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J Am Coll Cardiol, 2007; 50:600-606, doi:10.1016/j.jacc.2007.03.059 (Published online 29 July 2007).
© 2007 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: HEART FAILURE

Effects of Multiple Oral Doses of an A1 Adenosine Antagonist, BG9928, in Patients With Heart Failure

Results of a Placebo-Controlled, Dose-Escalation Study

Barry Greenberg, MD*,1,*, Ignatius Thomas, MD{dagger},2, Dorothy Banish, MD{ddagger}, Steven Goldman, MD§, Edward Havranek, MD||,3, Barry M. Massie, MD,4, Ying Zhu, PhD#,5, Barry Ticho, MD, PhD#,5 and William T. Abraham, MD**,6

* University of California, Advanced Heart Failure Treatment Program, San Diego, California
{dagger} Medical Research Institute, Slidell, Louisiana
{ddagger} Tchefuncte Cardiovascular Associates, Covington, Louisiana
§ Tucson VA Medical Center, SAVAHCS, Sarver Heart Center, and University of Arizona, Tucson, Arizona
|| Denver Health Medical Center, Denver, Colorado
University of California and San Francisco VA Medical Center, San Francisco, California
# Biogen Idec Inc., Cambridge, Massachusetts
** The Ohio State University Heart Center, Division of Cardiology, Columbus, Ohio.

Manuscript received August 22, 2006; revised manuscript received February 26, 2007, accepted March 20, 2007.

* Reprint requests and correspondence: Dr. Barry Greenberg, Advanced Heart Failure Treatment Program, University of California–San Diego, 200 West Arbor Drive-8411, San Diego, California 92103-8411. (Email: bgreenberg{at}ucsd.edu).


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
Objectives: This study sought to assess the pharmacokinetics and clinical effects of oral BG9928 in heart failure (HF) patients.

Background: Declining renal function during HF treatment is associated with poor outcomes. BG9928, a selective inhibitor of the A1 adenosine receptor, is proposed to cause natriuresis without causing a decline in renal function.

Methods: A randomized, double-blind, placebo-controlled study was conducted in patients with HF and systolic dysfunction who were receiving standard therapy. Patients were randomized to receive BG9928 (3, 15, 75, or 225 mg) or placebo orally for 10 days. The primary end point was change in sodium excretion. Changes in potassium excretion, creatinine clearance, and body weight also were evaluated.

Results: A total of 50 patients were studied. BG9928 increased sodium excretion compared with placebo, and natriuresis was maintained over 10 days with little kaliuresis. A linear trend in dose response was observed on day 1 (p = 0.04) but not on days 6 or 10. Adjusted creatinine clearance was unchanged over the 10 days. Patients who received 15, 75, or 225 mg of BG9928 had a reduction in body weight compared with placebo (–0.6, –0.7, –0.5, vs. +0.3 kg, respectively) at the end of study. BG9928 was well tolerated. The pharmacokinetic profile of BG9928 was consistent with once-daily dosing.

Conclusions: Oral BG9928 over the dose range of 3 to 225 mg/day produced significant increases in sodium excretion in patients with stable HF without causing kaliuresis or reducing renal function.

Abbreviations and Acronyms
  ACE = angiotensin-converting enzyme
  ARB = angiotensin II receptor blocker
  AUC = area under the concentration time curve
  Cmax = peak concentration
  CrCl = creatinine clearance
  ECG = electrocardiogram
  HF = heart failure
  NYHA = New York Heart Association
  t1/2 = elimination half-life
  tmax = time to Cmax

Many patients with heart failure (HF) have underlying renal function abnormalities, and renal function often further deteriorates during treatment (1), especially in those taking diuretics and inhibitors of the renin-angiotensin system (2–4). Worsening renal function is associated with higher mortality and higher costs in hospitalized patients with HF (5–10). Consequently, preserving renal function in these patients may improve outcomes.

