cardiovascular-agents and rolofylline

Hospitalization for heart failure (HF) is a clinical entity associated with high postdischarge morbidity and mortality, yet few therapies are available to improve outcomes in patients with this condition. In the past decade, large phase III studies of HF treatments have failed to demonstrate drug efficacy, safety, or both, despite encouraging results from preceding phase II trials. This Review is focused on this disconnect between the results of phase II and phase III trials of drugs for HF and discusses findings from five drug-development programs (for levosimendan, tezosentan, tolvaptan, rolofylline, and nesiritide) to shed light on common themes in clinical trials conducted in patients hospitalized for HF. In particular, the importance of selecting the 'right' patient population, drug, and clinical end points to optimize the trial design is discussed. Areas that require further investigation are highlighted and we suggest possible directions that will help to guide future clinical trials in these patients. Large, expensive phase III trials should not be initiated without adequate phase II evidence or on the basis of overly optimistic interpretation of phase II data. Additionally, drug development programs should be targeted not only to change short-term symptoms, but also to improve the postdischarge event rate.

Topics: Animals; Benzazepines; Cardiovascular Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Evidence-Based Medicine; Heart Failure; Humans; Hydrazones; Natriuretic Peptide, Brain; Patient Readmission; Patient Selection; Pyridazines; Pyridines; Risk Assessment; Risk Factors; Simendan; Tetrazoles; Time Factors; Tolvaptan; Treatment Outcome; Xanthines

Co-existent cardiac and renal dysfunction is increasingly recognized as both a predictor and mediator of poor outcomes in patients with advanced heart failure. Novel therapies, including adenosine receptor antagonists, are currently under development for the treatment of 'cardiorenal syndrome'.. To review the pathophysiologic rationale for using rolofylline, a selective adenosine 1 receptor antagonist, in patients with cardiorenal syndrome; and to provide a critical overview of safety and efficacy data from clinical studies.. We reviewed published data on the pharmacology of rolofylline, and used this to inform a comprehensive summary of preclinical and clinical trials. Cardiac and renal effects, and safety data with a particular reference to seizures, are highlighted.. Rolofylline facilitates diuresis and preserves renal function in patients with acute decompensated heart failure and renal dysfunction. Pilot data also suggest beneficial effects on symptoms and short-term outcomes. The risk of seizures may be minimized by excluding high-risk patients.

Topics: Adenosine A1 Receptor Antagonists; Animals; Cardiovascular Agents; Clinical Trials as Topic; Dose-Response Relationship, Drug; Heart Failure; Humans; Renal Insufficiency, Chronic; Syndrome; Xanthines

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.. 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.. 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).. 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.

Topics: Acute Disease; Adenosine A1 Receptor Antagonists; Aged; Cardiovascular Agents; Confidence Intervals; Disease Progression; Diuresis; Dyspnea; Female; Heart Failure; Humans; Male; Pilot Projects; Renal Insufficiency; Risk; Risk Factors; Xanthines