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.).

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 microg/kg (n=40), 30 microg/kg (n=43), 100 microg/kg (n=39), or 250 microg/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 microg/kg per day group, 42 in the relaxin 30 microg/kg per day group, 37 in the relaxin 100 microg/kg per day group, and 49 in the relaxin 250 microg/kg per day group. Dyspnoea improved with relaxin 30 microg/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 mm x h [SD 8712] vs 4622 mm x h [9003]; 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% CI 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.

Design and rationale of the PROTECT study: a 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.

BACKGROUND: Current treatment for acute decompensated heart failure (ADHF) is associated with incomplete resolution of symptoms and signs, recurrent symptoms of heart failure in-hospital and after discharge and high mortality. Studies have consistently demonstrated an association between worsening renal function in ADHF and adverse outcomes. Adenosine A(1) receptor antagonists, such as rolofylline, appear in preliminary studies to produce potentially beneficial effects on natriuresis, diuresis, renal blood flow, and glomerular filtration rate. In a previous dose-finding study, rolofylline 30 mg intravenously daily for 3 days was associated with symptom improvement, less worsening of renal function, and trends toward lower 60-day rates of death or readmission for cardiovascular or renal causes. METHODS AND RESULTS: This manuscript describes the rationale underlying the design of the phase 3 PROTECT (Placebo-controlled Randomized study of the selective A(1) adenosine receptor antagonist rolofylline for patients hospitalized with acute heart failure and volume Overload to assess Treatment Effect on Congestion and renal funcTion) trial. CONCLUSION: Rolofylline 30 mg or matching placebo was given intravenously as a 4-hour continuous infusion on 3 consecutive days and the hospital course was assessed by measurements dyspnea, clinical status, renal function, and subsequent morbidity and mortality in a large population of patients with ADHF with renal impairment.

Physician-determined worsening heart failure: a novel definition for early worsening heart failure in patients hospitalized for acute heart failure--association with signs and symptoms, hospitalization duration, and 60-day outcomes.

OBJECTIVES: To evaluate physician-determined worsening heart failure (PD-WHF) in patients admitted with acute heart failure (AHF). METHODS: The PROTECT pilot study evaluated rolofylline, an adenosine A(1) receptor antagonist, versus placebo in patients with AHF and renal impairment. Signs and symptoms of heart failure (HF) and diuretic administration were prospectively recorded daily for 7 days and patients were followed for 60 days. Patients were categorized into three groups: (A) PD-WHF, based on worsening symptoms and signs of HF and need for additional intravenous (IV) or mechanical therapy (n = 29); (B) increased IV diuretic therapy without PD-WHF (n = 61), and (C) neither PD-WHF nor increase in IV diuretic dose (n = 211). RESULTS: Patients in group A had slower resolution of dyspnea, longer mean (+/-SD) length of hospitalization (13.8 +/- 6.8 vs. 10.5 +/- 8.5 and 9.3 +/- 5.9 days in groups B and C, respectively; p < 0.05 for both), and higher 60-day death and cardiovascular or renal readmission rates [49.7 (95% confidence interval: 33.1-69.1) vs. 37.3 (26.4-50.9) vs. 19.5% (14.7-25.6) in groups B and C, respectively]. PD-WHF was a strong independent predictor of length of stay and 60-day death and cardiovascular or renal readmission. CONCLUSIONS: PD-WHF may be an indicator of short-term risk and treatment efficacy in AHF.

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.

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.

Early worsening heart failure in patients admitted for acute heart failure: time course, hemodynamic predictors, and outcome.

BACKGROUND: The most common outcome currently assessed in acute heart failure trials (AHF) is dyspnea improvement. Worsening hear failure (WHF) is a new outcome measure that incorporates failure to improve or recurrent symptoms of AHF requiring rescue intravenous therapy, mechanical circulatory or ventilatory support, or readmission because of AHF, occurring within 30 days of AHF admission. METHODS AND RESULTS: Retrospective data analysis of 120 patients with AHF requiring hemodynamic monitoring who enrolled in the placebo arm of 2 prospective randomized studies. The incidence of WHF was 42% at 30 days from enrollment. Most WHF events occurred in-hospital during the first 7 days after admission (early WHF). Thirty-day readmission from AHF was an infrequent event in the present cohort (5.0%). The strongest hemodynamic predictors of WHF were cardiac power at baseline and its change during the initial 6 hours of monitoring. Other hemodynamic parameters associated with WHF events were blood pressure and its increase, cardiac output, and pulmonary wedge pressure change during the initial 6 hours of monitoring. WHF was found to be a strong predictor of 6-month mortality. CONCLUSIONS: WHF is a common morbid event clustered mostly during the first week of AHF admission and is associated with higher 6-month mortality. The hemodynamic measurements associated with WHF are similar to those predicting adverse outcome in AHF and cardiogenic shock (low cardiac power, higher pulmonary capillary wedge pressure, and vascular resistance), emphasizing the notion that early WHF should become an important AHF-specific outcome measure.

Rapid clinical assessment of patients with acute heart failure: first blood pressure and oxygen saturation--is that all we need?