Adenosine modulates glomerular filtration by several mechanisms and may contribute to renal dysfunction in patients with HF by reducing glomerular filtration (11,12). Selective A1 adenosine receptor blockade decreases afferent arteriole tone, increases urine flow, and causes natriuresis (13). In patients with HF treated with single intravenous doses of furosemide alone, the adenosine blocker alone, and the combination, the addition of the A1 adenosine receptor antagonist prevented reductions in renal function associated with furosemide use (3,14). BG9928 (Biogen Idec, Cambridge, Massachusetts) is an orally active, potent, and selective inhibitor of the A1 adenosine receptor (15), and its use in patients receiving standard therapy for HF, including diuretics and angiotensin-converting enzyme (ACE) inhibitors, is being investigated.

This study was designed to evaluate the pharmacokinetics and effects on volume status and renal function of multiple oral doses of BG9928 given over 10 days.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Patient population.   Patients were eligible for the study if they had a diagnosis of HF for at least 3 months before screening, had stable New York Heart Association (NYHA) functional class II to IV symptoms, and an ejection fraction of ≤40% documented within the past 12 months. Additional inclusion criteria included age between 18 and 80 years, weight ≥50 kg, and body mass index >19 kg/m2. All patients were screened within 28 days of study drug administration and had to be on a stable medical regimen for at least 2 weeks, including an ACE inhibitor or an angiotensin II receptor blocker (ARB). Those who required more than short-acting nitrates to treat angina or had unstable angina were excluded. Patients with renal impairment (i.e., >3 g proteinuria in a 24-h period or creatinine clearance [CrCl] <30 ml/min/1.73 m2), potential for recent renal injury (i.e., significant episode of hypotension or any surgery requiring general anesthesia, coronary artery bypass graft, or percutaneous coronary intervention within 8 weeks before screening, any dose of radiologic contrast agents or aminoglycosides within 4 weeks before screening, treatment with nephrotoxic drugs within 2 weeks before screening, or any other agents capable of affecting renal function within 24 h before baseline), history of urinary obstruction, myocardial infarction or stroke within the prior 3 months, or other serious systemic disease were not eligible for study entry. Written informed consent was obtained from each patient before study entry. The study protocol was approved by the institutional review board of each study site and was conducted in accordance with the Declaration of Helsinki.

Study design and treatment.   This was a multicenter, randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation study in patients with stable HF. Daily oral doses of BG9928 were administered for 10 days during this study. Patients were evaluated in the hospital and clinic as shown in Figure 1. Postdosing clinic visits were required on days 12, 14, and 16, and telephone follow-up was performed on day 38.


Figure 1
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  		Figure 1 Schematic Illustration of Study Design and Assessments

Timing and hourly intervals for assessments are described in the text. *Inpatient stays until 4 h after second and seventh dose and 32 h after tenth dose. {dagger}Also collected on day 16. {ddagger}Assessment hourly intervals at baseline: 0 to 4, 4 to 8, 8 to 12, and 12 to 24; on days 1, 6, 10, and 16: 0 to 2, 2 to 4, 4 to 8, 8 to 12, and 12 to 24. §Collection hourly intervals at baseline: 0 to 4, 4 to 8, 8 to 12, and 12 to 24; on days 1, 6, 10: 0 to 2, 2 to 4, 4 to 8, 8 to 12, and 12 to 24; on day 11: 28 h to 32 h after last dose. ||Collection hourly intervals at baseline: 0, 4, 8, 12, and 24; on days 1, 6, and 10: 2, 4, 8, and 12; on days 4 and 8: 0; on day 11: 4 and 8. NYHA = New York Heart Association; PGA = Physician’s Global Assessment; PO = per os (by mouth).

