Clinical development of pharmacologic agents for acute heart failure syndromes: A proposal for a mechanistic translational phase

Hospitalization for acute heart failure syndromes (AHFS) predicts a poor prognosis, with postdischarge mortality and rehospitalization rates reaching 45% within 60 to 90 days. Despite the use of evidence-based therapies and adherence to national process measures, these event rates have largely remained the same over the past decade. Given the current and growing burden of AHFS, there exists a substantial unmet need for novel therapies that improve outcomes. However, attempts to improve symptoms and/or reduce postdischarge events have failed to produce positive results, either because of safety and/or efficacy. These negative results may be related to the drug itself, the protocol in terms of patient selection and/or end points, and/or the trial execution. Although experts may not agree on the exact reasons to explain the lack of success to date of phase III trials in AHFS, there is agreement that clinical benefits observed in phase II trials were not reproduced in phase III trials. A different approach may be needed. In November of 2009, a meeting was held at the Food and Drug Administration with the primary purpose of identifying the reasons why benefits observed during phase II did not translate into benefits in phase III to improve future trial design. Although multiple domains of trial design were discussed, the participants identified a lack of in-depth understanding of novel molecules before pivotal trials in AHFS as a possible contributor to the disappointing results of recent large trials. In this brief report, we outline the T1 or translational phase of research for AHFS clinical development as an important first step toward greater success in AHFS clinical trials

Drug development in oncology and devices—lessons for heart failure drug development and approval? a review

Heart failure (HF) and cancer are of the most common diseases globally, both associated with significant adverse outcomes and greatly impaired quality of life. Despite those similarities, over the last 15 years, the United States (USA) and European authorities have approved only 5 and 3 new drugs for HF respectively, none using an accelerated process and none for patients with either acute HF (AHF) or with HF and preserved ejection fraction (HFpEF). During the same period, more than 100 new drugs were approved for treatment of various cancers, several receiving accelerated approval. HF drugs in the last 15 years were mostly approved for reduction in mortality, whereas most approved cancer drugs addressed disease progression and surrogate markers. Consequently, the size of the trials in HF were far greater than those in oncology which was associated with lower probability of success. Given the larger study size and smaller probability of approval, pharma progressively reduces the necessary investments in new HF drugs. We suggest for HF drugs be developed, especially those used to treat patients with HFpEF and AHF, consideration of approval based beyond morbidity and mortality on improvements in symptoms and functional capacity and, like oncology, based on measures of disease progression and end organ damage. At the same time, HF drug development should adopt some approaches used in other diseases (such as oncology) focusing on better defining specific phenotypes and defining specific disease-related targets for new drugs. © 2020, Springer Science+Business Media, LLC, part of Springer Nature

Dyspnoea and worsening heart failure in patients with acute heart failure: Results from the Pre-RELAX-AHF study

AimsAlthough dyspnoea is the most common cause of admission for acute heart failure (AHF), more needs to be known about its clinical course and prognostic significance.Methods and resultsThe Pre-RELAX-AHF study randomized 232 subjects with AHF to placebo or four doses of relaxin and evaluated early (6-24 h Likert scale) and persistent [change in visual analogue scale area under the curve (VAS AUC) through Day 5] dyspnoea relief. Worsening heart failure (WHF) was defined as worsening AHF signs and symptoms requiring additional therapy. Patients were followed until Day 180. Early dyspnoea relief was observed in only 25 of all patients, and VAS AUC at 5 days was 45 over baseline values in all patients (32 placebo; 50 all relaxin-treated patients). Worsening heart failure to Day 5 was observed in 16 of all patients (21 placebo; 14 relaxin). Lack of persistent dyspnoea relief and WHF were associated with a longer length of initial hospital stay and worse 60-day outcomes.ConclusionDyspnoea relief in patients admitted with AHF is often incomplete, and many may show WHF after the initial stabilization. Both lack of persistent dyspnoea relief and in-hospital WHF predict a longer length of stay and worse outcome. © 2010 The Author

Association of left ventricular ejection fraction with worsening renal function in patients with acute heart failure: insights from the RELAX-AHF-2 study

Aims: Whether risk of worsening renal function (WRF) during acute heart failure (AHF) hospitalization or the association between in-hospital WRF and post-discharge outcomes vary according to left ventricular ejection fraction (LVEF) is uncertain. We assessed incidence of WRF, factors related to its development and impact of WRF on post-discharge outcomes across the spectrum of LVEF in patients enrolled in RELAX-AHF-2. Methods and results: A total of 6112 patients who had LVEF measured on admission and renal function determined prospectively during hospitalization were included. WRF, defined as a rise in serum creatinine ≥0.3 mg/dL from baseline through day 5, occurred in 1722 patients (28.2%). Incidence increased progressively from lowest to highest LVEF quartile (P < 0.001). After baseline adjustment, WRF risk in Q4 (LVEF >50%) remained significantly greater than in Q1 (LVEF ≤29%; hazard ratio 1.2, 95% confidence interval 1–1.43; P = 0.050). Age and comorbidity burden including chronic kidney disease increased as LVEF increased. Neither admission haemodynamic abnormalities, extent of diuresis during hospitalization nor residual congestion explained the increased incidence of WRF in patients with higher LVEF. Serelaxin treatment and diuretic responsiveness were associated with reduced risk of WRF in all LVEF quartiles. WRF in patients in the upper three LVEF quartiles increased risk of post-discharge events. Conclusions: Worsening renal function incidence during AHF hospitalization increases progressively with LVEF. Greater susceptibility of patients with higher LVEF to WRF appears more related to their advanced age and worse underlying kidney function rather than haemodynamic or treatment effects. WRF is associated with increased risk of post-discharge events except in patients in the lowest LVEF quartile. © 2020 European Society of Cardiolog

