On-treatment analysis of torsemide versus furosemide for patients hospitalized for heart failure: A post-hoc analysis of TRANSFORM-HF.

AIM: The TRANSFORM-HF trial demonstrated no significant outcome differences between torsemide and furosemide following hospitalization for heart failure (HF), but may have been impacted by non-adherence to the randomized diuretic. The current study sought to determine the treatment effect of torsemide versus furosemide using an on-treatment analysis inclusive of all randomized patients except those confirmed non-adherent to study diuretic. METHODS AND RESULTS: TRANSFORM-HF was an open-label, pragmatic randomized trial of 2859 patients hospitalized for HF from June 2018 through March 2022. Patients were randomized to a loop diuretic strategy of torsemide versus furosemide with investigator-selected dosage. This post-hoc on-treatment analysis included all patients alive with either known or unknown diuretic status, and excluded patients confirmed to be non-adherent to study diuretic. This modified on-treatment definition was applied separately at time of hospital discharge and 30-day follow-up. All-cause mortality and hospitalization outcomes were assessed over 12 months. Overall, 2570 (89.9%) and 2374 (83.0%) patients were included in on-treatment analyses at discharge and 30-day follow-up, respectively. There was no significant difference in all-cause mortality between torsemide and furosemide in patients on-treatment at discharge (17.5% vs. 17.8%; hazard ratio [HR] 1.01 [95% confidence interval [CI] 0.83-1.22], p = 0.96) and at 30-day follow-up (14.5% vs. 15.0%; HR 1.02 [95% CI 0.81-1.27], p = 0.90). All-cause mortality or all-cause hospitalization was similar between torsemide and furosemide in patients who were on-treatment at discharge (58.3% vs. 61.3%; HR 0.92 [95% CI 0.82-1.03]) and 30-day follow-up (60.9% vs. 64.4%; HR 0.93 [95% CI 0.82-1.05]). In patients who were on-treatment at 30-day follow-up, there were 677 total hospitalizations in the torsemide group and 686 total hospitalizations in the furosemide group (rate ratio 0.99 [95% CI 0.86-1.14], p = 0.87). CONCLUSIONS: In TRANSFORM-HF, a post-hoc on-treatment analysis did not meaningfully differ from the original trial results. Among those deemed compliant with the assigned diuretic, there remained no significant difference in mortality or hospitalization after HF hospitalization with a strategy of torsemide versus furosemide. CLINICAL TRAIL REGISTRATION: ClinicalTrials.gov Identifier: NCT03296813.

A Multimodal Video-Based AI Biomarker for Aortic Stenosis Development and Progression.

Importance: Aortic stenosis (AS) is a major public health challenge with a growing therapeutic landscape, but current biomarkers do not inform personalized screening and follow-up. A video-based artificial intelligence (AI) biomarker (Digital AS Severity index [DASSi]) can detect severe AS using single-view long-axis echocardiography without Doppler characterization. Objective: To deploy DASSi to patients with no AS or with mild or moderate AS at baseline to identify AS development and progression. Design, Setting, and Participants: This is a cohort study that examined 2 cohorts of patients without severe AS undergoing echocardiography in the Yale New Haven Health System (YNHHS; 2015-2021) and Cedars-Sinai Medical Center (CSMC; 2018-2019). A novel computational pipeline for the cross-modal translation of DASSi into cardiac magnetic resonance (CMR) imaging was further developed in the UK Biobank. Analyses were performed between August 2023 and February 2024. Exposure: DASSi (range, 0-1) derived from AI applied to echocardiography and CMR videos. Main Outcomes and Measures: Annualized change in peak aortic valve velocity (AV-Vmax) and late (>6 months) aortic valve replacement (AVR). Results: A total of 12 599 participants were included in the echocardiographic study (YNHHS: n = 8798; median [IQR] age, 71 [60-80] years; 4250 [48.3%] women; median [IQR] follow-up, 4.1 [2.4-5.4] years; and CSMC: n = 3801; median [IQR] age, 67 [54-78] years; 1685 [44.3%] women; median [IQR] follow-up, 3.4 [2.8-3.9] years). Higher baseline DASSi was associated with faster progression in AV-Vmax (per 0.1 DASSi increment: YNHHS, 0.033 m/s per year [95% CI, 0.028-0.038] among 5483 participants; CSMC, 0.082 m/s per year [95% CI, 0.053-0.111] among 1292 participants), with values of 0.2 or greater associated with a 4- to 5-fold higher AVR risk than values less than 0.2 (YNHHS: 715 events; adjusted hazard ratio [HR], 4.97 [95% CI, 2.71-5.82]; CSMC: 56 events; adjusted HR, 4.04 [95% CI, 0.92-17.70]), independent of age, sex, race, ethnicity, ejection fraction, and AV-Vmax. This was reproduced across 45 474 participants (median [IQR] age, 65 [59-71] years; 23 559 [51.8%] women; median [IQR] follow-up, 2.5 [1.6-3.9] years) undergoing CMR imaging in the UK Biobank (for participants with DASSi ≥0.2 vs those with DASSi <.02, adjusted HR, 11.38 [95% CI, 2.56-50.57]). Saliency maps and phenome-wide association studies supported associations with cardiac structure and function and traditional cardiovascular risk factors. Conclusions and Relevance: In this cohort study of patients without severe AS undergoing echocardiography or CMR imaging, a new AI-based video biomarker was independently associated with AS development and progression, enabling opportunistic risk stratification across cardiovascular imaging modalities as well as potential application on handheld devices.

