysis of the DAPA-HF and DELIVER trials of more than 11,000 patients with heart failure (HF) across the range of ejection fractions, an investigator-reported history of sleep apnea was associated with higher rates of worsening HF events but not mortality. The beneficial effects of dapagliflozin on clinical outcomes were consistent in patients with and without sleep apnea. These findings provide further evidence for dapagliflozin as a new treatment option for patients with heart failure across the range of ejection fractions.

Comparative effectiveness of GDMT in the prevention of HF morbidity and death among patients with HFrEF in a U.S. database

Abstract Background The incremental benefit of comprehensive over conventional guideline-directed medical therapy (GDMT) in real-world setting has not been well demonstrated in patients with heart failure with reduced ejection fraction (HFrEF). This study aims to compare patients on GDMT, including first-line therapy from the most recent US guidelines on the prevention of worsening heart failure events (WHFE) and all-cause death. Methods This study used Optum’s de-identified Clinformatics® Data Mart Database to identify patients who have diagnosed HFrEF and prescription fills for components of GDMT ("Conventional GDMT" i.e., ACEi or ARB, and beta-blocker) and first-line therapy from the most recent US guidelines ("2022 GDMT:" i.e., ARNi, MRA, beta-blocker, SGLT2i) between Jan2020 and Mar2022. This study characterized patients on both types of GDMT and compared the residual risk of WHF events (HF hospitalizations or receipt of IV diuresis) and death. Results The Conventional and 2022 GDMT cohorts included 26,517 and 2,775 patients, respectively. The Conventional GDMT cohort was older (74 vs. 68 years), more often female (41% vs. 33%) and white (67% vs. 60%). In general, they had more comorbidities, but a smaller proportion had diabetes mellitus (53% vs. 67%) and PVD (37% vs. 58%). The unadjusted Kaplan Meier curves show time from GDMT initiation to WHFE, or all-cause death was significantly (p&amp;lt;0.01) faster in the Conventional GDMT cohort compared to 2022 GDMT cohort. The unadjusted HR for experiencing a WHFE or all-cause death after starting GDMT was 0.88 (p&amp;lt;0.01) and 0.48 (p&amp;lt;0.001), comparing the 2022 GDMT cohort to Conventional GDMT cohort. These results were attenuated (WHFE: HR: 0.90, p = 0.02; all-cause death: HR: 0.66, p&amp;lt;0.001) after adjusting for demographic characteristics and comorbidities. Conclusion In this sample, patients on the most recent GDMT (2022 GDMT cohort) had better outcomes than those on conventional GDMT. However, the improvement was less noticeable in the prevention of WHFE. Results highlight the ongoing risk of HF-related morbidity and all-cause mortality among patients with HFrEF, despite the use of first-line therapy and underscores the need for therapeutics beyond optimized GDMT to lower the risk in this high-risk population.

Effect of dapagliflozin on outpatient worsening heart failure in patients with mildly reduced or preserved ejection fraction: the DELIVER trial

