Currently, no acute heart failure (AHF) therapy definitively improves outcomes. Reducing morbidity and mortality from acute heart failure (AHF) remains an unmet need. TRV027 is a novel 'biased' ...ligand of the angiotensin II type 1 receptor (AT1R), selectively antagonizing the negative effects of angiotensin II, while preserving the potential pro-contractility effects of AT1R stimulation. BLAST-AHF was designed to determine the safety, efficacy, and optimal dose of TRV027 to advance into future studies.
BLAST-AHF was a multi-centre, international, randomized, double-blind, placebo-controlled, parallel group, phase IIb dose-ranging study, enrolling patients with AHF into 4 groups: placebo, 1, 5, or 25 mg/h of TRV027. Treatment was by IV infusion for 48-96 h. The primary composite endpoint was comprised of the following: (i) time from baseline to death through day 30, (ii) time from baseline to heart failure re-hospitalization through day 30, (iii) the first assessment time point following worsening heart failure through day 5, (iv) change in dyspnea visual analogue scale (VAS) score calculated as the area under the curve (AUC) representing the change from baseline over time from baseline through day 5, and (v) length of initial hospital stay (in days) from baseline. Analyses were by modified intention-to-treat. Overall, 621 patients were enrolled. After 254 patients, a pre-specified interim analysis resulted in several protocol changes, including a lower blood pressure inclusion criterion as well as a new allocation scheme of 2:1:2:1, overweighting both placebo, and the 5 mg/h dose. TRV027 did not confer any benefit over placebo at any dose with regards to the primary composite endpoint or any of the individual components. There were no significant safety issues with TRV027.
In this phase IIb dose-ranging AHF study, TRV027 did not improve clinical status through 30-day follow-up compared with placebo.
With the current landscape of approved therapies for heart failure (HF), there is a need to determine the role of a standard background therapy against which novel therapies are studied. The ...Heart Failure Collaboratory convened a multistakeholder group of clinical investigators, clinicians, patients, government representatives including U.S. Food and Drug Administration and National Institutes of Health participants, payers, and industry in March 2021 to discuss whether standardization of background drug therapy is necessary in clinical trials in patients with HF. The current paper summarizes the discussion and provides potential conceptual approaches, with a focus on therapies indicated for HF with reduced ejection fraction.
Aim
The clinical value of single biomarkers at single time‐points to predict outcomes in patients with acute heart failure (AHF) is limited. We performed a multimarker, multi‐time‐point analysis of ...biomarkers for the prediction of post‐discharge clinical outcomes in high‐risk AHF patients.
Methods and results
A set of 48 circulating biomarkers were measured in the PROTECT trial which enrolled 2033 patients with AHF. Associations between baseline levels of biomarkers and outcomes (30‐day all‐cause mortality, 30‐day death or rehospitalization for renal/cardiovascular causes and 180‐day all‐cause mortality) were evaluated. Prognostic accuracies of baseline, days 2 or 3, 7, and 14 biomarker measurements were estimated and compared utilizing a time‐dependent area under the curve (AUC) analysis. Forty‐four biomarkers were significantly associated with outcomes, but 42 had limited prognostic value (C‐index < 0.70). However, multimarker models combining best‐performing biomarkers from different clusters had a much stronger prognostic value. Combining blood urea nitrogen (BUN), chloride, interleukin (IL)‐6, cTnI, sST‐2 and VEGFR‐1 into a clinical model yielded a 11% increase in C‐index to 0.84 and 0.78 for 30‐day and 180‐day all‐cause mortality, respectively, and cNRI of 0.86 95% CI 0.55–1.11 and 0.76 95% CI 0.57–0.87. Prognostic gain was modest for the 30‐day death/rehospitalization for cardiovascular or renal causes endpoint. Comparative time‐dependent AUC analysis indicated that late measurements provided superior accuracy for the prediction of all‐cause mortality over 180 days, with few exceptions including BUN and galectin‐3. However, the predictive value of most biomarkers showed a diminishing pattern over time irrespective of moment of measurement.
Conclusions
Multimarker models significantly improve risk prediction. Subsequent measurements, beyond admission, are needed for majority of biomarkers to maximize prognostic value over time, particularly in the long term.
This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the U.S. Food and Drug ...Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials.
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Worsening renal function, which is associated with adverse outcomes, often develops in patients with acute heart failure. Experimental and clinical studies suggest that counterregulatory responses ...mediated by adenosine may be involved. We tested the hypothesis that the use of rolofylline, an adenosine A1-receptor antagonist, would improve dyspnea, reduce the risk of worsening renal function, and lead to a more favorable clinical course in patients with acute heart failure.
