Rolofylline, an adenosine A1−receptor antagonist, in acute heart failure

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

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

Although 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. The 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. Dyspnoea 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

Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF):a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study

Background Most patients admitted for acute heart failure have normal or increase blood pressure. Relaxin is a natural human peptide that affects multiple vascular control pathways, suggesting potential mechanisms of benefit for such patients. We assessed the dose response of relaxin's effect on symptom relief, other clinical outcomes, and safety. Methods In a placebo-controlled, parallel-group, dose-ranging study, 234 patients with acute heart failure, dyspnoea, congestion on chest radiograph, and increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic blood pressure greater than 125 mm Hg were recruited from 54 sites in eight countries and enrolled within 16 h of presentation. Patients were randomly assigned, in a double-blind manner via a telephone-based interactive voice response system, to standard care plus 48-h intravenous infusion Of placebo (n=62) or relaxin 10 mu g/kg (n=40), 30 mu g/kg (n=43), 100 mu g/kg (n=39), or 250 mu g/kg (n=50) per day. Several clinical endpoints were explored to assess whether intravenous relaxin should be pursued in larger studies of acute heart failure, to identify an optimum dose, and to help to assess endpoint selection and power calculations. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT00520806. Findings In the modified intention-to-treat population, 61 patients were assessed in the placebo group, 40 in the relaxin 10 mu g/kg per day group, 42 in the relaxin 30 mu g/kg per day group, 37 in the relaxin 100 mu g/kg per day group, and 49 in the relaxin 250 mu g/kg per day group. Dyspnoea improved with relaxin 30 mu g/kg compared with placebo, as assessed by Likert scale (17 of 42 patients [40%] moderately or markedly improved at 6 h, 12 h, and 24 h vs 14 of 61 [23%]; p=0.044) and visual analogue scale through day 14 (8214 mmxh [SD 87121 vs 4622 mmxh [90031; p=0.053). Length of stay was 10.2 days (SD 6.1) for relaxin-treated patients versus 12.0 days (7.3) for those given placebo, and days alive out of hospital were 47.9 (10.1) versus 44.2 (14.2). Cardiovascular death or readmission due to heart or renal failure at day 60 was reduced with relaxin (2.6% [95% Cl 0.4-16.8] vs 17.2% [9.6-29.6]; p=0.053). The number of serious adverse events was similar between groups. Interpretation When given to patients with acute heart failure and normal-to-increased blood pressure, relaxin was associated with favourable relief of dyspnoea and other clinical outcomes, with acceptable safety

Dyspnoea in patients with acute heart failure:an analysis of its clinical course, determinants, and relationship to 60-day outcomes in the PROTECT pilot study

Dyspnoea is the most common symptom leading to hospitalization for acute heart failure (AHF). Its early and persistent relief is an important goal of therapy, but little is known about its course, determinants, and prognostic significance. In a post hoc analysis, we studied changes in dyspnoea and in-hospital course in 303 subjects with AHF enrolled in the PROTECT pilot trial. Changes in dyspnoea were assessed by patient self-report using a seven-point Likert scale daily to discharge and at Days 7 and 14. We defined dyspnoea relief as a moderate to marked improvement of dyspnoea at both 24 and 48 h, and treatment success as dyspnoea relief without worsening HF or renal function or death during the first 7 days. Dyspnoea relief occurred in 54% of the patients, while treatment success was achieved in 44% of the patients. By Day 14, only 75% of patients reported a moderate or marked improvement in dyspnoea. Both dyspnoea relief and treatment success were associated with greater improvement in signs of congestion, shorter hospitalization duration, and a lower 60-day mortality rate. Treatment success, but not dyspnoea relief, was also associated with a lower incidence of 60-day death or re-hospitalization for HF or renal failure. Half of patients admitted for AHF do not have substantial improvement in dyspnoea at 24 h and 25% do not have substantial improvement at 7 and 14 days from admission. Dyspnoea relief and treatment success are associated with shorter length of stay and lower 60-day mortality. These analyses should be confirmed in larger studies

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%, except for a higher baseline WBC count, elevated baseline glucose, older age and higher rates of peripheral vascular disease. However, patients with Ly

Acute Heart Failure Clinical Drug Development:From Planning to Proof of Activity to Phase III

Over the last decades, attempts to develop new therapies for acute heart failure (AHF) have largely failed. Limitations in understanding the pathophysiology of AHF, its natural history, the effects of current therapies, the properties of new agents, and, importantly, study designs and execution have contributed to these disappointing results. We propose a novel approach for the development of new agents for AHF. Initial stages of development (proof of activity and phase IIa studies) should provide a granular understanding of the mechanism of the actions and pharmacodynamic properties of the new intervention, first in animal models of HF and then in small tightly designed human studies. This will facilitate the identification of patients who are more likely to show a favorable response. In phase II studies (proof of concept), the assessment of efficacy and final dose selection should not be based on surrogate endpoints but rather on clinically meaningful endpoints such as the relief of AHF symptoms, i.e. breathlessness, as well as consistent trends in the relief of other symptoms and clinical signs of recurrence (worsening HF either in hospital or after discharge) and short-term mortality. Lastly, other safety parameters, i.e. effects such as renal and myocardial damage, should be assessed. In some instances, the decision to move to phase III may be based on clear consistent trends rather than on 1 statistically significant endpoint. In studies that confirm clinical utility (phase III), efficacy will be judged relative to the magnitude of the benefit, i.e. improvements in symptoms (breathlessness), the prevention of symptom recurrence, and short-term mortality, balanced by the consideration of safety signals including an estimation of absolute mortality. Copyright (C) 2010 S. Karger AG, Base

Rolofylline, an Adenosine A(sub 1)-Receptor Antagonist, in Acute Heart Failure.

Background: 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 A(sub 1)-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. Methods: 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. Results: 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 A(sub 1)-receptor antagonists. Conclusions: 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.) N Engl J Med 2010;363:1419-28