Rationale, design, and methods for the Transplant-Eligible MAnagement of Congestive Heart Failure (TMAC) trial: a multicenter clinical outcomes trial using nesiritide for TMAC.
BACKGROUND
Urgent heart transplant candidates classified as United Network for Organ Sharing status 1B who require continuous infusions of inotropic agents for hemodynamic stability often have hemodynamic, electrical, or multisystem decompensation. This multicenter trial will study both traditional safety and efficacy parameters and the physiologic mechanisms of benefit of the addition to conventional therapy of nesiritide, a recombinant analog of brain-type natriuretic peptide, in this population.


METHODS
TMAC is a prospective, randomized, parallel, multicenter, double-blind, placebo-controlled study in patients awaiting heart transplantation who meet United Network for Organ Sharing status 1B criteria (N = 120) and receive continuous dobutamine or milrinone through a double-lumen central catheter for at least 3 consecutive days before randomization. Patients will receive standard care and continuous intravenous inotrope therapy plus a 28-day continuous infusion of nesiritide or placebo. There will be up to 6 months of follow-up. Primary efficacy end point will be days alive after treatment without renal, hemodynamic, or electrical worsening at completion. Secondary analyses will evaluate effects on hemodynamics, echocardiographic parameters, endogenous brain-type natriuretic peptide levels, modification of diet in renal disease-calculated glomerular filtration rate, and all-cause and cardiovascular mortality. Two mechanistic substudies will evaluate the effect on iohexol-determined glomerular filtration rate and assess changes in lung mechanics.


CONCLUSIONS
This investigation will provide key data for clinical profiles of heart transplant candidates bound to inotropic support. It will investigate the efficacy and safety (especially renal) of nesiritide and provide mechanistic insight into benefits of its use for the relief of breathlessness.
Mehra
Mandeep R
MR
University of Maryland School of Medicine, Baltimore, MD 21201-1595, USA. mmehra@medicine.umaryland.edu
McCluskey
Ted
T
Barr
Mark
M
Bourge
Robert C
RC
Jessup
Mariell L
ML
Mancini
Donna
D
Radovancevic
Branislav
B
Rayburn
Barry
B
Taylor
David O
DO
Lilly-Hersley
Jane
J
Linde
Peter
P
D002316:Cardiotonic Agents / Q000627:therapeutic use*; D004280:Dobutamine / Q000008:administration & dosage; D004311:Double-Blind Method; D004452:Echocardiography; D004608:Eligibility Determination; D006333:Heart Failure / Q000145:classification / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D016027:Heart Transplantation; D006801:Humans; D007262:Infusions, Intravenous; D045283:Natriuretic Agents / Q000627:therapeutic use*; D020097:Natriuretic Peptide, Brain / Q000627:therapeutic use*; D018579:Patient Selection; D011300:Preoperative Care; D012107:Research Design; D018401:Sample Size; D012720:Severity of Illness Index; D015996:Survival Rate; D016896:Treatment Outcome
D002316:Cardiotonic Agents; D045283:Natriuretic Agents; D020097:Natriuretic Peptide, Brain; D004280:Dobutamine