UNLABELLED: The risk stratification of patients with acute heart failure (AHF) has been addressed repeatedly in recent years. Low oxygen saturation (SaO2) and systolic blood pressure (SBP) are signs of impending respiratory and circulatory failure that can be obtained quickly in patients with AHF. METHODS: Admissions for AHF (340 patients) in a city hospital were recorded and patients were followed for symptoms of heart failure, re-admission and mortality for 6 months. RESULTS: Patients with low (<90%) SaO2 had higher rates of worsening heart failure at 1 month and 6 months (p < 0.001 and p < 0.001, respectively) and higher rates of mortality (p = 0.013). SBP <120 mm Hg was not associated with a significant increase in worsening heart failure, but was associated with a statistically significant increase in mortality at 1 and 6 months (p < 0.001 and p < 0.001, respectively). Combined low SaO2 and SBP had a particularly strong prognostic implication. Patients who developed frank respiratory failure and/or circulatory failure fared the worst. Patients requiring ventilatory support had a recurrent heart failure rate of 81% and a mortality of 41% at 1 month of follow-up. Patients requiring intravenous pressors without respiratory mechanical support had a recurrent heart failure rate of 72% and a mortality rate of 28% at 1 month (p < 0.001). CONCLUSIONS: Simple assessment of impending respiratory and circulatory failure at admission by measuring SaO2 and SBP enables rapid and accurate risk stratification of patients admitted for AHF. This may enable more aggressive therapeutic interventions for stabilization and treatment of AHF.

The PROTECT pilot study: a randomized, placebo-controlled, dose-finding study of the adenosine A1 receptor antagonist rolofylline in patients with acute heart failure and renal impairment.

BACKGROUND: Rolofylline, an adenosine A(1) receptor antagonist, facilitates diuresis and preserves renal function in patients with acute heart failure (AHF) with renal impairment. Although not powered around any specific hypothesis, this pilot study was designed to identify an efficacious dose while refining inclusion criteria and end points. METHODS: A total of 301 patients hospitalized for AHF with an estimated creatinine clearance of 20 to 80 mL/min and elevated natriuretic peptide levels were enrolled within 24 hours of presentation to placebo or rolofylline 10, 20, or 30 mg administered as 4-hour infusions for 3 days in addition to intravenously administered loop diuretics. Post hoc analyses for end points chosen for subsequent Phase III studies were performed. RESULTS: Compared with placebo, rolofylline produced trends toward greater proportions of patients with marked or moderately improved dyspnea and fewer patients with worsening heart failure or renal function. Serum creatinine increased in patients receiving placebo and remained stable or tended to decrease in those receiving rolofylline. On day 14 the absolute differences between placebo and rolofylline for change in creatinine increased with increasing rolofylline dose, reflecting the lesser increase in creatinine in rolofylline-treated patients (r = -0.12, P = .030). Treatment with 30 mg, the dose selected for the pivotal trials, was associated with a trend toward reduced 60-day mortality or readmission for cardiovascular or renal cause (hazard ratio, 0.55; 95% confidence interval, 0.28-1.04). CONCLUSION: These results demonstrate that adenosine A(1) receptor blockade with rolofylline can prevent renal impairment in patients with AHF and may positively affect acute symptoms and 60-day outcome. A 2000-patient trial of this agent is now under way.

Patterns of leukocyte counts on admissions for acute heart failure--presentation and outcome--results from a community based registry.

OBJECTIVE: To determine the correlation between differential white blood cell (WBC) count and characteristics and outcome of acute heart failure (AHF) syndromes. BACKGROUND: Previous studies suggested that different white blood cell count patterns are related to outcome in patients with heart failure (HF) and other cardiovascular disorders. METHODS: Data from all qualifying AHF admissions to a city hospital (n=340) was prospectively collected. Patients were followed from admission up to 6 months post-discharge. The relationship between patients' demographics, clinical and laboratory characteristics and outcome were assessed in relation to WBC count and lymphocyte to WBC ratio (LWR). RESULTS: WBC count >10,100×10 (9)/L (upper tertile) on admission was associated with higher admission blood pressure, lower oxygen saturation, higher heart rate and increased troponin, with no impact on either short-term worsening HF or long-term adverse outcome. Lower LWR was associated with higher BUN and troponin and lower hemoglobin, but not with a distinct clinical presentation. The lower LWR tertile (≤13%) was associated with a 60% increase in worsening HF risk and a substantially higher 1 month (15% versus 2%) and 6 months mortality (23% vs. 3%) for lowest versus highest quartile (p<0.0001). CONCLUSIONS: While increased WBC count is associated with a more "vascular presentation" and certain severity markers, it is not related to worse patient outcome. Low LWR (≤13%) is predictive of worse outcome and higher mortality. It is also associated with certain laboratory abnormalities, but not related to a specific clinical profile.

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

AIMS: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.

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.

AIMS: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.

Early worsening heart failure in patients admitted with acute heart failure--a new outcome measure associated with long-term prognosis?

A major limitation in acute heart failure (AHF) research has been the lack of an outcome measure paralleling re-infarction in acute coronary syndromes. The aim of the present study was to assess the time course, prognostic factors and outcome of early worsening heart failure (WHF) in patients admitted for AHF to a community hospital. All AHF admissions between December 2003 and March 2004 in a regional medical center were recorded. Patients were followed through admission and for 6 months after discharge. Early WHF was defined as WHF occurring during the initial 7 days from admission. Study endpoints were cardiovascular mortality and WHF (defined as worsening or persistent signs or symptoms of AHF requiring rescue therapy or hospital readmission). Early WHF rate was 29% and was associated with markers of AHF severity on presentation (higher troponin I, lower oxygen saturation, need for mechanical ventilation, intravascular diuretics and inotropes). Early WHF was a powerful predictor of death during 6 months of follow up, with an age-adjusted hazard ratio of 3.3 (95% confidence interval 1.7-6.3). Early WHF is a common adverse event in patients admitted with AHF, and is associated with AHF severity and excessive 6-month mortality. WHF should be considered as a clinically important endpoint in AHF studies.