We conducted a multicenter, double-blind, placebo-controlled trial involving patients hospitalized for acute heart failure with impaired renal function. Within 24 hours after presentation, 2033 patients were randomly assigned, in a 2:1 ratio, to receive daily intravenous rolofylline (30 mg) or placebo for up to 3 days. The primary end point was treatment success, treatment failure, or no change in the patient's clinical condition; this end point was defined according to survival, heart-failure status, and changes in renal function. Secondary end points were the post-treatment development of persistent renal impairment and the 60-day rate of death or readmission for cardiovascular or renal causes.
Rolofylline, as compared with placebo, did not provide a benefit with respect to the primary end point (odds ratio, 0.92; 95% confidence interval, 0.78 to 1.09; P=0.35). Persistent renal impairment developed in 15.0% of patients in the rolofylline group and in 13.7% of patients in the placebo group (P=0.44). By 60 days, death or readmission for cardiovascular or renal causes had occurred in similar proportions of patients assigned to rolofylline and placebo (30.7% and 31.9%, respectively; P=0.86). Adverse-event rates were similar overall; however, only patients in the rolofylline group had seizures, a known potential adverse effect of A1-receptor antagonists.
Rolofylline did not have a favorable effect with respect to the primary clinical composite end point, nor did it improve renal function or 60-day outcomes. It does not show promise in the treatment of acute heart failure with renal dysfunction. (Funded by NovaCardia, a subsidiary of Merck; ClinicalTrials.gov numbers, NCT00328692 and NCT00354458.).
Aims
Left ventricular (LV) reverse remodelling is an important marker of improved outcomes in patients with advanced heart failure (HF). We examined the impact of the intramyocardial administration ...of bone‐marrow‐derived, lineage‐directed, autologous cardiopoietic mesenchymal stem cells (C3BS‐CQR‐1) on LV remodelling in patients with advanced HF enrolled in the CHART‐1 study.
Methods and results
Patients (n=351) with symptomatic advanced HF secondary to ischaemic heart disease, and reduced LV ejection fraction (LVEF <35%) were randomized to receive C3BS‐CQR‐1 or a sham procedure. In a post hoc analysis we examined the effect of C3BS‐CQR‐1 on LV reverse remodelling within 1 year of the procedure and the influence of C3BS‐CQR‐1 dosing in the 271 patients treated as randomized. Delivery of C3BS‐CQR‐1 was associated with a progressive decrease in both LV end‐diastolic volume (LVEDV) and end‐systolic volume (LVESV) within 52 weeks after treatment. At 1 year, the LVEDV and LVESV of treated patients decreased by 17.0 mL and 12.8 mL greater than controls (P=0.006 and P=0.017, respectively). The effect on LVEDV was maintained after multivariable adjustment for baseline age, systolic blood pressure, LVEDV, LVEF and history of myocardial infarction. The largest reverse remodelling was evident in the patients receiving a moderate number of injections (<20).
Conclusion
In CHART‐1, intramyocardial administration of cardiopoietic stem cells led to reverse remodelling as evidenced by significant progressive decreases in LVEDV and LVESV through the 52 weeks of follow‐up. Further studies are needed to explore the dose response with regard to cell number and injected volume, and reverse remodelling.
Left ventricular ejection time (LVET) is defined as the time interval from aortic valve opening to aortic valve closure, and is the phase of systole during which the left ventricle ejects blood into ...the aorta. LVET has been used for several decades to assess left ventricular function and contractility. However, there is a recent interest in LVET as a measure of therapeutic action for novel drugs in patients with heart failure with reduced ejection fraction (HFrEF), since LVET is shortened in these patients. This review provides an overview of the available information on LVET including methods of measuring LVET, mechanistic understanding of LVET, association of LVET with outcomes, mechanisms behind shortened LVET in HFrEF and the potential implications of drugs that affect and normalize LVET.
The impact of therapeutic agents on left ventricular ejection time (LVET) in heart failure with reduced ejection fraction (HFrEF). ACEI, angiotensin‐converting enzyme inhibitor; HR, heart rate; LV, left ventricular; LVEF, left ventricular ejection fraction.
Aims
Serelaxin is effective in relieving dyspnoea and improving multiple outcomes in acute heart failure (AHF). Many AHF patients have preserved ejection fraction (HFpEF). Given the lack of ...evidence-based therapies in this population, we evaluated the effects of serelaxin according to EF in RELAX-AHF trial.
