Effects of BG9928, an adenosine A₁ receptor antagonist, in patients with congestive heart failure.
ABSTRACT Previous studies suggest that adenosine A₁ receptor antagonists may promote natriuresis without deleterious effects on renal function. This study evaluated renal and hemodynamic effects as well as safety, pharmacokinetics, and tolerability of BG9928, a selective adenosine A₁-receptor antagonist, in patients with heart failure. In this multicenter, randomized, double-blind, placebo-controlled, dose-escalation study, 33 patients received a single dose of BG9928 (0.03, 0.3, 1.0, or 3.0 mg/kg) or placebo intravenously. Change from baseline in urinary sodium excretion for the 8-hour postdose interval was greater for all dosing groups versus placebo. The 0.03-mg/kg and 0.3-mg/kg groups had significant reductions in body weight versus placebo (-0.8 kg, -1.1 kg, 0.3 kg, respectively; P < 005). No changes in creatinine clearance or hemodynamic parameters were observed among any of the BG9928 groups versus placebo. However, pulmonary capillary wedge pressure tended to decrease and correlated with weight loss. Across the range of doses studied, pharmacokinetic parameters were linear and predictable. One patient who received the highest dose (3.0 mg/kg) developed seizures, and no further patients received that dose. Single intravenous BG9928 doses of up to 1.0 mg/kg were well tolerated and increased sodium excretion without worsening renal function. Further studies are needed to determine the clinical benefit of adenosine A₁ receptor antagonism.
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ABSTRACT: Worsening renal function in patients hospitalized for heart failure portends a poor prognosis. However, criteria used to define worsening renal function are arbitrary, and the implications of different definitions remain unclear. We therefore compared the prognostic importance of various definitions of worsening renal function in 1,002 patients hospitalized for congestive heart failure (CHF). The patient population was 49% female, aged 67 +/- 15 years. Twenty-three percent had a prior history of renal failure, 73% had known depressed ejection fraction, and 63% had known CHF. On admission to the hospital, 47% were receiving ACE inhibitors, 22% beta-blockers, 70% diuretics and 6% NAID's. 72% developed increased serum creatinine during the hospitalization, with 20% developing an increase of > or = 0.5 mg/dL. Worsening renal function predicted both in-hospital mortality and length of stay > 10 days. Even an increased creatinine of 0.1 mg/dL was associated with worse outcome. Sensitivity for death decreased from 92% to 65% as the threshold for increased creatinine was raised from 0.1 to 0.5 mg/dL, with specificity increasing from 28% to 81%. At a threshold of a 0.3 mg/dL increase, sensitivity was 81% and specificity was 62% for death and 64% and 65% for length of stay >10 days. Adding a requirement of final creatinine of > or = 1.5 mg/dL improved specificity. This analysis demonstrates that any detectable decrease in renal function is associated with increased mortality and prolonged hospital stay. This suggests that therapeutic interventions which improve renal function might be beneficial.Journal of Cardiac Failure 06/2002; 8(3):136-41. · 3.32 Impact Factor
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ABSTRACT: The aim of the study was to evaluate the effects of adenosine on renal blood flow in humans. Eleven normotensive patients (mean age 53 +/- 11 years) with normal renal angiograms were enrolled in the study. Arterial blood pressure, one ECG lead and arterial renal blood flow velocity, by intravascular Doppler catheter, were monitored throughout the procedure. Incremental doses (10(-5), 10(-4), 10(-3), 2 x 10(-3), 5 x 10(-3), 10(-2), 10(-1), 1 mg) were selectively injected, at 5-min intervals, in a renal artery. Adenosine administration had no significant effects on blood pressure, heart rate and atrio-ventricular conduction. A progressive reduction in renal blood flow velocity (from 16.36 +/- 1.9 to 3.9 +/- 0.8 cm/s, P < 0.0001) was observed. Following adenosine the decrease of flow velocity was immediate and its duration was proportional to dosage (from 0.5 +/- 0.4 s at 10(-5) mg to 31 +/- 6.5 s at 1 mg). Renal angiography, repeated in four patients during flow velocity decrement, showed no changes in vessel diameter. Exogenous adenosine-induced a marked and transient reduction in renal blood flow in man. This effect suggests that adenosine or its metabolites may be directly implicated in rapid and powerful mechanisms of cardiac output redistribution. Thus endogenous adenosine could have a role in regulating renal blood flow in physiological and pathological situations like strenuous exercise, hemorrhage shock and cardiac failure.Cardiovascular Research 11/1996; 32(5):949-53. · 5.94 Impact Factor
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ABSTRACT: Little randomized evidence is available to guide the in-hospital management of patients with an acute exacerbation of chronic heart failure. Although intravenous inotropic therapy usually produces beneficial hemodynamic effects and is labeled for use in the care of such patients, the effect of such therapy on intermediate-term clinical outcomes is uncertain. To prospectively test whether a strategy that includes short-term use of milrinone in addition to standard therapy can improve clinical outcomes of patients hospitalized with an exacerbation of chronic heart failure. Prospective, randomized, double-blind, placebo-controlled trial conducted from July 1997 through November 1999. Seventy-eight community and tertiary care hospitals in the United States. A total of 951 patients admitted with an exacerbation of systolic heart failure not requiring intravenous inotropic support (mean age, 65 years; 92% with baseline New York Heart Association class III or IV; mean left ventricular ejection fraction, 23%). Patients were randomly assigned to receive a 48-hour infusion of either milrinone, 0.5 microg/kg per minute initially (n = 477), or saline placebo (n = 472). Cumulative days of hospitalization for cardiovascular cause within 60 days following randomization. The median number of days hospitalized for cardiovascular causes within 60 days after randomization did not differ significantly between patients given milrinone (6 days) compared with placebo (7 days; P =.71). Sustained hypotension requiring intervention (10.7% vs 3.2%; P<.001) and new atrial arrhythmias (4.6% vs 1.5%; P =.004) occurred more frequently in patients who received milrinone. The milrinone and placebo groups did not differ significantly in in-hospital mortality (3.8% vs 2.3%; P =.19), 60-day mortality (10.3% vs 8.9%; P =.41), or the composite incidence of death or readmission (35.0% vs 35.3%; P =.92) These results do not support the routine use of intravenous milrinone as an adjunct to standard therapy in the treatment of patients hospitalized for an exacerbation of chronic heart failure.JAMA The Journal of the American Medical Association 03/2002; 287(12):1541-7. · 29.98 Impact Factor