BACKGROUND:Despite rapid percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI), large infarcts contribute to heart failure and mortality. Left ventricular (LV) wall tension and load are major determinants of infarct size. Preclinical studies identified that delaying reperfusion to permit LV unloading with a transvalvular microaxial flow pump (TV-mAFP) reduces infarct size. We tested whether this combination reduces infarct size compared with reperfusion alone in patients with anterior STEMI without cardiogenic shock. OBJECTIVES:The STEMI-Door to Unload (DTU) pivotal trial tested the central hypothesis that the combination of mechanical LV unloading plus a 30-minute delay before PCI reduces infarct size compared with immediate PCI alone in patients with anterior STEMI without cardiogenic shock. METHODS:We conducted an open-label, randomized controlled trial at 55 hospitals in the United States, Germany, Italy, United Kingdom, Switzerland, and Canada. Adults aged 18 to 85 years with no prior myocardial infarction and presenting with acute anterior STEMI within 1 to 6 hours of symptom onset before hospital arrival were eligible for inclusion. Patients were randomly assigned (1:1) by study site personnel to either LV unloading with a TV-mAFP for 30 minutes before PCI (treatment group) or PCI alone (control group). The primary outcome was infarct size normalized to LV mass (IS/LVM) evaluated by cardiac magnetic resonance imaging 3 to 5 days after PCI and was evaluated in all randomized patients. The trial is closed to new participants. RESULTS:Between December 12, 2019 and September 3, 2024, 527 patients were randomized; 262 patients were assigned to the treatment group and 265 to the control group. Mean patient age was 61 ± 11 years, and 417 patients (79.1%) were men. Total ischemic time was longer in the treatment arm. IS/LVM was 30.8% ± 16.2% in the treatment group and 31.9% ± 16.9% in the control group (mean difference: -1.1%; 95% CI: -4.2 to 2.0; P = 0.50). Major bleeding or vascular complications at 30-day follow-up occurred more frequently in the treatment group when compared with either a prespecified performance goal or the control group. CONCLUSIONS:Combination of a TV-mAFP plus delayed PCI did not reduce infarct size in patients with anterior STEMI without cardiogenic shock compared with PCI alone. (Primary Unloading and Delayed Reperfusion in ST-Elevation Myocardial Infarction: The STEMI-DTU Trial [DTU-STEMI]; NCT03947619).

BACKGROUND AND AIMS:In the VICTOR trial (NCT05093933), vericiguat was neutral for the primary composite endpoint of cardiovascular death or hospitalization for heart failure (HF). VICTOR was powered to independently assess cardiovascular death. This study reports detailed analysis on the effects of vericiguat on mortality. METHODS:VICTOR, a double-blind, placebo-controlled, randomized trial, enrolled 6105 ambulatory patients with HF and reduced ejection fraction (HFrEF) without recent worsening and randomized them to vericiguat or placebo. The main outcome for this analysis was the pre-specified secondary endpoint of cardiovascular death. All-cause death, sudden cardiac death, and death related to HF were also assessed. RESULTS:Over a median of 19.7 months (inter-quartile range 14.6-25.4), cardiovascular deaths occurred in 292 patients (5.7 deaths per 100 patient-years) and 346 patients (6.8 deaths per 100 patient-years) in the vericiguat and placebo groups, respectively (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.71-0.97; P = .020). Risk of death from any cause was lower with vericiguat vs placebo (377 [7.3 deaths per 100 patient-years] vs 440 [8.6 deaths per 100 patient-years]; HR 0.84, 95% CI 0.74-0.97; P = .015). Sudden cardiac death and HF-related deaths were lower with vericiguat vs placebo (1.6 vs 2.2 events per 100 patient-years; HR 0.75, 95% CI 0.56-0.99; P = .042 and 1.7 vs 2.4 events per 100 patient-years; HR 0.71, 95% CI 0.54-0.94; P = .016, respectively). Lower mortality rates were consistent across subgroups including baseline therapy. Consistent cardiovascular and all-cause mortality benefit was seen across baseline N-terminal pro-B-type natriuretic peptide levels. CONCLUSIONS:In ambulatory well-treated participants with HFrEF, vericiguat was associated with clinically meaningful reductions in the key secondary outcome of cardiovascular death, as well as all-cause mortality.