 
Patients were enrolled by increasing dose cohorts and were randomized to receive BG9928 or placebo within each cohort using a centralized randomization process (interactive voice response system) with a simple randomization scheme and no stratification factors. The site pharmacist was not blinded and prepared all doses of study medication; all other study personnel remained blinded. Doses of all prescription medication and nonprescription medication were to remain stable for at least 2 weeks before day 1 and through day 16. Patients were not to receive treatment with nephrotoxic drugs within 2 weeks before screening or agents capable of affecting renal function within 24 h before baseline day until day 16. Patients were not permitted to consume medications, foods, or beverages containing caffeine 8 h before until 8 h after the oral dose was taken on baseline days 1, 6, and 10. Also, on inpatient assessment days, patients were not permitted to take other medications from 8 h before study drug administration through the 8-h postdose time point. Permitted medications were reinstated after the 8-h postdose evaluations.

Alcohol was not permitted 48 h before baseline, and patients could not use tobacco products within the 24 h before baseline through day 16. On inpatient assessment days (baseline days 1, 6, and 10) all patients fasted before study drug administration through 4 h after dosing.

Efficacy assessments.   The primary measures of efficacy were changes in urinary sodium excretion and urine volume. Additional measures assessed were urinary potassium excretion, adjusted CrCl, body weight, the Cody Edema Score (2), physician global assessment, and NYHA functional classification. Basic urine chemistry analysis (sodium, potassium, calcium, phosphate, creatinine) was performed on urine samples collected at baseline and on days 1, 6, 10, and 16. Urine volumes were recorded for urine collections at baseline and on days 1, 6, 10, and 11. Blood samples were collected for blood chemistry analysis at baseline and on days 1, 4, 6, 8, 10, and 11. The frequency and timing of assessments are summarized in Figure 1. All laboratory analyses were conducted at a central location, Covance Central Laboratory Services.

Adjusted CrCl was calculated as CrCl x 1.73/body surface area, where body surface area = (height [in cm])0.725 x (weight [in kg])0.425 x 0.007184. Body weight was determined at screening, at baseline, and on days 1, 6, and 10. The Cody Edema Score was evaluated at screening; at baseline; on days 1, 6, and 10 (predose and at 4 h); and on the other days at the time of study drug administration. The physician global assessment and NYHA functional class determination were made at baseline and on day 10. Physician global assessment was performed using a visual analog scale of 0 to 100; a positive change from baseline to day 10 reflects improvement in status.

Pharmacokinetic evaluation.   Blood was collected for pharmacokinetic analysis on days 1, 6, and 10 (predose, 30 min, 60 min, 90 min, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 24 h); days 2 and 7 (predose); days 4 and 8 (0 h); day 11 (4 h and 8 h); and days 12, 14, and 16 (all at 0 h). Peak concentration (Cmax), time to Cmax (tmax), area under the concentration time curve (AUC), uncorrected clearance, and elimination half-life (t1/2) were calculated noncompartmentally using WinNonlin Professional software (version 2.1, Pharsight Corp., Mountain View, California).

Safety assessments.   All patients who received at least 1 dose of study drug were included in the safety analysis. Assessments included physical examinations, an examination for HF, and monitoring of vital signs. An electrocardiogram (ECG) was performed at the screening visit, on days 1, 6, and 10 at 5 to 60 min before dosing and at 2.5 h after dosing, and on days 2, 7, 11, and 12 at the start of the visit (0 h). On hospital admission (day 1), all patients received continuous telemetry monitoring. Adverse events, clinically significant abnormal laboratory results, medical diagnosis noted by medical personnel, and symptoms reported by the patient (regardless of relationship to study drug) were monitored continually throughout the study.

Statistical analyses.   The primary end point for determination of sample size was the change from baseline in sodium excretion over 0 to 8 h. The 0 to 8-h interval was evaluated as the primary end point because patients resumed their usual concomitant medications 8 h after study drug dosing. A sample size of 8 patients per treatment group was calculated to provide 90% power to show a dose response after both the first and the last dose, based on a 2-sided test for linear trend with a 5% type I error. Ten patients were planned for each of 4 dose cohorts (3, 15, 75, and 225 mg of active drug), with 2 patients receiving matching placebo in the 3- and 15-mg cohorts and 3 receiving placebo in the 75- and 225-mg cohorts.