Abstract Background Hospitalization is recognized as a sentinel event in the disease trajectory of patients with heart failure (HF), but not all patients experiencing decompensation are hospitalized. Outpatient intensification of diuretics is common in response to worsening symptoms suggestive of HF, yet its prognostic and clinical relevance is less certain. Purpose To evaluate the prognostic importance of outpatient oral diuretic intensification and assess the treatment effect of dapagliflozin across the spectrum of worsening HF events. Methods DELIVER was a global, randomized clinical trial of dapagliflozin vs. placebo in 6,263 participants with HF with mildly reduced or preserved ejection fraction. In this prespecified landmark analysis, we assessed the association between various non-fatal worsening HF events (those requiring hospitalization, urgent outpatient visits requiring intravenous HF therapies, and outpatient oral diuretic intensification) and rates of subsequent mortality. Diuretic intensification was defined as new initiation (among those not on diuretics at baseline) or dose uptitration sustained for at least 30 days (among those on diuretics at baseline). We also examined the treatment effect of dapagliflozin on an expanded composite endpoint of CV death, HF hospitalization, urgent HF visit, or outpatient oral diuretic intensification. Results In DELIVER, 4,532 (72%) patients experienced no worsening HF event, while 789 (13%) had outpatient oral diuretic intensification, 86 (1%) required an urgent HF visit, 585 (9%) had a HF hospitalization, and 271 (4%) died of CV causes as a first manifestation of worsening HF. Patients with a first presentation manifesting as outpatient oral diuretic intensification experienced rates of subsequent mortality that were higher (10 per 100py) than those without a worsening HF event (4 per 100py) but similar to rates of subsequent death following urgent HF visit (10 per 100py). Patients with a HF hospitalization as a first presentation of worsening HF had the highest rates of subsequent death (35 per 100py); Figure 1. The addition of outpatient diuretic intensification to the adjudicated DELIVER primary endpoint (CV death, HF hospitalization, or urgent HF visit) increased the overall number of patients experiencing an event from 1,122 to 1,731. Dapagliflozin reduced the need for outpatient diuretic intensification alone (HR 0.72; 95% CI: 0.64-0.82; P&amp;lt;0.001) and when analyzed as a part of an expanded composite endpoint of worsening HF (HR 0.76; 95% CI: 0.69-0.84; P&amp;lt;0.001); Figure 2. Conclusions Even in patients with HF with mildly reduced or preserved ejection fraction, hospitalization as a first presentation of worsening HF is associated with significant subsequent mortality. Moreover, oral diuretic intensification in ambulatory care was frequent, adversely prognostic, and significantly reduced by dapagliflozin.Figure 1Figure 2

The impact of worsening heart failure (WHF) status on subsequent outcomes among patients with HFrEF: History of WHF events is associated with worse subsequent outcomes regardless of extent of GDMT

Abstract Background Patients with worsening heart failure (WHF) have increased risk of future WHF events and death. Guideline directed medical therapy (GDMT) reduces this risk in clinical trials, but few patients in the real-world receive optimal GDMT, leaving its comparative effectiveness unclear. Methods Using Optum’s de-identified Clinformatics® Data Mart Database, we identified patients with heart failure with reduced ejection fraction (HFrEF) who filled HF prescriptions for components of GDMT ("Conventional GDMT:" i.e., ACEi or ARB, and beta-blocker) or first-line therapy from the most recent US guidelines ("2022 GDMT:" i.e., ARNi, MRA, beta-blocker, SGLT2i) between Jan2020 and Mar2022. The ongoing risk of HF hospitalizations (HFH), receipt of IV diuretics, and all-cause death, was assessed by history of (HFH, receipt of IV diuresis in past 12 months) WHF. Event rates reflect counts of first events, whereas cumulative incidence is first and recurrent events. Both are presented per 1,000 person-years. Results Conventional GDMT Cohort: Overall, 26,517 were in the cohort and 51% had WHF. Patients with and without WHF were alike in age (72 vs. 73 years) and a similar proportion were female (43% vs. 40%), and white (67% vs. 67%) (Table). Per 1,000 person-years, the event rates for death, HFH, and IV diuresis were 109, 404, and 106 among patients with WHF and 38, 194, and 29 among patients without WHF, respectively. The cumulative incidence, per 1,000 person-years, for HFH and IV diuretics use among those with WHF were 622 and 241 compared to 258 and 44 among those without WHF (Table). The time to WHF event or death was shorter for patients with WHF (Figure) and HR for all-cause death or WHF was 1.91 for those with WHF compared to those without. 2022 GDMT Cohort: There were 2,775 patients receiving 2022 GDMT and just under half (47%) had WHF. Patients with and without WHF were both an average of 66 years of age, one-third were female, and 60% were white (Table). The event rates (per 1,000 person-years) for death, HFH, and IV diuretic use among those with WHF were 176, 395, and 87 compared to 106, 179, and 40, among those without WHF, respectively (Table). The cumulative incidence (per 1,000 person-years) for HFH and IV diuresis were 577 and 157 among patients with WHF and 268 and 63 among patients without WHF. The time to WHF event or death was also shorter for patients with WHF (Figure). The HR for all-cause death or WHF event comparing patients with and without WHF was 2.28. Conclusion Our study quantified the excess risk of HF morbidity and all-cause death associated with WHF, regardless of extent of GDMT. WHF resulted in higher hospitalizations, morbidity, and deaths and was the strongest predictor of subsequent WHF and all-cause death. This places patients with WHF in a high-risk group. Results can help clinicians better assess the clinical trajectory of their patients and underscore the need for additional therapies and optimized care.Table.Patient CharacteristicsFigure.Clinical Trajectory