Aim Describe the baseline characteristics of the VICTOR (Vericiguat Global Study in Patients with Chronic Heart Failure) trial with comparison to the most recent randomized controlled trials in patients with heart failure with reduced ejection fraction (HFrEF). Methods and Results VICTOR is a double-blind, placebo-controlled, parallel-group, 1:1 randomized, event-driven trial testing the effects of oral vericiguat (target dose 10 mg) vs. placebo in ambulatory patients with HFrEF and no recent worsening HF event. This population represents a complementary population to that studied in VICTORIA. Baseline characteristics were evaluated in 6105 patients randomized in the VICTOR trial (Table 1). Key characteristics in the VICTOR population were assessed and compared with other recent HFrEF trials including PARADIGM-HF, DAPA HF, EMPEROR Reduced, VICTORIA and GALACTIC HF. Baseline standard of care HFrEF therapy was notable for the higher incidence of SGLT2i, ARNI, and ICD use in VICTOR compared with other contemporary HFrEF trials. Conclusions The VICTOR trial includes a contemporary HFrEF population with high use of foundational HF therapy and will facilitate assessment of outcomes and the incremental benefit of vericiguat for patients with HFrEF. VICTOR trial will establish the role of vericiguat in a global and diverse population of patients with chronic HFrEF without recent worsening HF.

BACKGROUND:Following completion of the VICTORIA trial, vericiguat was approved for the treatment of worsening heart failure with reduced ejection fraction (HFrEF) and received a class IIb recommendation in European and North American guidelines. The subsequent VICTOR trial evaluated the use of vericiguat in patients with HFrEF and no recent worsening. We aimed to assess the effect of vericiguat on clinical endpoints through pooled analyses of patient-level data from the VICTORIA and VICTOR trials. METHODS:This prespecified, pooled individual participant-level analysis was conducted on data from two trials: VICTORIA, which was active from Sept 25, 2016, to Sept 2, 2019 in 42 countries, and VICTOR, which was active from Nov 2, 2021, to Feb 5, 2025 in 36 countries. The VICTORIA trial enrolled adult (aged ≥18 years) participants with HFrEF with recent worsening (defined as either hospitalisation for heart failure within the previous 6 months or outpatient use of intravenous diuretics within the previous 3 months) and increased NT-proBNP concentrations; the VICTOR trial had similar eligibility criteria but participants had no recent worsening of heart failure. Participants in both trials received contemporary background guideline-directed heart failure therapy as appropriate. The primary endpoint was a composite endpoint of cardiovascular death or hospitalisation for heart failure (also assessed individually). This study is registered with PROSPERO, CRD420251065636. FINDINGS:Data from 11 155 patients (5050 in the VICTORIA trial and 6105 in the VICTOR trial) were included in the pooled analysis. The primary endpoint of cardiovascular death or hospitalisation for heart failure occurred in 1446 (25·9%) of 5579 patients in the vericiguat group and 1556 (27·9%) of 5576 patients in the placebo group (hazard ratio [HR] 0·91 [95% CI 0·85-0·98]; p=0·0088), with similar reductions in its individual components of cardiovascular death (0·89 [0·80-0·98]; p=0·020) and hospitalisation for heart failure (0·92 [0·84-1·00]; p=0·043) as first events. INTERPRETATION:Vericiguat reduced the risk of hospitalisation for heart failure and cardiovascular death in patients with HFrEF across a broad range of clinical severity, including those receiving contemporary guideline-directed medical therapy. Vericiguat might be suitable as an additional treatment option for selected patients with HFrEF. FUNDING:Merck Sharp & Dohme (a subsidiary of Merck) and Bayer.