Impact of baseline kidney dysfunction on oral diuretic efficacy following hospitalization for heart failure - insights from TRANSFORM-HF.

AIM: Among patients discharged after hospitalization for heart failure (HF), a strategy of torsemide versus furosemide showed no difference in all-cause mortality or hospitalization. Clinicians have traditionally favoured torsemide in the setting of kidney dysfunction due to better oral bioavailability and longer half-life, but direct supportive evidence is lacking. METHODS AND RESULTS: The TRANSFORM-HF trial randomized patients hospitalized for HF to a long-term strategy of torsemide versus furosemide, and enrolled patients across the spectrum of renal function (without dialysis). In this post-hoc analysis, baseline renal function during the index hospitalization was assessed as categories of estimated glomerular filtration rate (eGFR; <30, 30-<60, ≥60 ml/min/1.73 m2). The interaction between baseline renal function and treatment effect of torsemide versus furosemide was assessed with respect to mortality and hospitalization outcomes, and the change in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS). Of 2859 patients randomized, 336 (11.8%) had eGFR <30 ml/min/1.73 m2, 1138 (39.8%) had eGFR 30-<60 ml/min/1.73 m2, and 1385 (48.4%) had eGFR ≥60 ml/min/1.73 m2. Baseline eGFR did not modify treatment effects of torsemide versus furosemide on all adverse clinical outcomes including individual components or composites of all-cause mortality and all-cause (re)-hospitalizations, both when assessing eGFR categorically or continuously (p-value for interaction all >0.108). Similarly, no treatment effect modification by eGFR was found for the change in KCCQ-CSS (p-value for interaction all >0.052) when assessing eGFR categorically or continuously. CONCLUSION: Among patients discharged after hospitalization for HF, there was no significant difference in clinical and patient-reported outcomes between torsemide and furosemide, irrespective of renal function.

Sacubitril/Valsartan in Patients Hospitalized With Decompensated Heart Failure.

BACKGROUND: The 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. OBJECTIVES: Data 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. METHODS: The 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. RESULTS: The 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). CONCLUSIONS: In 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).

Torsemide Versus Furosemide After Discharge in Patients Hospitalized With Heart Failure Across the Spectrum of Ejection Fraction: Findings From TRANSFORM-HF.

BACKGROUND: The TRANSFORM-HF trial (Torsemide Comparison With Furosemide for Management of Heart Failure) found no significant difference in all-cause mortality or hospitalization among patients randomized to a strategy of torsemide versus furosemide following a heart failure (HF) hospitalization. However, outcomes and responses to some therapies differ by left ventricular ejection fraction (LVEF). Thus, we sought to explore the effect of torsemide versus furosemide by baseline LVEF and to assess outcomes across LVEF groups. METHODS: We compared baseline patient characteristics and randomized treatment effects for various end points in TRANSFORM-HF stratified by LVEF: HF with reduced LVEF, ≤40% versus HF with mildly reduced LVEF, 41% to 49% versus HF with preserved LVEF, ≥50%. We also evaluated associations between LVEF and clinical outcomes. Study end points were all-cause mortality or hospitalization at 30 days and 12 months, total hospitalizations at 12 months, and change from baseline in Kansas City Cardiomyopathy Questionnaire clinical summary score. RESULTS: Overall, 2635 patients (median 64 years, 36% female, 34% Black) had LVEF data. Compared with HF with reduced LVEF, patients with HF with mildly reduced LVEF and HF with preserved LVEF had a higher prevalence of comorbidities. After adjusting for covariates, there was no significant difference in risk of clinical outcomes across the LVEF groups (adjusted hazard ratio for 12-month all-cause mortality, 0.91 [95% CI, 0.59-1.39] for HF with mildly reduced LVEF versus HF with reduced LVEF and 0.91 [95% CI, 0.70-1.17] for HF with preserved LVEF versus HF with reduced LVEF; P=0.73). In addition, there was no significant difference between torsemide and furosemide (1) for mortality and hospitalization outcomes, irrespective of LVEF group and (2) in changes in Kansas City Cardiomyopathy Questionnaire clinical summary score in any LVEF subgroup. CONCLUSIONS: Despite baseline demographic and clinical differences between LVEF cohorts in TRANSFORM-HF, there were no significant differences in the clinical end points with torsemide versus furosemide across the LVEF spectrum. There was a substantial risk for all-cause mortality and subsequent hospitalization independent of baseline LVEF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03296813.

