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Rapid uptitration of guideline-directed medical therapy (GDMT) before and after discharge in hospitalized heart failure (HF) patients is feasible, is safe, and improves outcomes; whether this is also true in patients with coexistent atrial fibrillation/flutter (AF/AFL) is not known.

Multimorbidity frequently occurs in patients with acute heart failure (AHF). The co-occurrence of comorbidities often follows specific patterns.

Guideline-directed medical therapy (GDMT) decisions may be less affected by single patient variables such as blood pressure or kidney function and more by overall risk profile. In STRONG-HF (Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure), high-intensity care (HIC) in the form of rapid uptitration of heart failure (HF) GDMT was effective overall, but the safety, tolerability and efficacy of HIC across the spectrum of HF severity is unknown. Evaluating this with a simple risk-based framework offers an alternative and more clinically translatable approach than traditional subgroup analyses.

Patients with heart failure experience limitations in daily activity and poor quality-of-life. Prospective surveillance of health-related quality-of-life supplemented traditional death and hospitalization outcomes in the multinational, randomized, double-blinded CHART-1 clinical trial that assessed cardiopoiesis-guided cell therapy in ischemic heart failure patients with reduced left ventricular ejection fraction. The Minnesota Living with Heart Failure Questionnaire (MLHFQ), a Food and Drug Administration qualified instrument for evaluating therapeutic effectiveness, was applied through the 1-year follow-up. Cell treated (n= 109) and sham procedure (n= 140) cohorts reported improved MLHFQ scores comparable between the 2 study arms (mean treatment difference with baseline adjustment −3.2 points, P= .107). Superiority of cell treatment over sham in betterment of the MLHFQ score was demonstrated in patients with pre-existing advanced left ventricular enlargement (baseline-adjusted mean treatment difference −6.4 points, P= .009). In this highly responsive subpopulation, benefit on the MLHFQ score paralleled reduction in death and hospitalization post-cell therapy (adjusted Mann-Whitney odds 1.43, 95% CI, 1.01-2.01; P= .039). The potential of cell therapy in addressing the quality-of-life dimension of heart failure requires further evaluation for disease relief.Graphical AbstractBenefit afforded by regenerative biotherapy is typically assessed using physician-reported outcomes, such as functional recovery, hospitalization, and mortality. In the setting of a phase III clinical trial for heart failure, this study integrates the patients’ perception of disease burden on daily living documenting that stem cell therapy, delivered as an adjunct to standard-of-care, significantly improved health-related quality-of-life.

IMPORTANCE: The Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by N-Terminal Pro–Brain Natriuretic Peptide Testing of Heart Failure Therapies (STRONG-HF) trial strived for rapid uptitration aiming to reach 100% optimal doses of guideline-directed medical therapy (GDMT) within 2 weeks after discharge from an acute heart failure (AHF) admission. OBJECTIVE: To assess the association between degree of GDMT doses achieved in high-intensity care and outcomes. DESIGN, SETTING, AND PARTICIPANTS: This was a post hoc secondary analysis of the STRONG-HF randomized clinical trial, conducted from May 2018 to September 2022. Included in the study were patients with AHF who were not treated with optimal doses of GDMT before and after discharge from an AHF admission. Data were analyzed from January to October 2023. INTERVENTIONS: The mean percentage of the doses of 3 classes of HF medications (renin-angiotensin system inhibitors, β-blockers, and mineralocorticoid receptor antagonists) relative to their optimal doses was computed. Patients were classified into 3 dose categories: low (<50%), medium (≥50% to <90%), and high (≥90%). Dose and dose group were included as a time-dependent covariate in Cox regression models, which were used to test whether outcomes differed by dose. MAIN OUTCOME MEASURES: Post hoc secondary analyses of postdischarge 180-day HF readmission or death and 90-day change in quality of life. RESULTS: A total of 515 patients (mean [SD] age, 62.7 [13.4] years; 311 male [60.4%]) assigned high-intensity care were included in this analysis. At 2 weeks, 39 patients (7.6%) achieved low doses, 254 patients (49.3%) achieved medium doses, and 222 patients (43.1%) achieved high doses. Patients with lower blood pressure and more congestion were less likely to be uptitrated to optimal GDMT doses at week 2. As a continuous time-dependent covariate, an increase of 10% in the average percentage optimal dose was associated with a reduction in 180-day HF readmission or all-cause death (primary end point: adjusted hazard ratio [aHR], 0.89; 95% CI, 0.81-0.98; P = .01) and a decrease in 180-day all-cause mortality (aHR, 0.84; 95% CI, 0.73-0.95; P = .007). Quality of life at 90 days, measured by the EQ-5D visual analog scale, improved more in patients treated with higher doses of GDMT (mean difference, 0.10; 95% CI, −4.88 to 5.07 and 3.13; 95% CI, −1.98 to 8.24 points in the medium- and high-dose groups relative to the low-dose group, respectively; P = .07). Adverse events to day 90 occurred less frequently in participants with HIC who were prescribed higher GDMT doses at week 2. CONCLUSIONS AND RELEVANCE: Results of this post hoc analysis of the STRONG-HF randomized clinical trial show that, among patients randomly assigned to high-intensity care, achieving higher doses of HF GDMT 2 weeks after discharge was feasible and safe in most patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03412201