AIMS:The efficacy and safety of vericiguat in patients with chronic heart failure with reduced ejection fraction (HFrEF) on contemporary heart failure (HF) therapies and without recent worsening was investigated in the VICTOR trial, yet some subgroups may be more susceptible to symptomatic hypotension. METHODS AND RESULTS:Among VICTOR trial participants that received at least one dose of study drug or placebo, we describe the systolic blood pressure (SBP) trajectories over time (mean change from baseline), symptomatic hypotension events and efficacy of vericiguat in potentially vulnerable patient subgroups: lower baseline blood pressure (SBP ≤110 mmHg), older patients (>75 years) and those taking angiotensin receptor-neprilysin inhibitors (ARNI) or sodium-glucose co-transporter 2 inhibitors (SGLT2i) at baseline. The efficacy outcomes of cardiovascular death and HF hospitalization and cardiovascular death alone across baseline SBP were examined using Cox proportional hazards models. Overall SBP trajectories showed a small initial decline from baseline in vericiguat-treated patients compared with placebo (placebo-corrected differences of -1.17 [-1.84, -0.50], p = 0.0007) that was relatively stable throughout follow-up. This trajectory was similar in those >75 years (vs. younger) as well as those receiving ARNI or SGLT2i (as compared with those not receiving these) or those with SBP ≤110 mmHg at baseline (compared with >110 mmHg). Symptomatic hypotension occurred in 11.3% of vericiguat-treated patients compared with 9.2% of placebo-treated patients with an adjusted hazard ratio of 1.24 (95% confidence interval 1.06-1.46), which was similar across age, SBP, SGLT2i and ARNI groups (all interaction p >0.05). The treatment effect of vericiguat compared with placebo on the efficacy outcomes was similar across the spectrum of baseline SBP (both interaction p >0.15). CONCLUSIONS:Vericiguat showed a slight adjusted decrease in SBP and resulted in more symptomatic hypotension compared with placebo but was overall well-tolerated in a broad population with HFrEF on contemporary therapy even among those predisposed to hypotension. Treatment effects on efficacy outcomes were consistent regardless of baseline SBP.

BACKGROUND:Transcatheter aortic valve intervention (TAVI) has revolutionized the care of older adults with aortic stenosis. OBJECTIVES:The objectives of the study were to examine associations between chronic conditions and outcomes after TAVI and to describe palliative care utilization rates. METHODS:This cohort study used the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy registry to identify patients who underwent TAVI and were eligible for linkage with Centers for Medicare & Medicaid Services claims data. The exposure was multiple chronic conditions (MCCs) in the year before TAVI. Associations between chronic conditions and outcomes were assessed using multivariable logistic regression. RESULTS:A total of 188,629 TAVI procedures were linked to Centers for Medicare & Medicaid Services claims. The median (IQR) age was 82.0 (76.0-87.0) years; 86,841 (46%) were female. Chronic conditions were associated with worse 1-year mortality (high MCC [≥6 conditions] vs low MCC [<4 chronic conditions], adjusted HR: 2.33 [95% CI: 2.22-2.44]). Chronic conditions were associated with lower Kansas City Cardiomyopathy Questionnaire at baseline (high MCC median score 37.5 [21.4-56.8] vs low MCC median score 55.7 [37.5-75.0], P < 0.001); however, the average improvement in Kansas City Cardiomyopathy Questionnaire after TAVI was large and appeared independent of chronic disease burden (median score change high MCC 28.7 [9.9-48.4] vs low MCC 24.5 [8.3-42.2], standardized difference +13.8%). Palliative care encounters were rare (8,946, 4.7%) and varied significantly across centers (range 0% to 25% of cases). CONCLUSIONS:Chronic conditions are associated with worse survival after TAVI. However, most patients with high MCC are alive 1 year after treatment, and quality of life improvements appear independent of chronic disease burden. These data help clarify expected health gains for patients with chronic conditions and symptomatic aortic stenosis.

