Many physicians may be overwhelmed by the success of contemporary heart failure therapeutics, with multiple trials of medicines demonstrating improved survival and decreased morbidity in patients ...with heart failure with reduced ejection fraction (HFrEF).2–4 Unfortunately, few patients are treated with the ideal, guideline-directed cocktail of these medications.5 There is difficulty in translating the trial results into meaningful values for clinicians and patients, and long-term benefits are rarely studied due to cost constraints. In the analysis by Vaduganathan and colleagues,6 the use of a comprehensive contemporary regimen (β blocker, angiotensin–neprilysin inhibitor ARNI, MRA, and SGLT2 inhibitor) reduces the hazard of cardiovascular death or admission to hospital for heart failure (hazard ratio 0·38 95% CI 0·30–0·47), and might lengthen life by 1–6 years, depending on the age at which treatment is initiated. The authors also found that switching to an ARNI from an ACE inhibitor or ARB and adding an SGLT2 inhibitor to a β blocker and MRA regimen reduces the risk of cardiovascular death or hospital admission for heart failure (hazard ratio 0·64 95% CI 0·52–0·78) and might lengthen life by 0·8–3·1 years.
A central factor in the pathogenesis of heart failure (HF) with reduced ejection fraction is the initial decrease in systolic function. Prior attempts at increasing cardiac contractility with oral ...drugs have uniformly resulted in signals of increased mortality at pharmacologically effective doses. Omecamtiv mecarbil is a novel, selective cardiac myosin activator that has been shown to improve cardiac function and to decrease ventricular volumes, heart rate, and N-terminal pro-B-type natriuretic peptide in patients with chronic HF. The GALACTIC-HF (Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure) trial tests the hypotheses that omecamtiv mecarbil can safely improve symptoms, prevent clinical HF events, and delay CV death in patients with chronic HF. The GALACTIC-HF trial is an international, multicenter, randomized, double-blind, placebo-controlled, event-driven cardiovascular outcomes trial. More than 8,000 patients with chronic symptomatic (New York Heart Association functional class II to IV) HF, left ventricular ejection fraction ≤35%, elevated natriuretic peptides, and either current hospitalization for HF or history of hospitalization or emergency department visit for HF within a year of screening will be randomized to either oral placebo or omecamtiv mecarbil employing a pharmacokinetic-guided dose titration strategy using doses of 25, 37.5, or 50 mg twice daily. The primary efficacy outcome is the time to cardiovascular death or first HF event. The study has 90% power to assess a final hazard ratio of approximately 0.80 in cardiovascular death, the first secondary outcome. The GALACTIC-HF trial is the first trial examining whether selectively increasing cardiac contractility in patients with HF with reduced ejection fraction will result in improved clinical outcomes. (Registrational Study With Omecamtiv Mecarbil/AMG 423 to Treat Chronic Heart Failure With Reduced Ejection Fraction GALACTIC-HF; NCT02929329).
Background
Growth differentiation factor 15 (GDF‐15) was found to be upregulated in patients with chronic heart failure (HF) and associated with disease severity, however, data on patients with acute ...heart failure (AHF) is lacking.
Methods and results
Levels of GDF‐15 were measured at pre‐specified time‐points (baseline and at days 2, 5, 14, and 60) in patients enrolled in the placebo‐controlled RELAXin in Acute Heart Failure (RELAX‐AHF) study, which examined the effect of serelaxin in 1161 patients with AHF, systolic blood pressure >125 mmHg, and mild to moderate renal impairment. Neither baseline nor changes in GDF‐15 were associated with the degree of dyspnoea or dyspnoea relief. After adjustment for baseline characteristics, baseline GDF‐15 was not associated with the composite endpoint of heart failure or renal failure (HF/RF) readmission at 60 days/cardiovascular (CV) death or CV death at 180 days. In contrast, larger increases in GDF‐15 levels at days 2 and 14 were associated with a greater risk of 60‐day HF/RF rehospitalizations/CV death and CV death at 180 days. Serelaxin treatment was associated with significantly larger decreases of GDF‐15 at days 2 and 5 than placebo.
Conclusions
In AHF patients enrolled in the RELAX‐AHF study, increases in GDF‐15 levels, but not baseline measurements, were associated with a greater likelihood of adverse outcomes. Serelaxin administration was associated with greater decreases in GDF‐15 compared with placebo.