Interleukin-6 plasma levels predict mortality and heart failure events in cardiac transthyretin amyloidosis

Abstract Background Low-grade systemic inflammation is a key component in the pathophysiology of heart failure (HF). In particular, the pleiotropic effects of interleukin-6 (IL-6) signaling are of interest as circulating IL-6 levels are associated with mortality in HF patients. Purpose The purpose of this study was to investigate whether IL-6 plasma levels predict mortality and HF events in patients with cardiac transthyretin amyloidosis (ATTR-CM). Methods This was an analysis of a prospective single-center cohort study comprising 98 ATTR-CM patients. The endpoint was defined as a composite of all-cause mortality and worsening HF events. HF events included HF related hospitalizations and urgent outpatient clinic visits with concomitant intravenous diuretic treatment. Follow-up data were collected using central medical records. Kaplan-Meier estimates and Cox regression analyses were calculated to assess the association between IL-6 and the composite endpoint. Moreover, receiver operator characteristics (ROC) analysis was performed to evaluate the predictive accuracy of IL-6 for the composite endpoint. Results Median age was 79 years (76-81), 86 patients (88%) were male, and 46 patients (47%) received the transthyretin (TTR) stabilizer tafamidis at baseline. Median NT-proBNP levels were 2813 pg/ml (1365-4856), mean estimated glomerular filtration rate (eGFR) was 57.9±17.6 ml/min/1.73m², and median urine protein to creatinine ratio (UPCR) was 122.0 mg/g (89.8-204.5). Median IL-6 plasma levels were 4.9 pg/ml (3.0-9.4). During a median observation period of 21.2 months (11.4-32.4), 27 patiens (28%) reached the composite endpoint. IL-6 levels were associated with the composite endpoint (hazard ratio = 1.028, 95% confidence interval = 1.004 to 1.051; p = 0.012). The association was independent of age, TTR stabilizing medication, log-transformed and eGFR-adjusted NT-proBNP levels, as well as UPCR. The area under the ROC curve for IL-6 was 0.70 (95% confidence interval = 0.59 to 0.81; p = 0.003). The optimal cutoff value was 5.3 pg/ml, as determined by Youden’s index, with a sensitivity of 70% and specificity of 66%. Kaplan-Meier estimates demonstrated a mean survival time of 1030 days (95% confidence interval = 911 to 1150) for the study population. A statistically significant difference between the survival rates of ATTR-CM patients with IL-6 levels ≥5.3 pg/ml and those with IL-6 levels below the threshold was indicated by the log-rank test (p = 0.002). Conclusion Circulating levels of IL-6 independently predicted adverse outcomes in patients with ATTR-CM. IL-6 plasma levels may be useful for identifying a high-risk ATTR-CM subpopulation.Tablewith baseline characteristicsFigurewith Kaplan-Meier estimates

SGLT2 inhibitors and vericiguat in real-world patients admitted for worsening heart failure