Background/Objectives: Sudden cardiac arrest (SCA) accounts for ~50% of cardiovascular mortality in the U.S. Cardiovascular complications are common in acute and post-acute COVID-19 infection. We aimed to examine nationwide trends in SCA-related hospitalizations in the United States before and during the COVID-19 outbreak. Methods: Using data from the National Inpatient Sample, we conducted a retrospective analysis of hospitalizations for SCA in the U.S. between 2016 and 2020. Sociodemographic and clinical characteristics and in-hospital mortality were compared between the pre-COVID (2016–2019) and COVID (2020) eras. Multivariable analysis was performed to identify factors associated with mortality. Results: Among a weighted total of 153,100 SCA hospitalizations between 2016 and 2020, the median age was 65 years, 62.7% were male, and 66.6% were white. There was a trend towards fewer hospitalizations in 2020 compared to prior years (n = 28,585 vs. naverage = 32,129, p = 0.07). In-hospital mortality remained unchanged between the pre-COVID and COVID eras (47.7% vs. 47.3%, p = 0.66). Increased mortality was associated with female sex (OR: 1.21; 95% CI: 1.15–1.28; p < 0.001), non-white race (OR: 1.24; 95% CI: 1.15–1.28; p < 0.001), history of renal failure (OR: 1.08; 95% CI: 1.02–1.15; p = 0.007), and diabetes (OR: 1.32; 95% CI: 1.25–1.39; p < 0.001). In 2020, 1.5% of the study population was diagnosed with COVID-19 infection, which was found to be independently associated with increased in-hospital mortality (OR: 1.57; 95% CI: 1.27–1.95; p < 0.001). Conclusions: In 2020, there was a trend towards a decrease in hospitalizations for SCA, while COVID-19 infection was independently associated with higher in-hospital mortality among patients admitted with SCA.

AIMS:To describe the baseline characteristics of the participants in the VICTOR (Vericiguat Global Study in Patients with Chronic Heart Failure; NCT05093933) trial and compare them to recent trials in patients with heart failure and reduced ejection fraction (HFrEF). METHODS AND RESULTS:Baseline characteristics were evaluated in 6105 patients randomized to vericiguat or placebo. The mean age of the participants was 67 ± 11 years, 23.6% were women, 64.4% were White, and 10.7% were self-identified Black. Overall, 29.1% of participants were enrolled in Latin and South America, 27.8% and 18.5% in Eastern and Western Europe, 14.0% in Asia-Pacific and 10.6% in North America. The mean left ventricular ejection fraction was 30 ± 7% and 79% had New York Heart Association class II symptoms. Mean estimated glomerular filtration rate was 70.9 ± 24.0 ml/min/1.73 m2. Median N-terminal pro-B-type natriuretic peptide level was 1476 (970-2495) pg/ml and 47.5% of participants had no prior hospitalization for heart failure. Baseline therapy included 94.4% beta-blockers, 94.3% renin-angiotensin system modulation (including 56.0% on an angiotensin receptor-neprilysin inhibitor), 77.7% mineralocorticoid receptor antagonists, 59.1% sodium-glucose cotransporter 2 inhibitors, and 32.9% implantable cardioverter-defibrillators. Overall characteristics were relatively similar to other recent HFrEF trials but the VICTOR trial enrolled a higher proportion of participants receiving contemporary drug and device therapy. CONCLUSION:The VICTOR trial enrolled the most optimally treated population in a phase III heart failure trial. These features will facilitate assessment of the benefit of vericiguat and elucidate the outcomes of patients on up-to-date medical therapy.

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BACKGROUND:In the VICTOR (Vericiguat Global Study in Participants With Chronic Heart Failure) trial, in a contemporary ambulatory cohort with heart failure and reduced ejection fraction (HFrEF) and no recent hospitalization, the primary outcome of hospitalization for heart failure (HHF) and cardiovascular death was not statistically significantly reduced with vericiguat. Vericiguat reduced risk of mortality but not HHF. In this ambulatory compensated cohort, time to first HHF may underestimate the overall worsening HF burden by failing to consider the high proportion of outpatient worsening HF events. OBJECTIVES:This study aimed to determine the effect of vericiguat on the overall risk of worsening HF by incorporating the entire patient experience of worsening outpatient and inpatient HF episodes. METHODS:VICTOR was a phase 3, double-blind, placebo-controlled trial testing the effect of vericiguat in ambulatory patients with HFrEF who had not experienced recent worsening (defined as HHF admission within 6 months or outpatient intravenous diuretic use within 3 months) and were on a background of high use of contemporary guideline therapy. The primary endpoint was a composite of cardiovascular death or HHF. The current analysis provides detailed effects of vericiguat on overall worsening HF in both the inpatient and outpatient settings, including urgent care visits for intravenous diuretics or outpatient oral diuretic initiation or intensification. RESULTS:A total of 6,105 participants were randomized. Outpatient worsening HF was more common as the first worsening HF event (n = 851, 59.3%), compared with HHF (n = 507, 35.4%) or urgent HF visits (n = 76, 5.3%). Outpatient oral diuretic initiation or intensification was associated with increased mortality (RR: 1.69; 95% CI: 1.47-1.94; P < 0.001). Overall worsening HF occurred in 686 participants (22.5%) in the vericiguat group and 748 participants (24.8%) in the placebo group (HR: 0.90; 95% CI: 0.81-1.00; P = 0.047). The composite of all-cause death and overall worsening HF occurred in 917 participants (30.0%) in the vericiguat group and 1,004 participants (32.9%) in the placebo group (HR: 0.90; 95% CI: 0.82-0.98; P = 0.016). CONCLUSIONS:In compensated patients with HFrEF on contemporary guideline therapy, worsening HF in outpatients was more common than HHF and was associated with higher risk of mortality. Exploratory analyses suggested a potential reduction in overall worsening HF events when both inpatient and outpatient settings were considered.