There is a paucity of evidence for dose and pace of up-titration of guideline-directed medical therapies after admission to hospital for acute heart failure.

The aim of this study was to investigate the association between systolic blood pressure (SBP) drop, worsening renal function (WRF), and prognosis in patients with acute heart failure (AHF).

This study sought to better understand the discrepant results of 2 trials of serelaxin on acute heart failure (AHF) and short-term mortality after AHF by analyzing causes of death of patients in the RELAX-AHF-2 (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF-2) trial.

In this study, the authors used biomarker profiles to characterize differences between patients with acute heart failure with a midrange ejection fraction (HFmrEF) and compare them with patients with a reduced (heart failure with a reduced ejection fraction [HFrEF]) and preserved (heart failure with a preserved ejection fraction [HFpEF]) ejection fraction.

ObjectiveThe blood urea nitrogen-to-creatinine (BUN/creatinine) ratio has been proposed as a useful parameter in acute heart failure (AHF), but data on the normal range and the added value of the ratio compared with its separate components in patients with AHF are lacking. The aim of this study is to define the normal range of BUN/creatinine ratio and to investigate its clinical significance in patients with AHF.MethodsIn 4484 subjects from the general population without cardiovascular comorbidities, we calculated age-specific and sex-specific normal values of the BUN/creatinine ratio, deriving a higher and lower than normal range of BUN/creatinine ratio (exceeding the 95% prediction intervals). Association of abnormal range to prognosis was tested in 2033 patients with AHF for the outcome of all-cause death through 180 days, death or cardiovascular or renal rehospitalisation through 60 days and heart failure (HF) rehospitalisation within 60 days.ResultsIn a cohort of patients with AHF, 482 (24.6%) and 28 (1.4%) patients with HF were classified into higher and lower than normal range groups, respectively. In Cox regression analysis, higher than normal range of BUN/creatinine ratio group was an independent predictor for all-cause death (HR: 1.86, 95% CI 1.29 to 2.66) and death or cardiovascular or renal rehospitalisation (HR: 1.37, 95% CI 1.03 to 1.82), but not for HF rehospitalisation (HR: 1.23, 95% CI 0.81 to 1.86) after adjustment for other prognostic factors including both creatinine and BUN.ConclusionsIn patients with AHF, BUN/creatinine higher than age-specific and sex-specific normal range is associated with worse prognosis independently from both creatinine and BUN.Clinical Trialsgov identifier NCT00328692and NCT00354458

Poor medication adherence leads to poor health outcomes and increased healthcare costs among patients with heart failure (HF). This study aimed to objectively assess medication adherence by measuring carvedilol and enalaprilat plasma concentrations among patients with HF.

The aim of this study was to determine if a baseline high-sensitivity troponin T (hsTnT) value ≤99th percentile upper reference limit (0.014 μg/l [“low hsTnT”]) identifies patients at low risk for adverse outcomes.

These studies conducted analyses to examine patient characteristics and outcomes associated with worsening heart failure (WHF).