Abstract Introduction Worsening heart failure (WHF) is an emerging concept that is defined by escalating signs and symptoms of heart failure (HF) in patients with chronic heart failure (CHF) despite stable therapy. After a WHF event, there is a vulnerable period in which the risk of hospitalization and mortality is high. Sodium-glucose-co-transporter inhibitors (SGLT2i) and vericiguat, a soluble guanylate cyclase stimulator (sGCs), have been investigated in patients with WHF bother during hospitalization (EMPULSE) and right after the discharge (VICTORIA and SOLOIST-WHF) in the management of this condition with positive results. Aims This study aims to investigate the eligibility of VICTORIA, SOLOIST-WHF and EMPULSE in real-world population of patients admitted for worsening heart failure (WHF) and to analyze the differences between these groups of patients. Material and methods In this retrospective cohort study, 275 patients admitted for worsening heart failure in our cardiology department between 2017 and 2022 were enrolled. The percentages of eligible patients according to VICTORIA, SOLOIST-WHF and EMPULSE inclusion and exclusion criteria were analyzed, then the differences between the characteristics of our population and trials population were evaluated. Results 83 patients (30,2%) were eligible according to VICTORIA trial criteria, 35 patients (12,7%) according to SOLOIST-WHF and 186 patients (67,6%) according to EMPULSE. Limiting factors were ejection fraction (EF) &amp;gt; 45% in VICTORIA, the presence of diabetes in SOLOIST-WHF and the cut-off levels of NT-proBNP and BNP. Our patients were older (mean 78 years and median 80 years) than trials populations (67 years; 69 years; 71 years). EF was higher (mean 38% and median 35%) than VICTORIA (29%) and than EMPULSE (31%), but similar compared to SOLOIST-WHF (35%). Estimated glomerular filtration rate (eGFR) was lower compared to VICTORIA (56,0 ml/min vs 61,5 ml/min) whereas higher compared to EMPULSE and SOLOIST (54,0 ml/min vs 49,2 ml/min vs 50,0 ml/min). Diabetes was less common in our population (32,7% vs 47,1% vs 100% vs 46,8%); on the other hand, there were higher levels of NT-proBNP (median 5080 pg/ml) in our population compared to trials (3377 pg/ml; 1816,8 pg/ml; 3299 pg/ml). Conclusion SGLT2i and vericiguat are important drugs in the management of WHF. At the moment, vericiguat can be used only in patients with EF &amp;lt; 45% and this is the most limiting factor, whereas SGLT2i can be used regardless of EF. These data show that their applicability is high in patients with WHF and that the characteristics of trials populations reflect a real-world population. More data are needed about the use of vericiguat and SGLT2i, mostly in the first days of hospitalization. Recommendations for how to manage patients with WHF must be defined, national and international registries of HF hospitalizations may resolve this issue.Eligibility of vericiguat and SGLT2iComparison of baseline characteristics

A Novel Heart Failure Diagnostic Risk Score Using a Minimally Invasive Subcutaneous Insertable Cardiac Monitor

BackgroundThe authors tested the hypothesis that physiological information from sensors within a minimally invasive, subcutaneous, insertable cardiac monitor (ICM) could be used to develop an ambulatory heart failure risk score (HFRS) to accurately identify heart failure (HF) patients, across the ejection fraction spectrum, at high risk of an impending worsening heart failure event (HFE). ObjectivesThe purpose of this study was to examine performance of ICM-based, multiparameter, dynamic HFRS to predict HFEs in patients with NYHA functional class II/III HF. MethodsIn 2 observational cohorts, HF patients were implanted with an ICM; subcutaneous impedance, respiratory rate, heart rate and variability, atrial fibrillation burden, ventricular rate during atrial fibrillation, and activity duration were combined into an HFRS to identify the probability of HFE within 30 days. Patients and providers were blinded to the data. HFRS sensitivity and unexplained detection rate were defined in 2 independent patient population data sets. HFEs were defined as hospitalization, observation unit, or emergency department visit with a primary diagnosis of HF, and intravenous diuretic treatment. ResultsFirst data set (development): 42 patients had 19 HFE; second data set (validation): 94 patients had 19 HFE (mean age 66 ± 11 years, 63% men, 50% with LVEF ≥40%, 80% NYHA functional class III). Using a high-risk threshold = 7.5%, development and validation data sets: sensitivity was 73.7% and 68.4%; unexplained detection rate of 1.4 and 1.5 per patient-year; median 47 and 64 days early warning before HFE. ConclusionsICM-HFRS provides a multiparameter, integrated diagnostic method with the ability to identify when HF patients are at increased risk of heart failure events. (Reveal LINQ Evaluation of Fluid [REEF]; NCT02275923, Reveal LINQ Heart Failure [LINQ HF]; NCT02758301, Algorithm Using LINQ Sensors for Evaluation and Treatment of Heart Failure [ALLEVIATE-HF]; NCT04452149)