PURPOSE:Furoscix (furosemide injection) 80 mg/10 mL is a pH neutral formulation administered subcutaneously (SC) over 5 hours to treat edema in adults with chronic HF or chronic kidney disease. Furosemide 80 mg/mL is a novel concentrated formulation administered as a single 1.0-mL SC injection that could improve convenience for patients. This randomized, open-label, phase 1 study assessed the pharmacokinetics, bioavailability, pharmacodynamics, and safety of furosemide 80 mg/mL SC versus furosemide 80 mg administered intravenously (IV). METHODS:Healthy volunteers were randomized 1:1 to furosemide 80 mg/mL SC or furosemide 80 mg IV (two 40-mg boluses, 2 hours apart), and after a 3-day washout, received the opposite treatment. Plasma furosemide pharmacokinetics, urine output, and urinary sodium and potassium excretion were measured through 12 hours post-dose. Bioavailability (the primary endpoint) was assessed as the least-squares mean ratio (LSMR) of area under the curve (AUC) from time 0-last (AUClast) and 0-infinity (AUCinf) between furosemide SC and furosemide IV. Plasma furosemide pharmacokinetics were assessed noncompartmentally. Pharmacodynamics were assessed using a repeated measures, mixed model analysis. Safety was assessed through end of study. RESULTS:Twenty-one participants were randomized (furosemide SC/IV, n = 10; furosemide IV/SC, n = 11). The furosemide SC/IV LSMR (90% confidence interval [CI]) AUClast was 106.1% (102.7%, 109.6%), and LSMR (90% CI) AUCinf was 107.3% (103.9%, 110.8%). Furosemide 80 mg/mL SC had bioavailability equivalent to furosemide 80 mg IV, as the CIs fell within 80.0%-125.0%. Mean (SD) Cmax was 4532.9 (1497.7) ng/mL with furosemide 80 mg/mL SC and 10,087.6 (2804.7) ng/mL with furosemide IV. The therapeutic effects of furosemide 80 mg/mL SC on diuresis, natriuresis, and kaliuresis occurred within 1 hour of treatment and were consistent with those of furosemide IV at all time points. There was no significant difference between furosemide 80 mg/mL SC versus furosemide IV in total urine output or urinary sodium or potassium excretion at 0-6 hours, 0-8 hours, or 0-12 hours. Adverse events (AEs) occurred in 14 (66.7%) participants (furosemide SC, n = 11 [52.4%]; furosemide IV, n = 7 [35.0%]) and were mild or moderate. Ten (47.6%) participants had injection site AEs, all of which were treatment-related, mild, non-serious, and resolved. Injection site pain scores graded on a Likert 11-point scale remained low (mean, <0.4; median, 0) at all time points, were similar between groups, and decreased over time. CONCLUSIONS:Furosemide 80 mg/mL SC injection was generally well tolerated and had bioavailability, diuresis, natriuresis, and kaliuresis consistent with those of furosemide IV.