Cardiac effects of deferasirox in transfusion-dependent patients with myelodysplastic syndromes: TELESTO study.

Iron overload from repeated transfusions has a negative impact on cardiac function, and iron chelation therapy may help prevent cardiac dysfunction in transfusion-dependent patients with myelodysplastic syndromes (MDS). TELESTO (NCT00940602) was a prospective, placebo-controlled, randomised study to evaluate the iron chelator deferasirox in patients with low- or intermediate-1-risk MDS and iron overload. Echocardiographic parameters were collected at screening and during treatment. Patients receiving deferasirox experienced a significant decrease in the composite risk of hospitalisation for congestive heart failure (CHF) or worsening of cardiac function (HR = 0.23; 95% CI: 0.05, 0.99; nominal p = 0.0322) versus placebo. No significant differences between the arms were found in left ventricular ejection fraction, ventricular diameter and mass or pulmonary artery pressure. The absolute number of events was low, but the enrolled patients were younger than average for patients with MDS, with no serious cardiac comorbidities and a modest cardiovascular risk profile. These results support the effectiveness of deferasirox in preventing cardiac damage caused by iron overload in this patient population. Identification of patients developing CHF is challenging due to the lack of distinctive echocardiographic features. The treatment of iron overload may be important to prevent cardiac dysfunction in these patients, even those with moderate CHF risk.

Factors associated with reporting left ventricular ejection fraction with 3D echocardiography in real-world practice.

BACKGROUND: Guidelines recommend 3D echocardiography (3DE) to assess left ventricular ejection fraction (LVEF) on transthoracic echocardiogram (TTE) when possible, but it is unclear which factors are most strongly associated with reporting 3DE LVEF in real-world practice. METHODS: We evaluated 3DE LVEF reporting by age, sex, BMI, TTE location and variation in reporting by sonographer and reader. All TTEs were performed without contrast enhancement agent at a large medical center from 9/2015 to 12/2020 using ultrasound machines capable of 3DE. We used multivariable logistic regression to assess which factors were most associated with reporting 3DE LVEF. RESULTS: Among 35 641 TTEs included in this study, 57.4% were performed on women. 3DE LVEF was reported on 18 391 TTEs (51.6% of cohort; 50.5% for women and 52.4% for men). Portable inpatient TTEs (n = 5569) had the lowest rates of 3DE LVEF reporting (30.9%), while general outpatient TTEs (n = 15 933) had greater reporting (56.9%). Outpatient TTEs with an indication for chemotherapy (n = 3244) had the highest rates of 3DE LVEF (87.2%). The median (IQR) percentage of TTEs reporting 3D LVEF was 52.7% (43.1%-68.1%) among sonographers and 51.6% (46.5%-59.6%) among readers. Among 20082 (56.3%) TTEs with 3DE LVEF measured by sonographers, 91.6% were included by readers in the final report. After adjustment, performing sonographer in the highest reporting quartile was most strongly associated with reporting 3DE LVEF (OR 7.04, 95% CI 6.55-7.56), while an inpatient portable study had the strongest negative association for reporting (OR .38, 95% CI .35-.40). CONCLUSIONS: Use of 3DE LVEF in real-world practice varies substantially based on performing sonographer and is low for hospitalized patients, but can be frequently used for chemotherapy. Initiatives are needed to increase sonographer 3DE acquisition in most clinical settings.

A Multimodality Video-Based AI Biomarker For Aortic Stenosis Development And Progression.