Abstract 12557: Vericiguat Use in a Real-World HFrEF Patient Population: Two Years Post-Launch

Background: Worsening heart failure events (WHFE) affect up to one-third of patients with HFrEF. Vericiguat, the first agent indicated specifically for a WHF population, is a novel soluble guanylate cyclase (sGC) stimulator approved in 2021 to reduce the risk of cardiovascular death and HF hospitalization. Objective: To describe baseline characteristics, comorbidities, and comedication among patients on vericiguat therapy during the first two years after FDA approval. Methods: We identified adults in the TriNetX Open Claims Database who filled a prescription for vericiguat between 1 Jan 2021 and 24 April 2023. Summary statistics were computed describing patient and treatment patterns including those of other guideline-directed medical therapy (GDMT), stratified by record of achieving 10mg target dose. Categorical variables compared across groups using Pearson Chi-Square tests and continuous variables were compared across groups using non-parametric Kruskal-Wallis tests. Results: Among 5527 patients treated with vericiguat, mean age was 68 years, most were men (67%), and insured by Medicare (47%). Just over one third had a record of achieving the 10mg target dose before data cutoff. Other common GDMT used included beta-blockers (71%), ARNi (47%), MRA (38%) and SGLT2i (39%). Although comorbidities were similar between groups, use of these GDMT classes was statistically significantly higher among patients with a record of achieving target dose of vericiguat (P &lt; 0.05). Similar trends were observed among use of GDMT combinations based on record of achieving target dose (P &lt;0.002). Conclusions: Patients with a record of achieving vericiguat target dose were significantly more likely to be on other recommended GDMT and on GDMT combinations despite a similar comorbidity burden. Additional analyses are needed to better understand factors associated with patients reaching classes and target doses of GDMT, including vericiguat.

Abstract 15420: Cost-Effectiveness of Sacubitril-Valsartan in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction With a Recent Worsening Heart Failure Event

Background: In a pooled analysis of the PARAGON-HF and PARAGLIDE-HF trials, sacubitril-valsartan was effective in the treatment of heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) in patients who experienced a recent worsening heart failure event. Research Question: The cost-effectiveness of sacubitril-valsartan in this patient population has yet to be established. Aim: We performed a cost-effectiveness analysis of sacubitril-valsartan in patients with HFmrEF/HFpEF in patients with a recent worsening heart failure event. Methods: Using a 2-state Markov model, we simulated treatment with sacubitril-valsartan vs. placebo in populations of 1,000 patients with HFmrEF/HFpEF and a recent worsening heart failure event. Clinical event rates were based on 5-year data from the I-PRESERVE trial and calibrated to reproduce event rates observed in the pooled analysis of the PARAGON-HF and PARAGLIDE-HF trials. Based on a United States health care system perspective, outcome data from the trials were used to calculate incremental cost-effectiveness ratios. Results: Treatment with sacubitril-valsartan resulted in an increase of 0.88 and 0.53 life years and quality-adjusted life years, respectively, compared to placebo. Lifetime costs increased due to the cost of sacubitril-valsartan. The incremental cost-effectiveness ratio was $96,762 (Table 1). Conclusions: Use of sacubitril-valsartan in patients HFmrEF/HFpEF with a recent worsening heart failure event displayed intermediate value by American Heart Association/American College of Cardiology standards. This study supports the current guideline recommendation to consider sacubitril-valsartan in HFmrEF/HFpEF.