The analysis population for evaluating pharmacodynamic and efficacy data was defined for all patients who received study drug, had at least 1 postdose assessment, and had no major protocol violations. An analysis of covariance adjusting for the baseline value of each parameter was used to test for a linear trend in dose response and also to compare each BG9928 dose group with the placebo group in change from baseline in sodium excretion, urine volume, potassium excretion, CrCl, and weight. Because this was an exploratory study, no adjustment was made to the type I error rate for multiple comparisons.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
At the 8 study sites, 53 patients were enrolled. Of these, 50 patients were randomized and received study medication and 3 withdrew before study drug administration. The distributions of gender, age, and race were similar among the dose groups (Table 1). All patients received concomitant ACE inhibitor or ARB therapy, and 70% to 100% of patients across the treatment groups received diuretics during the study (Table 1). Other commonly received concomitant medications included beta-blockers (80%), digoxin (58%), and spironolactone (24%).


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  		Table 1 Demographics and Baseline Disease Characteristics
 
Efficacy assessments.   Urinary Measures
Urinary sodium excretion was increased in patients who received BG9928 compared with baseline and those who received placebo, when measured over the first 8 h on day 1 (Fig. 2). The mean changes from baseline on day 1 in the 3-, 15-, and 225-mg groups were statistically significantly different from placebo (marginally significant at 75 mg). The test for linear trend in dose response was statistically significant (p = 0.04), although the maximum change from baseline on day 1 occurred with the 15-mg dose without evidence of an increased effect at higher doses (Fig. 2). The natriuretic effect was maintained over the 10-day dosing period in all BG9928 dose groups. However, the linear trend in dose response was no longer evident on days 6 or 10, and the 3-mg dose seemed to have an equal effect to the higher doses.


Figure 2
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  		Figure 2 Cumulative Urinary Sodium Excretion During Dosing

Cumulative urinary sodium excretion (mEq) over the interval of 0 to 8 h at baseline and after placebo or BG9928 administration on days 1, 6, and 10. *p < 0.05 versus placebo. {dagger}p = 0.055 versus placebo. n = 10/group except for 15- and 75-mg dose groups on day 10 (n = 9/group).

 
Urine volume increased from baseline for all dose groups during the 0 to 8-h interval on day 1 and was greatest with the 15-mg dose group (p = 0.005) (Table 2). The results for urine volume were similar to those for cumulative sodium excretion, but because of increased variability, the urine volume results did not reach statistical significance at some time points when sodium excretion was significant (Fig. 2, Table 2).


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  		Table 2 Change From Baseline in Urine Volume for the 0 to 8 h After Study Drug Administration on Days 1, 6, and 10
 
On days 1, 6, and 10, there was no significant linear trend for dose response for the change from baseline in cumulative potassium excretion over the 0 to 8-h interval (Fig. 3). The increase from baseline in potassium excretion was higher than the placebo group to a statistically significant degree in several dosing groups and dosing days. However, these differences were relatively small (<19 mEq over the 0 to 8-h interval) and are unlikely to be of clinical importance.


Figure 3
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  		Figure 3 Cumulative Urinary Potassium Excretion During Dosing

Cumulative urinary potassium excretion (mEq) over the interval of 0 to 8 h at baseline and after placebo or BG9928 administration on days 1, 6, and 10. *p < 0.05 versus placebo. n = 10/group except for 15- and 75-mg dose groups on day 10 (n = 9/group).

 
Similarly, no significant linear trend in dose response was identified for adjusted CrCl over the 2- to 8-h interval or the 2- to 24-h interval. The CrCl was relatively unaffected by BG9928 administration (Fig. 4). There were no significant reductions in adjusted CrCl in any treatment group.


Figure 4
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  		Figure 4 Change in Renal Function During Dosing

Absolute change from baseline in adjusted creatinine clearance (CrCl) (ml/min/1.73 m2) for the interval of 2 to 24 h after placebo or BG9928 administration on days 1, 6, and 10. *p < 0.05 versus placebo. n = 7 to 10 per group.