Importance: Aortic stenosis (AS) is a major public health challenge with a growing therapeutic landscape, but current biomarkers do not inform personalized screening and follow-up. Objective: A video-based artificial intelligence (AI) biomarker (Digital AS Severity index [DASSi]) can detect severe AS using single-view long-axis echocardiography without Doppler. Here, we deploy DASSi to patients with no or mild/moderate AS at baseline to identify AS development and progression. Design Setting and Participants: We defined two cohorts of patients without severe AS undergoing echocardiography in the Yale-New Haven Health System (YNHHS) (2015-2021, 4.1[IQR:2.4-5.4] follow-up years) and Cedars-Sinai Medical Center (CSMC) (2018-2019, 3.4[IQR:2.8-3.9] follow-up years). We further developed a novel computational pipeline for the cross-modality translation of DASSi into cardiac magnetic resonance (CMR) imaging in the UK Biobank (2.5[IQR:1.6-3.9] follow-up years). Analyses were performed between August 2023-February 2024. Exposure: DASSi (range: 0-1) derived from AI applied to echocardiography and CMR videos. Main Outcomes and Measures: Annualized change in peak aortic valve velocity (AV-Vmax) and late (>6 months) aortic valve replacement (AVR). Results: A total of 12,599 participants were included in the echocardiographic study (YNHHS: n=8,798, median age of 71 [IQR (interquartile range):60-80] years, 4250 [48.3%] women, and CSMC: n=3,801, 67 [IQR:54-78] years, 1685 [44.3%] women). Higher baseline DASSi was associated with faster progression in AV-Vmax (per 0.1 DASSi increments: YNHHS: +0.033 m/s/year [95%CI:0.028-0.038], n=5,483, and CSMC: +0.082 m/s/year [0.053-0.111], n=1,292), with levels ≥ vs <0.2 linked to a 4-to-5-fold higher AVR risk (715 events in YNHHS; adj.HR 4.97 [95%CI: 2.71-5.82], 56 events in CSMC: 4.04 [0.92-17.7]), independent of age, sex, ethnicity/race, ejection fraction and AV-Vmax. This was reproduced across 45,474 participants (median age 65 [IQR:59-71] years, 23,559 [51.8%] women) undergoing CMR in the UK Biobank (adj.HR 11.4 [95%CI:2.56-50.60] for DASSi ≥vs<0.2). Saliency maps and phenome-wide association studies supported links with traditional cardiovascular risk factors and diastolic dysfunction. Conclusions and Relevance: In this cohort study of patients without severe AS undergoing echocardiography or CMR imaging, a new AI-based video biomarker is independently associated with AS development and progression, enabling opportunistic risk stratification across cardiovascular imaging modalities as well as potential application on handheld devices.

Torsemide vs Furosemide Among Patients With New-Onset vs Worsening Chronic Heart Failure: A Substudy of the TRANSFORM-HF Randomized Clinical Trial.

Importance: Differences in clinical profiles, outcomes, and diuretic treatment effects may exist between patients with de novo heart failure (HF) and worsening chronic HF (WHF). Objectives: To compare clinical characteristics and treatment outcomes of torsemide vs furosemide in patients hospitalized with de novo HF vs WHF. Design, Setting, and Participants: All patients with a documented ejection fraction who were randomized in the Torsemide Comparison With Furosemide for Management of Heart Failure (TRANSFORM-HF) trial, conducted from June 18 through March 2022, were included in this post hoc analysis. Study data were analyzed March to May 2023. Exposure: Patients were categorized by HF type and further divided by loop diuretic strategy. Main Outcomes and Measures: End points included all-cause mortality and hospitalization outcomes over 12 months, as well as change from baseline in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS). Results: Among 2858 patients (mean [SD] age, 64.5 [14.0] years; 1803 male [63.1%]), 838 patients (29.3%) had de novo HF, and 2020 patients (70.7%) had WHF. Patients with de novo HF were younger (mean [SD] age, 60.6 [14.5] years vs 66.1 [13.5] years), had a higher glomerular filtration rate (mean [SD], 68.6 [24.9] vs 57.0 [24.0]), lower levels of natriuretic peptides (median [IQR], brain-type natriuretic peptide, 855.0 [423.0-1555.0] pg/mL vs 1022.0 [500.0-1927.0] pg/mL), and tended to be discharged on lower doses of loop diuretic (mean [SD], 50.3 [46.2] mg vs 63.8 [52.4] mg). De novo HF was associated with lower all-cause mortality at 12 months (de novo, 65 of 838 [9.1%] vs WHF, 408 of 2020 [25.4%]; adjusted hazard ratio [aHR], 0.50; 95% CI, 0.38-0.66; P < .001). Similarly, lower all-cause first rehospitalization at 12 months and greater improvement from baseline in KCCQ-CSS at 12 months were noted among patients with de novo HF (median [IQR]: de novo, 29.94 [27.35-32.54] vs WHF, 23.68 [21.62-25.74]; adjusted estimated difference in means: 6.26; 95% CI, 3.72-8.81; P < .001). There was no significant difference in mortality with torsemide vs furosemide in either de novo (No. of events [rate per 100 patient-years]: torsemide, 27 [7.4%] vs furosemide, 38 [10.9%]; aHR, 0.70; 95% CI, 0.40-1.14; P = .15) or WHF (torsemide 212 [26.8%] vs furosemide, 196 [24.0%]; aHR, 1.08; 95% CI, 0.89-1.32; P = .42; P for interaction = .10), In addition, no significant differences in hospitalizations, first all-cause hospitalization, or total hospitalizations at 12 months were noted with a strategy of torsemide vs furosemide in either de novo HF or WHF. Conclusions and Relevance: Among patients discharged after hospitalization for HF, de novo HF was associated with better clinical and patient-reported outcomes when compared with WHF. Regardless of HF type, there was no significant difference between torsemide and furosemide with respect to 12-month clinical or patient-reported outcomes.