AIMS:Balanced dual V1a/ V2 vasopressin receptor antagonism may offer potential advantages as an adjunctive and/or a replacement therapy to loop diuretic therapy. METHODS AND RESULTS:AVANTI was a double-blind, randomized trial in patients hospitalized with heart failure and residual congestion. In Part A, patients received pecavaptan or placebo as adjunctive therapy to standard of care for 30 days. In Part B, patients were randomized to continuation of furosemide or replacement by pecavaptan, as single diuretic therapies for 30 days. Co-primary endpoints were for Part A changes in weight and serum creatinine and for Part B, changes in weight and blood urea nitrogen/creatinine ratio. Among 483 patients randomized into Part A, there was no difference in weight reduction between pecavaptan and placebo (between-group difference: -0.27 kg, upper one-sided 95% confidence interval [CI] -0.29, p = 0.21) and no effect on serum creatinine (between-group difference: 0.05 mg/dl, upper one-sided 95% CI 0.12, p = 0.87). Subsequently, 286 patients were randomized into Part B. The difference in weight change between the pecavaptan and furosemide monotherapy groups over 30 days was 0.69 kg (upper one-sided 80% CI 0.95, p = 0.16), satisfying non-inferiority criteria of 1 kg. The between-group difference in log-transformed change in blood urea nitrogen/creatinine ratio was -0.22 (upper one-sided 80% CI -0.19, p < 0.0001) favouring pecavaptan. Adverse events and serious adverse events related to congestion including heart failure hospitalizations were numerically higher in the pecavaptan groups in both parts of the trial. CONCLUSIONS:Adjunctive pecavaptan for 30 days in patients with residual congestion had no impact on weight loss nor on renal function. Post-discharge pecavaptan monotherapy was non-inferior to furosemide monotherapy for weight change over 30 days, but was associated with improved renal function. The increase in congestion events suggests that future trials will need optimized background diuretic dosing. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov NCT03901729.

BACKGROUND:Vericiguat is indicated to reduce the risk of cardiovascular death and hospitalisation for heart failure in patients with heart failure and reduced ejection fraction (HFrEF) following a recent worsening event. The aim of the VICTOR trial was to assess the effect of vericiguat in patients with HFrEF without recent heart failure worsening. METHODS:In this double-blind, placebo-controlled, phase 3 trial, conducted at 482 sites across 36 countries, patients aged 18 years or older with HFrEF (left ventricular ejection fraction of ≤40%) without heart failure hospitalisation within 6 months or outpatient intravenous diuretic use within 3 months before randomisation were randomly assigned (1:1) using an intervention randomisation system with interactive response technology to oral vericiguat (target 10 mg dose) or matching placebo. The primary composite endpoint was time to cardiovascular death or heart failure hospitalisation. Efficacy endpoints were assessed in the intention-to-treat population. Adverse events were assessed in all randomly assigned patients who received at least one dose of study drug (safety population). This trial is registered with ClinicalTrials.gov, NCT05093933, and is complete. FINDINGS:Between Nov 2, 2021, and Dec 21, 2023, 10 921 patients were screened and 6105 were randomly assigned: 3053 to vericiguat and 3052 to placebo. The median age was 68·0 years (IQR 61·0-75·0), 1440 (23·6%) patients were women, 4665 (76·4%) were men, 3934 (64·4%) were White, and 2899 (47·5%) had no previous hospitalisation for heart failure. During a median follow-up of 18·5 months (IQR 13·6-24·7), primary outcome events occurred in 549 (18·0%) patients in the vericiguat group and 584 (19·1%) patients in the placebo group (hazard ratio [HR] 0·93 [95% CI 0·83-1·04]; p=0·22). As prespecified in the protocol, because the primary endpoint was not statistically significant, all analyses of secondary and exploratory endpoints are considered nominal. Cardiovascular death occurred in 292 (9·6%) patients in the vericiguat group and 346 (11·3%) patients in the placebo group (HR 0·83 [95% CI 0·71-0·97]). Hospitalisation for heart failure occurred in 348 (11·4%) patients in the vericiguat group and in 362 (11·9%) patients in the placebo group (HR 0·95 [95% CI 0·82-1·10]). Serious adverse events occurred in 717 (23·5%) of 3049 patients in the vericiguat group and 751 (24·6%) of 3049 patients in the placebo group. The most common adverse event was symptomatic hypotension (345 [11·3%] patients in the vericiguat group and 281 [9·2%] in the placebo group). All-cause death occurred in 377 (12·3%) patients in the vericiguat group and 440 (14·4%) patients in the placebo group (HR 0·84 [95% CI 0·74-0·97]). INTERPRETATION:Among patients with HFrEF and no recent worsening, vericiguat did not reduce the risk of a composite endpoint of time to cardiovascular death or heart failure hospitalisation. Fewer cardiovascular deaths were observed in the vericiguat group than in the placebo group. FUNDING:Merck Sharp & Dohme (a subsidiary of Merck) and Bayer.