 
Clinical Measures
The mean changes in body weight from day 1 to day 11 are shown in Figure 5. The placebo group gained an average of 0.3 kg in weight, whereas there was a trend toward a decrease in weight in the BG9928 (0.7 kg in the 75-mg group; p = 0.082, unadjusted). No linear trend for dose response was found for BG9928 dose and weight change.


Figure 5
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  		Figure 5 Change in Body Weight During Dosing

Average change in body weight (kg) from baseline to day 11 after placebo or BG9928 administration. n = 10/group.

 
Although there were no significant differences in clinical status, HF patients treated with BG9928 showed favorable directional trends, in other measures of clinical status, including the Cody Edema Score, physician global assessment, and NYHA functional class. The mean change from day 1 to day 11 in the Cody Edema Score was 0 in the placebo group, –0.4 in the 3-mg group, –0.6 in the 15-mg group, –0.6 in the 75-mg group, and –0.4 in the 225-mg group, where a negative change indicates an improvement in HF signs. The mean change from baseline in the physician global assessment showed a worsened assessment in the placebo group compared with a positive effect in all BG9928 groups. Changes in NYHA functional class from baseline to day 10 occurred in 1 placebo patient who worsened by 1 level and 5 BG9928-treated patients, each improved by 1 level.

Pharmacokinetics.   Pharmacokinetic parameters are summarized in Table 3. BG9928 was rapidly absorbed, with a tmax of 1.5 to 3.1 h. The Cmax, t1/2, and drug clearance were generally similar within doses for days 1, 6, and 10. Significant increases in AUC were observed at all dose levels between days 1 and 6, with no significant increases between days 6 and 10, suggesting that a steady state was reached by day 6. In general, BG9928 Cmax and AUC values increased linearly with dose. Steady-state AUC values showed moderate nonlinearity for the 75-mg dose. Elimination half-life ranged from 8 to 16 h after a single dose and from 14 to 25 h on day 10 (steady state), which is consistent with once-daily dosing.


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  		Table 3 Pharmacokinetic Parameters on Days 1, 6, and 10
 
Safety assessments.   The incidence of adverse events was not higher among patients who received BG9928 compared with those who received placebo, and no apparent dose-related effects were observed. The most frequently reported adverse event in all patients during this study was asymptomatic orthostatic hypotension, which occurred in 3 patients (30%) given placebo compared with 8 of 40 patients (20%) who received any dose of BG9928. Other commonly reported adverse events are shown in Table 4. Most treatment-emergent adverse events were mild or moderate in severity. Two serious adverse events were reported. One patient who received BG9928 3 mg had a cerebral infarction that occurred 11 days after the last dose of study drug and was classified as moderate in severity. The patient had a previous history that included stroke, cerebral artery occlusion, carotid endarterectomy, and coronary artery disease. Another patient with a prior history of atrial fibrillation had a one-time recurrence on day 6 of administration of 15 mg of BG9928. No significant changes in blood pressure were reported in any patient in this study. No clinically significant changes in laboratory or ECG findings were observed.


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  		Table 4 Adverse Events Reported by at Least 2 Patients (20%) in Any BG9928 Group
 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Oral dosages of BG9928 (3 to 225 mg per day) were associated with increased cumulative sodium excretion on day 1, and in some doses on day 6, when administered to patients with HF caused by systolic dysfunction. These doses were associated with, at most, mild increases in potassium excretion without adversely affecting renal function. The incidence of adverse events was similar to placebo, and higher doses of BG9928 were not associated with an increase in adverse events.

The pharmacokinetic profile of BG9928 was consistent with once-daily dosing, and dose-proportional pharmacokinetics were displayed over the entire dose range. No evidence of drug accumulation was seen after the 10-day dosing period, and steady-state concentrations were achieved by day 6.