The Impact of Ejection Fraction on Major Adverse Limb Events after Lower Extremity Revascularization.

BACKGROUND: Peripheral arterial disease (PAD) is commonly associated with coronary artery disease, and echocardiography is frequently performed before lower extremity revascularization (LER). However, the incidence of various echocardiographic findings in patients with PAD and their impact on the outcomes of LER has not been well studied. Reduced ejection fraction (EF) ≤ 40% is associated with increased major adverse limb events (MALE) after LER. METHODS: The electronic medical records of patients undergoing LER in a single center were reviewed. Patients were divided based on the presence or absence of reduced EF. Patient, transthoracic echocardiogram, procedural characteristics, and outcomes were compared between the 2 groups. RESULTS: A total of 1,114 patients (N = 131, 11.8% with reduced EF) underwent LER between 2013 and 2019. Patients with reduced EF were more likely to be male and have a history of coronary artery disease and heart failure. Furthermore, they were more likely to have diastolic dysfunction with moderate to severe mitral and tricuspid valve regurgitation. Patients with reduced EF were more likely to undergo LER for chronic limb-threatening ischemia, and to be treated with endovascular procedures. Perioperatively, patients with reduced EF were more likely to develop myocardial infarction. Lastly, the 2 groups had no difference in overall MALE or major amputation. However, on Kaplan-Meier curves, MALE-free survival was significantly lower for patients with reduced EF. Regression analysis demonstrated that indication and not EF was associated with MALE and MALE-free survival. CONCLUSIONS: Reduced EF is associated with decreased MALE-free survival for patients with PAD undergoing LER.

Electronic health record alerts for management of heart failure with reduced ejection fraction in hospitalized patients: the PROMPT-AHF trial.

BACKGROUND AND AIMS: Patients hospitalized for acute heart failure (AHF) continue to be discharged on an inadequate number of guideline-directed medical therapies (GDMT) despite evidence that inpatient initiation is beneficial. This study aimed to examine whether a tailored electronic health record (EHR) alert increased rates of GDMT prescription at discharge in eligible patients hospitalized for AHF. METHODS: Pragmatic trial of messaging to providers about treatment of acute heart failure (PROMPT-AHF) was a pragmatic, multicenter, EHR-based, and randomized clinical trial. Patients were automatically enrolled 48 h after admission if they met pre-specified criteria for an AHF hospitalization. Providers of patients in the intervention arm received an alert during order entry with relevant patient characteristics along with individualized GDMT recommendations with links to an order set. The primary outcome was an increase in the number of GDMT prescriptions at discharge. RESULTS: Thousand and twelve patients were enrolled between May 2021 and November 2022. The median age was 74 years; 26% were female, and 24% were Black. At the time of the alert, 85% of patients were on ß-blockers, 55% on angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, 20% on mineralocorticoid receptor antagonist (MRA) and 17% on sodium-glucose cotransporter 2 inhibitor. The primary outcome occurred in 34% of both the alert and no alert groups [adjusted risk ratio (RR): 0.95 (0.81, 1.12), P = .99]. Patients randomized to the alert arm were more likely to have an increase in MRA [adjusted RR: 1.54 (1.10, 2.16), P = .01]. At the time of discharge, 11.2% of patients were on all four pillars of GDMT. CONCLUSIONS: A real-time, targeted, and tailored EHR-based alert system for AHF did not lead to a higher number of overall GDMT prescriptions at discharge. Further refinement and improvement of such alerts and changes to clinician incentives are needed to overcome barriers to the implementation of GDMT during hospitalizations for AHF. GDMT remains suboptimal in this setting, with only one in nine patients being discharged on a comprehensive evidence-based regimen for heart failure.

Detection of Left Ventricular Systolic Dysfunction From Electrocardiographic Images.