Summary Background Decreased systolic function is central to the pathogenesis of heart failure in millions of patients worldwide, but mechanism-related adverse effects restrict existing inotropic ...treatments. This study tested the hypothesis that omecamtiv mecarbil, a selective cardiac myosin activator, will augment cardiac function in human beings. Methods In this dose-escalating, crossover study, 34 healthy men received a 6-h double-blind intravenous infusion of omecamtiv mecarbil or placebo once a week for 4 weeks. Each sequence consisted of three ascending omecamtiv mecarbil doses (ranging from 0·005 to 1·0 mg/kg per h) with a placebo infusion randomised into the sequence. Vital signs, blood samples, electrocardiographs (ECGs), and echocardiograms were obtained before, during, and after each infusion. The primary aim was to establish maximum tolerated dose (the highest infusion rate tolerated by at least eight participants) and plasma concentrations of omecamtiv mecarbil; secondary aims were evaluation of pharmacodynamic and pharmacokinetic characteristics, safety, and tolerability. This study is registered at ClinicalTrials.gov , number NCT01380223. Findings The maximum tolerated dose of omecamtiv mecarbil was 0·5 mg/kg per h. Omecamtiv mecarbil infusion resulted in dose-related and concentration-related increases in systolic ejection time (mean increase from baseline at maximum tolerated dose, 85 SD 5 ms), the most sensitive indicator of drug effect ( r2 =0·99 by dose), associated with increases in stroke volume (15 2 mL), fractional shortening (8% 1), and ejection fraction (7% 1; all p<0·0001). Omecamtiv mecarbil increased atrial contractile function, and there were no clinically relevant changes in diastolic function. There were no clinically significant dose-related adverse effects on vital signs, serum chemistries, ECGs, or adverse events up to a dose of 0·625 mg/kg per h. The dose-limiting toxic effect was myocardial ischaemia due to excessive prolongation of systolic ejection time. Interpretation These first-in-man data show highly dose-dependent augmentation of left ventricular systolic function in response to omecamtiv mecarbil and support potential clinical use of the drug in patients with heart failure. Funding Cytokinetics Inc.
With few notable exceptions, drug development for heart failure (HF) has become progressively more challenging, and there remain no definitively proven therapies for patients with acute HF or HF with ...preserved ejection fraction. Inspection of temporal trends suggests an increasing rate of disagreement between early-phase and phase III trial end points. Preliminary results from phase II HF trials are frequently promising, but increasingly followed by disappointing phase III results. Given this potential disconnect, it is reasonable to carefully re-evaluate the purpose, design, and execution of phase II HF trials, with particular attention directed toward the surrogate end points commonly used by these studies. In this review, we offer a critical reappraisal of the role of phase II HF trials and surrogate end points, highlighting challenges in their use and interpretation, lessons learned from past experiences, and specific strengths and weaknesses of various surrogate outcomes. We conclude by proposing a series of approaches that should be considered for the goal of optimizing the efficiency of HF drug development. This review is based on discussions between scientists, clinical trialists, industry and government sponsors, and regulators that took place at the Cardiovascular Clinical Trialists Forum in Washington, DC, on December 2, 2016.
Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy ...(CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort.
This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein-Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann-Whitney estimator 0.54, 95% confidence interval CI 0.47-0.61 value > 0.5 favours cell treatment, P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200-370 mL (60% of patients) (Mann-Whitney estimator 0.61, 95% CI 0.52-0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death.
The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.
The aim of this study was to assess the effects of serelaxin on short-term changes in markers of organ damage and congestion and relate them to 180-day mortality in patients with acute heart failure.
...Hospitalization for acute heart failure is associated with high post-discharge mortality, and this may be related to organ damage.
The Pre-RELAX-AHF (Relaxin in Acute Heart Failure) phase II study and RELAX-AHF phase III study were international, multicenter, double-blind, placebo-controlled trials in which patients hospitalized for acute heart failure were randomized within 16 h to intravenous placebo or serelaxin. Each patient was followed daily to day 5 or discharge and at days 5, 14, and 60 after enrollment. Vital status was assessed through 180 days. In RELAX-AHF, laboratory evaluations were performed daily to day 5 and at day 14. Plasma levels of biomarkers were measured at baseline and days 2, 5, and 14. All-cause mortality was assessed as a safety endpoint in both studies.
Serelaxin reduced 180-day mortality, with similar effects in the phase II and phase III studies (combined studies: N = 1,395; hazard ratio: 0.62; 95% confidence interval: 0.43 to 0.88; p = 0.0076). In RELAX-AHF, changes in markers of cardiac (high-sensitivity cardiac troponin T), renal (creatinine and cystatin-C), and hepatic (aspartate transaminase and alanine transaminase) damage and of decongestion (N-terminal pro-brain natriuretic peptide) at day 2 and worsening heart failure during admission were associated with 180-day mortality. Serelaxin administration improved these markers, consistent with the prevention of organ damage and faster decongestion.
Early administration of serelaxin was associated with a reduction of 180-day mortality, and this occurred with fewer signs of organ damage and more rapid relief of congestion during the first days after admission.
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.
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