Low lymphocyte ratio as a novel prognostic factor in acute heart failure: Results from the Pre-RELAX-AHF study

Background: Previous studies have suggested that a lower lymphocyte ratio (Ly%) in the white blood cell (WBC) differential count is related to worse outcomes in patients with acute heart failure (AHF) and other cardiovascular disorders. Methods: In the Pre-RELAX-AHF study, 234 patients with AHF, systolic blood pressure >125 mm Hg and brain natriuretic peptide ≥350 pg/ml or equivalent were randomized to 1 of 4 intravenous doses of relaxin or placebo and followed up for 6 months following randomization. Complete blood count and differential were performed by a central laboratory at baseline and then daily to day 5 and on day 14. Results: The WBC count by itself was not associated with measures of disease severity or outcome, and patients with Ly% <13% had similar baseline characteristics to patients with Ly% >13%, except for a higher baseline WBC count, elevated baseline glucose, older age and higher rates of peripheral vascular disease. However, patients with Ly% <13% had less improvement of dyspnea, greater worsening of heart failure, longer length of initial hospital stay and fewer days alive and out of hospital. Statistical significance was reached for all-cause death by days 60 and 180 (hazard ratio = 1.11 per percent decrease, 95% confidence interval 1.03-1.19; p = 0.0048). Conclusions: Despite no association with any baseline characteristic known to strongly predict outcome in AHF, low Ly% is associated with less symptom relief and worse in-hospital and postdischarge clinical outcomes. Copyright © 2010 S. Karger AG, Basel

Hepatorenal dysfunction identifies high-risk patients with acute heart failure: insights from the RELAX-AHF trial

Aims: Episodes of acute heart failure (AHF) may lead to end-organ dysfunction. In this post hoc analysis of the Relaxin in Acute Heart Failure trial, we used the MELD-XI (Model of End-Stage Liver Dysfunction) score to examine hepatorenal dysfunction in patients with AHF. Methods and results: On admission, the MELD-XI score was elevated (abnormal) in 918 (82%) patients, with 638 (57%) having isolated renal dysfunction (creatinine > 1 mg/dL), 73 (6.5%) isolated liver dysfunction (bilirubin > 1 mg/dL), and 207 (18.5%) coexisting dysfunction of the kidneys and the liver (both creatinine and bilirubin > 1 mg/dL). The percentage of patients with elevated MELD-XI score remained constant through a 60 day follow-up, as we observed a gradual decrease of liver dysfunction prevalence, counterbalanced by an increase in renal dysfunction. Serelaxin treatment was associated with a lower MELD-XI score on Day 2 and Day 5 (both P < 0.05), but this difference vs. placebo disappeared during longer follow-up. In the multivariable model, an elevated MELD-XI score on admission was associated with higher 180 day mortality: hazard ratios (95% confidence interval) for cardiovascular death were 3.10 (1.22–7.87), and for all-cause death 2.47 (1.19–5.15); both P < 0.05. The addition of the MELD-XI score to a prespecified prognostic model increased the discrimination of the model for all-cause death, but the increment in the C-index was only modest: 0.013 (P = 0.02). Conclusions: In patients with AHF, hepatorenal dysfunction is prevalent and related to poor outcome. The MELD-XI score is a useful prognosticator in AHF. © 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology

Erratum to: Serelaxin in acute heart failure patients with and without atrial fibrillation: a secondary analysis of the RELAX-AHF trial (Clin Res Cardiol, (2017), 106, (444–456), 10.1007/s00392-016-1074-x)

The original article was published Online First without open access. After publication in volume 106, issue 6, pages 444–456 the author decided to opt for Open Choice and to make the article an open access publication. Therefore, the copyright of the article has been changed to © The Author(s) [2017] and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/ by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. © Springer-Verlag GmbH Germany 2017

Renal function trajectories and clinical outcomes in acute heart failure

Background—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. Methods and Results—We used linear mixed models of serial measurements of blood urea nitrogen and creatinine to describe trajectories of renal function in 1962 patients with acute heart failure and renal dysfunction enrolled in the Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function study. We assessed risk of 180-day mortality and 60-day cardiovascular or renal readmission and used Cox regression to determine association between renal trajectories and outcomes. Compared with patients alive at 180 days, patients who died were older, had lower blood pressure and ejection fraction, and higher creatinine levels at baseline. On average for the entire cohort, creatinine rose from days 1 to 3 and increased further after discharge, with the trajectory dependent on the day of discharge. Blood urea nitrogen, creatinine, and the rate of change in creatinine from baseline were the strongest independent predictors of 180-day mortality and 60-day readmission, whereas the rate of change of blood urea nitrogen from baseline was not predictive of outcomes. Baseline blood urea nitrogen >35 mg/dL and increase in creatinine >0.1 mg/dL per day increased the risk of mortality, whereas stable or decreasing creatinine was associated with reduced risk. Conclusions—Patients with acute heart failure and renal dysfunction demonstrate variable rise and fall in renal indices during and immediately after hospitalization. Risk of morbidity and mortality can be predicted based on baseline renal function and creatinine trajectory during the first 7 days. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00328692 and NCT00354458