BACKGROUND: Left ventricular (LV) systolic dysfunction is associated with a >8-fold increased risk of heart failure and a 2-fold risk of premature death. The use of ECG signals in screening for LV systolic dysfunction is limited by their availability to clinicians. We developed a novel deep learning-based approach that can use ECG images for the screening of LV systolic dysfunction. METHODS: Using 12-lead ECGs plotted in multiple different formats, and corresponding echocardiographic data recorded within 15 days from the Yale New Haven Hospital between 2015 and 2021, we developed a convolutional neural network algorithm to detect an LV ejection fraction <40%. The model was validated within clinical settings at Yale New Haven Hospital and externally on ECG images from Cedars Sinai Medical Center in Los Angeles, CA; Lake Regional Hospital in Osage Beach, MO; Memorial Hermann Southeast Hospital in Houston, TX; and Methodist Cardiology Clinic of San Antonio, TX. In addition, it was validated in the prospective Brazilian Longitudinal Study of Adult Health. Gradient-weighted class activation mapping was used to localize class-discriminating signals on ECG images. RESULTS: Overall, 385 601 ECGs with paired echocardiograms were used for model development. The model demonstrated high discrimination across various ECG image formats and calibrations in internal validation (area under receiving operation characteristics [AUROCs], 0.91; area under precision-recall curve [AUPRC], 0.55); and external sets of ECG images from Cedars Sinai (AUROC, 0.90 and AUPRC, 0.53), outpatient Yale New Haven Hospital clinics (AUROC, 0.94 and AUPRC, 0.77), Lake Regional Hospital (AUROC, 0.90 and AUPRC, 0.88), Memorial Hermann Southeast Hospital (AUROC, 0.91 and AUPRC 0.88), Methodist Cardiology Clinic (AUROC, 0.90 and AUPRC, 0.74), and Brazilian Longitudinal Study of Adult Health cohort (AUROC, 0.95 and AUPRC, 0.45). An ECG suggestive of LV systolic dysfunction portended >27-fold higher odds of LV systolic dysfunction on transthoracic echocardiogram (odds ratio, 27.5 [95% CI, 22.3-33.9] in the held-out set). Class-discriminative patterns localized to the anterior and anteroseptal leads (V2 and V3), corresponding to the left ventricle regardless of the ECG layout. A positive ECG screen in individuals with an LV ejection fraction ≥40% at the time of initial assessment was associated with a 3.9-fold increased risk of developing incident LV systolic dysfunction in the future (hazard ratio, 3.9 [95% CI, 3.3-4.7]; median follow-up, 3.2 years). CONCLUSIONS: We developed and externally validated a deep learning model that identifies LV systolic dysfunction from ECG images. This approach represents an automated and accessible screening strategy for LV systolic dysfunction, particularly in low-resource settings.

Cardiology Encounters for Underrepresented Racial and Ethnic Groups with Human Immunodeficiency Virus and Borderline Cardiovascular Disease Risk.

BACKGROUND: Underrepresented racial and ethnic groups (UREGs) with HIV have a higher risk of cardiovascular disease (CVD) compared with the general population. Referral to a cardiovascular specialist improves CVD risk factor management in high-risk individuals. However, patient and provider factors impacting the likelihood of UREGs with HIV to have an encounter with a cardiologist are unknown. METHODS: We evaluated a cohort of UREGs with HIV and borderline CVD risk (10-year risk ≥ 5% by the pooled cohort equations or ≥ 7.5% by Framingham risk score). Participants received HIV-related care from 2014-2020 at four academic medical centers in the United States (U.S.). Adjusted Cox proportional hazards regression was used to estimate the association of patient and provider characteristics with time to first ambulatory cardiology encounter. RESULTS: A total of 2,039 people with HIV (PWH) and borderline CVD risk were identified. The median age was 45 years (IQR: 36-50); 52% were female; and 94% were Black. Of these participants, 283 (14%) had an ambulatory visit with a cardiologist (17% of women vs. 11% of men, p < .001). In fully adjusted models, older age, higher body mass index (BMI), atrial fibrillation, multimorbidity, urban residence, and no recent insurance were associated with a greater likelihood of an encounter with a cardiologist. CONCLUSION: In UREGs with HIV and borderline CVD risk, the strongest determinants of a cardiology encounter were diagnosed CVD, insurance type, and urban residence. Future research is needed to determine the extent to which these encounters impact CVD care practices and outcomes in this population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04025125.

Effect of Torsemide Versus Furosemide on Symptoms and Quality of Life Among Patients Hospitalized for Heart Failure: The TRANSFORM-HF Randomized Clinical Trial.

