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
Received 22 July 2009; received in revised form 12 October 2009; accepted 27 October 2009. published online 11 December 2009.
Abstract
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 A1 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 A1 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.
Reprint requests: Howard C Dittrich, MD, 12750 High Bluff Drive, Suite 300, San Diego, CA 92130.
All decisions regarding this manuscript were made by a guest editor.
Funded by Merck & Co., Inc., Whitehouse Station, NJ.
Author Disclosures and Contributions
Howard C. Dittrich, MD, employee of NovaCardia, Inc, a wholly owned subsidiary of Merck & Co and consultant to Merck & Co (H.C.D.); Piotr Ponikowski, MD: Investigator and Executive Committee member (P.P.); Beth Davison Weatherley PhD: Employee of Momentum Research, Inc, a vendor to Merck & Co (B.D.W.); Marco Metra, MD: Investigator and Executive Committee member (M.M.); John R. Teerlink MD: Chair, Clinical Events Committee (J.R.T.); Gad Cotter MD: Employee of Momentum Research, Inc, a vendor to Merck & Co (G.C.); Paul DeLucca PhD: Employee of Merck & Co (P.D.); George A. Mansoor MD: Employee of Merck & Co (G.A.M.); Daniel M. Bloomfield, MD: Employee of Merck & Co (D.M.B.); Christopher M. O'Connor, MD: Co-Principal Investigator, Consultant to Merck & Co (C.M.O'C.); Barry M. Massie, MD: Co-Principal Investigator, Consultant to Merck & Co (B.M.M.).
The manuscript was primarily drafted by Drs Dittrich, Ponikowski, Bloomfield, and Massie, with substantial contributions from Drs Weatherley and DeLucca regarding the statistical and analysis plan. The other listed authors reviewed and commented on the manuscript at several stages and approved the final submitted version. No unlisted individuals contributed to the writing of this manuscript.
ABSTRACT