The BLAST-AHF (Biased Ligand of the Angiotensin Receptor Study in Acute Heart Failure) study is designed to test the efficacy and safety of TRV027, a novel biased ligand of the angiotensin-2 type 1 receptor, in patients with acute heart failure (AHF). AHF remains a major public health problem, and no currently-available therapies have been shown to favorably affect outcomes. TRV027 is a novel biased ligand of the angiotensin-2 type 1 receptor that antagonizes angiotensin-stimulated G-protein activation while stimulating β-arrestin. In animal models, these effects reduce afterload while increasing cardiac performance and maintaining stroke volume. In initial human studies, TRV027 appears to be hemodynamically active primarily in patients with activation of the renin-angiotensin-aldosterone system, a potentially attractive profile for an AHF therapeutic. BLAST-AHF is an international prospective, randomized, phase IIb, dose-ranging study that will randomize up to 500 AHF patients with systolic blood pressure ≥120 mm Hg and ≤200 mm Hg within 24 h of initial presentation to 1 of 3 doses of intravenous TRV027 (1, 5, or 25 mg/h) or matching placebo (1:1:1:1) for at least 48 h and up to 96 h. The primary endpoint is a composite of 5 clinical endpoints (dyspnea, worsening heart failure, length of hospital stay, 30-day rehospitalization, and 30-day mortality) combined using an average z-score. Secondary endpoints will include the assessment of dyspnea and change in amino-terminal pro–B-type natriuretic peptide. The BLAST-AHF study will assess the efficacy and safety of a novel biased ligand of the angiotensin-2 type 1 receptor in AHF.

This study aimed to investigate the association between the use of early echocardiography performed by the treating physician certified in critical care ultrasound and mortality in ICU patients.

Acute heart failure is a common reason for admission, and outcome is often poor. Improved prognostic risk stratification may assist in the design of future trials and in patient management. Using data from a large randomized trial, we explored the prognostic value of clinical variables, measured at hospital admission for acute heart failure, to determine whether a few selected variables were inferior to an extended data set.

Prior studies have demonstrated adverse risk associated with baseline and worsening renal function in acute heart failure, but none has modeled the trajectories of change in renal function and their impact on outcomes.

Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic effects. In a pilot study, serelaxin was safe and well tolerated with positive clinical outcome signals in patients with acute heart failure. The RELAX-AHF trial tested the hypothesis that serelaxin-treated patients would have greater dyspnoea relief compared with patients treated with standard care and placebo.

To assess concomitant simultaneous effects on multiple end points using global statistical methods in phase II acute heart failure studies.

Worsening renal function (WRF), traditionally defined as an increase in serum creatinine levels ≥0.3 mgdL, is a frequent finding in patients with acute heart failure (AHF) and has been associated with poorer outcomes in some but not all studies. We hypothesized that these discrepancies may be caused by the interaction between WRF and congestion in AHF patients.

Cardiac troponin T (cTnT) elevation is common and is a predictor of outcomes in patients with acute heart failure (AHF). The degree and progression of cTnT release during hospitalization of patients with AHF is unclear. We evaluated the incidence of cTnT release during AHF hospitalization and the relationship of cTnT release with outcomes.

Background:For patients with acute heart failure (AHF), a substantial diuresis after administration of loop diuretics is generally associated with better clinical outcomes but may cause creatinine to rise, suggesting a decline in renal function. We investigated the interaction between diuretic response and worsening renal function (WRF) on clinical outcomes in patients with AHF.Methods:In two cohorts of patients with AHF (PROTECT, n=1,698 and RELAX-AHF-2, n=5,586 in current analysis), the prognostic impact of WRF (creatinine ≥0.3 mg/dL increase baseline-day 4, sensitivity analyses were performed incorporating baseline renal function) by diuretic response (kg weight loss per 40 mg furosemide equivalent from baseline-day 4) was investigated with regards to (CV) death or cardiovascular/renal hospitalisation using subpopulation treatment effect pattern (STEPP) plots and survival analyses.Results:WRF occurred in 286 (16.8%) patients in PROTECT and 1,031 (18.5%) patients in RELAX-AHF-2. Patients with WRF had higher left ventricular ejection fraction and lower estimated glomerular filtration rate at baseline (P<0.05). Patients with WRF also received higher doses of loop diuretics and had a worse diuretic response (all P<0.001). In patients with a poor diuretic response (≤0.35 kg weight loss/40 mg furosemide equivalent as identified by STEPP), WRF was associated with a higher risk of (CV) death or cardiovascular/renal hospitalisation (P<0.001 in both cohorts), but this was not the case for patients with a good diuretic response (P=0.900 for both cohorts).Conclusion:In two large cohorts of patients with AHF, WRF in the first 4 days was not associated with worse outcomes when patients had a good diuretic response. The occurrence of WRF in patients with AHF should therefore be considered in the context of diuretic response.

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