BACKGROUND: Loop diuretics are a primary therapy for the symptomatic treatment of heart failure (HF), but whether torsemide improves patient symptoms and quality of life better than furosemide remains unknown. As prespecified secondary end points, the TRANSFORM-HF trial (Torsemide Comparison With Furosemide for Management of Heart Failure) compared the effect of torsemide versus furosemide on patient-reported outcomes among patients with HF. METHODS: TRANSFORM-HF was an open-label, pragmatic, randomized trial of 2859 patients hospitalized for HF (regardless of ejection fraction) across 60 hospitals in the United States. Patients were randomly assigned in a 1:1 ratio to a loop diuretic strategy of torsemide or furosemide with investigator-selected dosage. This report examined effects on prespecified secondary end points, which included Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; assessed as adjusted mean difference in change from baseline; range, 0-100 with 100 indicating best health status; clinically important difference, ≥5 points) and Patient Health Questionnaire-2 (range, 0-6; score ≥3 supporting evaluation for depression) over 12 months. RESULTS: Baseline data were available for 2787 (97.5%) patients for KCCQ-CSS and 2624 (91.8%) patients for Patient Health Questionnaire-2. Median (interquartile range) baseline KCCQ-CSS was 42 (27-60) in the torsemide group and 40 (24-59) in the furosemide group. At 12 months, there was no significant difference between torsemide and furosemide in change from baseline in KCCQ-CSS (adjusted mean difference, 0.06 [95% CI, -2.26 to 2.37]; P=0.96) or the proportion of patients with Patient Health Questionnaire-2 score ≥3 (15.1% versus 13.2%: P=0.34). Results for KCCQ-CSS were similar at 1 month (adjusted mean difference, 1.36 [95% CI, -0.64 to 3.36]; P=0.18) and 6-month follow-up (adjusted mean difference, -0.37 [95% CI, -2.52 to 1.78]; P=0.73), and across subgroups by ejection fraction phenotype, New York Heart Association class at randomization, and loop diuretic agent before hospitalization. Irrespective of baseline KCCQ-CSS tertile, there was no significant difference between torsemide and furosemide on change in KCCQ-CSS, all-cause mortality, or all-cause hospitalization. CONCLUSIONS: Among patients discharged after hospitalization for HF, a strategy of torsemide compared with furosemide did not improve symptoms or quality of life over 12 months. The effects of torsemide and furosemide on patient-reported outcomes were similar regardless of ejection fraction, previous loop diuretic use, and baseline health status. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03296813.

Angiotensin-Neprilysin Inhibition in Patients With Mildly Reduced or Preserved Ejection Fraction and Worsening Heart Failure.

BACKGROUND: U.S. guidelines recommend consideration of sacubitril/valsartan in chronic heart failure (HF) and mildly reduced or preserved ejection fraction (EF). Whether initiation is safe and effective in EF >40% after a worsening heart failure (WHF) event is unknown. OBJECTIVES: PARAGLIDE-HF (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF) assessed sacubitril/valsartan vs valsartan in EF >40% following a recent WHF event. METHODS: PARAGLIDE-HF is a double-blind, randomized controlled trial of sacubitril/valsartan vs valsartan in patients with EF >40% enrolled within 30 days of a WHF event. The primary endpoint was time-averaged proportional change in amino terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline through Weeks 4 and 8. A secondary hierarchical outcome (win ratio) consisted of: 1) cardiovascular death; 2) HF hospitalizations; 3) urgent HF visits; and 4) change in NT-proBNP. RESULTS: In 466 patients (233 sacubitril/valsartan; 233 valsartan), time-averaged reduction in the NT-proBNP was greater with sacubitril/valsartan (ratio of change: 0.85; 95% CI: 0.73-0.999; P = 0.049). The hierarchical outcome favored sacubitril/valsartan but was not significant (unmatched win ratio: 1.19; 95% CI: 0.93-1.52; P = 0.16). Sacubitril/valsartan reduced worsening renal function (OR: 0.61; 95% CI: 0.40-0.93) but increased symptomatic hypotension (OR: 1.73; 95% CI: 1.09-2.76). There was evidence of a larger treatment effect in the subgroup with EF ≤60% for NT-proBNP change (0.78; 95% CI: 0.61-0.98) and the hierarchical outcome (win ratio: 1.46; 95% CI: 1.09-1.95). CONCLUSIONS: Among patients with EF >40% stabilized after WHF, sacubitril/valsartan led to greater reduction in plasma NT-proBNP levels and was associated with clinical benefit compared with valsartan alone, despite more symptomatic hypotension. (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF; NCT03988634).

Sacubitril/valsartan in heart failure with mildly reduced or preserved ejection fraction: a pre-specified participant-level pooled analysis of PARAGLIDE-HF and PARAGON-HF.