Methods and results
RELAX-AHF randomized 1161 AHF patients to 48-h serelaxin (30 μg/kg/day) or placebo within 16 h from presentation. We compared the effects of serelaxin on efficacy endpoints, safety endpoints, and biomarkers of organ damage between preserved (≥50%) and reduced (<50%, HFrEF) EF. HFpEF was present in 26% of patients. Serelaxin induced a similar dyspnoea relief in HFpEF vs. HFrEF patients by visual analogue scale-area under the curve (VAS-AUC) through Day 5 mean change, 461 (−195, 1117) vs. 397 (10, 783) mm h, P = 0.87, but had possibly different effects on the proportion of patients with moderately or markedly dyspnoea improvement by Likert scale at 6, 12, and 24 h odds ratio for favourable response, 1.70 (0.98, 2.95) vs. 0.85 (0.62, 1.15), interaction P = 0.030. No differences were encountered in the effect of serelaxin on short- or long-term outcome between HFpEF and HFrEF patients including cardiovascular death or hospitalization for heart/renal failure through Day 60, cardiovascular death through Day 180, and all-cause death through Day 180. Similar safety and changes in biomarkers (high-sensitivity troponin T, cystatin-C, and alanine/aspartate aminotransferases) were found in both groups.
Conclusions
In AHF patients with HFpEF compared with those with HFrEF, serelaxin was well tolerated and effective in relieving dyspnoea and had a similar effect on short- and long-term outcome, including survival improvement.
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has important implications for the safety of participants in ...clinical trials and the research staff caring for them and, consequently, for the trials themselves. Patients with heart failure may be at greater risk of infection with COVID-19 and the consequences might also be more serious, but they are also at risk of adverse outcomes if their clinical care is compromised. As physicians and clinical trialists, it is our responsibility to ensure safe and effective care is delivered to trial participants without affecting the integrity of the trial. The social contract with our patients demands no less. Many regulatory authorities from different world regions have issued guidance statements regarding the conduct of clinical trials during this COVID-19 crisis. However, international trials may benefit from expert guidance from a global panel of experts to supplement local advice and regulations, thereby enhancing the safety of participants and the integrity of the trial. Accordingly, the Heart Failure Association of the European Society of Cardiology on 21 and 22 March 2020 conducted web-based meetings with expert clinical trialists in Europe, North America, South America, Australia, and Asia. The main objectives of this Expert Position Paper are to highlight the challenges that this pandemic poses for the conduct of clinical trials in heart failure and to offer advice on how they might be overcome, with some practical examples. While this panel of experts are focused on heart failure clinical trials, these discussions and recommendations may apply to clinical trials in other therapeutic areas.
Aim
The sodium–glucose cotransporter 2 (SGLT2) inhibitor empagliflozin improved clinical outcomes in patients hospitalized for acute heart failure. In patients with chronic heart failure, SGLT2 ...inhibitors cause an early decline in estimated glomerular filtration rate (eGFR) followed by a slower eGFR decline over time than placebo. However, the effects of SGLT2 inhibitors on renal function during a hospital admission for acute heart failure remain largely unknown.
Methods and results
Between 1 and 5 days after a hospitalization for acute heart failure, 530 patients with an eGFR >20 ml/min/1.73 m2 were randomized to 10 mg of empagliflozin or placebo and treated for 90 days. Renal function and electrolytes were measured at baseline, and after 15, 30 and 90 days. We evaluated the effect of empagliflozin on eGFR over time and the impact of baseline eGFR on the primary hierarchical outcome of death, worsening heart failure events and quality of life. Mean baseline eGFR was 52.4 ml/min/1.73 m2 in the empagliflozin group and 55.7 ml/min/1.73 m2 in the placebo group. Empagliflozin caused an initial decline in eGFR (−2 ml/min/1.73 m2 at day 15 compared to placebo). At day 90, eGFR was similar between empagliflozin and placebo. Investigator‐reported acute renal failure occurred in 7.7% of empagliflozin versus 12.1% of placebo patients. The overall clinical benefit (hierarchical composite of all‐cause death, heart failure events and quality of life) of empagliflozin was unaffected by baseline eGFR.
Conclusion
In patients hospitalized for acute heart failure, empagliflozin caused an early modest decline in renal function which was no longer evident after 90 days. Acute renal events were similar in both groups. The clinical benefit of empagliflozin was consistent regardless of baseline renal function.
In patients hospitalized for acute heart failure (HF) in the EMPULSE trial, empagliflozin caused an early, modest decline in estimated glomerular filtration rate (eGFR) which was no longer evident after 90 days. Empagliflozin did not influence sodium, and potassium was consistent regardless of baseline renal function. *The hierarchy and components of the primary outcome measured by the win ratio were: (1) time to all‐cause deaths; (2) number of HF events; (3) time to first HF event; (4) ≥5 point difference in change from baseline in Kansas City Cardiomyopathy Questionnaire total symptom score after 90 days of treatment. CI, confidence interval; SE, standard error.
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