Clinically relevant significant responses associated with BG9928 administration observed in this study included increased natriuresis without change in renal function. Importantly, these results were observed early and were maintained at 6 days, although linear trends in dose-dependent natriuresis were not observed subsequent to dosing day 1. At any given time point, maximal observed effects on sodium excretion and urine volume were achieved at submaximal doses (i.e., 3, 15, or 75 mg); however, there was no statistical evidence for a lesser effect at higher doses. Change in urine volume showed a similar trend, although again there were no statistically significant differences among dosages. It seems likely that the response to BG9928 reaches a plateau at submaximal doses and that apparent variation at higher doses is not significant. However, we cannot exclude the possibility that the apparently decreasing effects at higher dosages may result from activity at adenosine receptors other than the A1 type. In addition, at each dose used, maximal natriuretic and diuretic effects generally occurred early in the course of daily therapy (i.e., on day 1), with diminishing results thereafter. It is likely that differences in natriuresis observed between initial and subsequent BG9928 doses reflected differences in sodium intake before and after hospital admission for study participation, where dietary intake was restricted.

The effects of BG9928 occurred in patients who were receiving standard therapies for HF, including ACE inhibitors, ARBs, and diuretics that can adversely affect renal function and electrolyte balance (4). A sustained period of natriuresis and diuresis above baseline occurred over the 10 days of dosing with BG9928. A common physiological response to heightened sodium excretion, as occurs with diuresis, is a compensatory decrease in glomerular filtration rate. The lack of a decline in renal function in the presence of a significantly greater diuresis suggests that BG9928 was not detrimental to and may have had a protective effect on renal function. In addition, the minor kaliuresis that was observed is consistent with the site of action of BG9928 on the distal tubule (3,14,15).

This first published study of multiple doses of an oral selective A1 adenosine receptor antagonist in humans shows trends toward beneficial effects in clinical measures of HF, including body weight, edema, and physician global assessment in patients who received BG9928 for 10 days. Although statistical significance was not reached for the outcomes, the findings are noteworthy because the treatment period was relatively short and the effects occurred in combination with standard therapy in patients with stable disease. The results are consistent with prior clinical studies with single intravenous doses of a different A1 adenosine antagonist (BG9719), which showed natriuretic and renal protective effects in HF patients treated with standard therapy (3,14). Future studies that include larger numbers of patients will assess these effects more rigorously. Studies also are planned to investigate short-term intravenous treatment with BG9928 in acutely decompensated HF patients receiving intravenous diuretics. Continued research is also necessary to fully assess the safety profile of BG9928. In addition, the absence of renal function decline in the present study in both treatment and placebo-control groups prohibits a definite conclusion regarding potential renal-protective effects of BG9928 in this sample of HF patients. Longer-term studies with the oral formulation are planned to detect any renal protective effects, as well as effects on morbidity and mortality.

Oral doses of BG9928 (3 to 225 mg daily) for 10 days produced the desired physiological responses, and no safety concerns were observed. Additional studies of BG9928 are warranted in patients with HF in whom natriuresis, volume loss, and maintenance of renal function are desired.


   Acknowledgments
 
The authors thank Thomson Scientific Connexions for their editorial assistance.


   Footnotes
 
This study was supported by Biogen Idec, Cambridge, Massachusetts.

1 Dr. Greenberg received research support for this study and a prior study from Biogen Idec, Inc. He has received grant support for research from Amgen, Cardiodynamics, GlaxoSmithKline, Millennium, Novacardia, Otsuka, Pfizer, Sanofi-Aventis, and Titan. He has served as a consultant and speaker for Amgen, AstraZeneca, GlaxoSmithKline, Guidant Corp., Medtronic Inc., Merck & Co, Inc., Pfizer, Remon Medical Technologies, and Scios Inc. He is a member of the advisory board for CHF Solutions. He has received honoraria from AstraZeneca, GlaxoSmithKline, Medtronic Inc., Merck & Co, Inc., NitroMed, Novartis, Pfizer, and Scios Inc. He has served on the editorial board for Congestive Heart Failure and the Journal of the American College of Cardiology. Back

2 Dr. Thomas received research support for this study and a prior study from Biogen Idec, Inc. He owns stock in Biogen Idec, Inc. Back