AIMS: The PARAGLIDE-HF trial demonstrated reductions in natriuretic peptides with sacubitril/valsartan compared with valsartan in patients with heart failure (HF) with mildly reduced or preserved ejection fraction who had a recent worsening HF event, but was not adequately powered to examine clinical outcomes. PARAGON-HF included a subset of PARAGLIDE-HF-like patients who were recently hospitalized for HF. Participant-level data from PARAGLIDE-HF and PARAGON-HF were pooled to better estimate the efficacy and safety of sacubitril/valsartan in reducing cardiovascular and renal events in HF with mildly reduced or preserved ejection fraction. METHODS AND RESULTS: Both PARAGLIDE-HF and PARAGON-HF were multicentre, double-blind, randomized, active-controlled trials of sacubitril/valsartan vs. valsartan in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF >40% in PARAGLIDE-HF and ≥45% in PARAGON-HF). In the pre-specified primary analysis, we pooled participants in PARAGLIDE-HF (all of whom were enrolled during or within 30 days of a worsening HF event) with a 'PARAGLIDE-like' subset of PARAGON-HF (those hospitalized for HF within 30 days). We also pooled the entire PARAGLIDE-HF and PARAGON-HF populations for a broader context. The primary endpoint for this analysis was the composite of total worsening HF events (including first and recurrent HF hospitalizations and urgent visits) and cardiovascular death. The secondary endpoint was the pre-specified renal composite endpoint for both studies (≥50% decline in estimated glomerular filtration rate from baseline, end-stage renal disease, or renal death). Compared with valsartan, sacubitril/valsartan significantly reduced total worsening HF events and cardiovascular death in both the primary pooled analysis of participants with recent worsening HF [n = 1088; rate ratio (RR) 0.78; 95% confidence interval (CI) 0.61-0.99; P = 0.042] and in the pooled analysis of all participants (n = 5262; RR 0.86; 95% CI: 0.75-0.98; P = 0.027). In the pooled analysis of all participants, first nominal statistical significance was reached by Day 9 after randomization, and treatment benefits were larger in those with LVEF ≤60% (RR 0.78; 95% CI 0.66-0.91) compared with those with LVEF >60% (RR 1.09; 95% CI 0.86-1.40; Pinteraction = 0.021). Sacubitril/valsartan was also associated with lower rates of the renal composite endpoint in the primary pooled analysis [hazard ratio (HR) 0.67; 95% CI 0.43-1.05; P = 0.080] and the pooled analysis of all participants (HR 0.60; 95% CI 0.44-0.83; P = 0.002). CONCLUSION: In pooled analyses of PARAGLIDE-HF and PARAGON-HF, sacubitril/valsartan reduced cardiovascular and renal events among patients with HF with mildly reduced or preserved ejection fraction. These data provide support for use of sacubitril/valsartan in patients with HF with mildly reduced or preserved ejection fraction, particularly among those with an LVEF below normal, regardless of care setting.

Rationale, Design and Baseline Characteristics of the PARAGLIDE-HF Trial: Sacubitril/Valsartan vs Valsartan in HFmrEF and HFpEF With a Worsening Heart Failure Event.

BACKGROUND: The PARAGON-HF trial studied the effect of sacubitril/valsartan (Sac/Val) compared with valsartan (Val) on clinical outcomes in patients with chronic heart failure with preserved ejection fraction (HFpEF) or mildly reduced EF (HFmrEF). Further data are needed regarding the use of Sac/Val in these groups with EF and with recent worsening heart failure (WHF) events and in key populations not broadly represented in the PARAGON-HF trial, including those with de novo HF, the severely obese and Black patients. METHODS: The PARAGLIDE-HF trial is a multicenter, double-blind, randomized, controlled trial of Sac/Val vs Val that enrolled patients at 100 sites. Medically stable patients ≥ 18 years old with EF > 40%, amino terminal-pro B-type natriuretic peptide (NT-proBNP) levels ≥ 500 pg/mL and within 30 days of a WHF event were eligible for participation. Patients were randomly assigned 1:1 to Sac/Val vs Val. The primary efficacy endpoint is time-averaged proportional change in NT-proBNP from baseline through Weeks 4 and 8. Secondary endpoints include clinical outcomes during follow-up and additional biomarker assessments. Safety endpoints include symptomatic hypotension, worsening renal function and hyperkalemia. RESULTS: The trial enrolled 467 participants from June 2019 through October 2022 (52% women, 22% Black, age 70 ± 12 years, median (IQR) BMI 33 (27-40) kg/m2). The median (IQR) EF was 55% (50%-60%), 23% with HFmrEF (LVEF 41%-49%), 24% with EF > 60% and 33% with de novo HFpEF. Median screening NT-proBNP was 2009 (1291-3813) pg/mL, and 69% were enrolled in the hospital. CONCLUSIONS: The PARAGLIDE-HF trial enrolled a broad and diverse range of patients with heart failure with mildly reduced or preserved ejection fraction and will inform clinical practice by providing evidence about the safety, tolerability and efficacy of Sac/Val vs Val in those with a recent WHF event.