BACKGROUND:While both volume overload and reduced level of kidney function are associated with higher mortality in heart failure (HF), decongestion can lead to kidney function decline. The optimal balance between sustaining decongestion and preserving kidney function remains uncertain among outpatients with HF. We compared associations of post-discharge changes in kidney function and congestion status with mortality in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial. METHODS:This post-hoc analysis of a randomized controlled trial included 3,404 participants discharged from an HF hospitalization. Compared to estimated glomerular filtration rate (eGFR) and clinical congestion score at discharge, eight time-varying exposure groups were defined: improved or worsened congestion, with varying degrees of eGFR decline (no decline, 1-20%, 21-40%, and 41% or greater). The association of these groups with all-cause mortality was assessed using marginal structural models to account for time-dependent confounding. RESULTS:The mean (SD) age and eGFR at discharge were 66 (12) years and 59.6 (22.3) mL/min/1.73 m2, respectively. Over a median (IQR) follow-up of 44 (25-71) weeks, 740 patients died. Both higher degrees of eGFR decline and worsened congestion were associated with higher mortality risk. Compared to patients with worsened congestion and no eGFR decline, those with improved congestion had lower mortality risk (HR, 0.51 [95% CI, 0.35-0.74] for no eGFR decline; HR, 0.56 [95% CI, 0.38-0.85] for 1-20% eGFR decline; and HR, 0.80 [95% CI, 0.46-1.39] for 21-40% eGFR decline), while those with improved congestion and 41% or greater eGFR decline had higher risk (HR, 2.23; 95% CI, 1.06-4.66). CONCLUSIONS:Compared to worsened congestion and no GFR decline, improved congestion is generally associated with lower mortality risk but higher risk when eGFR decline exceeds 40%, suggesting the importance of sustaining decongestion over preserving kidney function if eGFR decline is modest.

BACKGROUND:Therapies are needed to address worsening congestion, without hospitalization, in patients with chronic heart failure (HF). OBJECTIVES:This pilot study assessed outcomes of a novel subcutaneous (SC) furosemide formulation compared to usual care in outpatients with worsening congestion. METHODS:Participants with chronic HF and worsening congestion were randomized open-label 2:1 to SC furosemide compared to usual care (UC). Decongestion was estimated by tracking body weight. The primary endpoint was a win ratio of a 30-day hierarchical composite of cardiovascular death, HF events, and change in N-terminal pro-B-type natriuretic peptide. Secondary endpoints included dyspnea severity, functional capacity, and quality of life. RESULTS:Thirty-four participants were randomized to SC furosemide and 17 to UC. SC furosemide caused greater reduction in body weight: between-group difference in least square mean change was -2.02 kg at day 3 (95% CI: -3.9 to -0.14; P = 0.035). SC furosemide-to-UC win ratio was 1.11 (95% CI: 0.48-2.50; P = 0.806). Significant between-group least square mean differences favoring SC furosemide occurred in 7-point dyspnea score (P = 0.017) and 6-minute walk test (P = 0.032), with trend in Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 Overall Summary Score of 9.15 (95% CI: 1.95-20.3; P = 0.106). The most common related adverse event with SC furosemide was mild infusion site pain (11.8%). CONCLUSIONS:SC furosemide augmented weight loss in patients with HF and worsening congestion. The composite primary endpoint was not statistically significant in this pilot investigation. However, findings of improved dyspnea scores and functional capacity, with favorable trend in KCCQ-12 score, warrant additional investigation to further document the clinical value of SC furosemide as an alternative to hospitalization (AT HOME-HF [Avoiding Treatment in the Hospital With Furoscix for the Management of Congestion in Heart Failure-A Pilot Study]; NCT04593823).