3 Dr. Havranek received research support for this study and a prior study from Biogen Idec, Inc. Back

4 Dr. Massie receives research support from Biogen Idec, Inc., and has been a consultant to Novacardia, Inc., which is developing another A1 antagonist for heart failure patients. He serves on Steering Committees for two trials sponsored by Scios/Johnson & Johnson and is principal investigator of a trial sponsored by Novacardia. He has also been a consultant for Bristol-Myers Squibb, Sanofi-Aventis, Novartis, GlaxoSmithKline, Amgen, AstraZeneca, Protein Design Laboratories, Cytokinetics, and Amylin. He serves on Data and Safety Monitoring Boards for trials sponsored by Scios, Otsuka, AstraZeneca, and Orquis. He receives research support from Bristol-Myers Squibb, Sanofi-Aventis, and Novacardia. Back

5 Drs. Ticho and Zhu are employees and shareholders of Biogen Idec, Inc. Back

6 Dr. Abraham received research support for this study from Biogen Idec, Inc. He has received grant support for research from Amgen, Biotronik, CHF Solutions, GlaxoSmithKline, the Heart Failure Society of America, the National Institutes of Health, Medtronic Inc., Myogen Inc., Orqis Medical, Otsuka Maryland Research Institute, Paracor Inc., and Scios Inc. He has served as a consultant and/or speaker for Amgen, AstraZeneca, Boehringer Ingelheim, CHF Solutions, GlaxoSmithKline, Guidant Corp., Medtronic Inc., Merck & Co., Inc., Pfizer, ResMed, Respironics, Scios Inc., and St. Jude Medical. He is a member of the advisory board for CardioKine, CardioKinetix Inc., CHF Solutions, the Department of Veterans Affairs Cooperative Studies Program, Inovise, the National Institutes of Health, and Savacor Inc. He has received honoraria from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Guidant Corp., Medtronic Inc., Merck & Co., Inc., Pfizer, ResMed, Respironics, Scios Inc., and St. Jude Medical. He has served on the editorial board for Congestive Heart Failure, Current Cardiology Reviews, Current Heart Failure Reports, Expert Review of Cardiovascular Therapy, Journal Watch Cardiology, PACE: Pacing and Clinical Electrophysiology, The American Heart Hospital Journal, and the Journal of Heart Failure. Back


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

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  3. Gottlieb SS, Skettino SL, Wolff A, et al. Effects of BG9719 (CVT-124), an A1-adenosine receptor antagonist, and furosemide on glomerular filtration rate and natriuresis in patients with congestive heart failure J Am Coll Cardiol 2000;35:56-59.[Abstract/Free Full Text]
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  10. Fonarow GC, Adams Jr KF, Abraham WT, Yancy CW, Boscardin WJ, ADHERE Scientific Advisory Committee, Study Group, and Investigators Risk stratification for in-hospital mortality in acutely decompensated heart failure: classification and regression tree analysis JAMA 2005;293:572-580.[Abstract/Free Full Text]
  11. Edlund A, Ohlsén H, Sollevi A. Renal effects of local infusion of adenosine in man Clin Sci 1994;87:143-149(Lond).[ISI][Medline]
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  13. Munger KA, Jackson EK. Effects of selective A1 receptor blockade on glomerular hemodynamics: involvement of renin-angiotensin system Am J Physiol 1994;267:F783-F790.[ISI][Medline]
  14. Gottlieb S, Brater C, Thomas I, et al. BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy Circulation 2002;105:1348-1353.[Abstract/Free Full Text]
  15. Ticho B, Whalley E, Gill A, et al. Renal effects of BG8828, an A1 adenosine receptor antagonist, in rats and nonhuman primates Drug Dev Res 2003;58:486-492.[CrossRef][ISI]



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 J Am Coll CardiolHome page
W.H. W. Tang and G. S. Francis
The Year in Heart Failure
J. Am. Coll. Cardiol., December 11, 2007; 50(24): 2344 - 2351.
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