Efficacy of zoniporide, an Na/H exchange ion inhibitor, for reducing perioperative cardiovascular events in vascular surgery patients.
OBJECTIVE
To determine whether a novel Na+/H+ exchange ion inhibitor, zoniporide, is associated with reduced perioperative myocardial ischemic injury in high-risk surgery patients.


METHODS
Randomized double-blind placebo-controlled multidose trial.


METHODS
Multicenter worldwide (105 centers) trial.


METHODS
Patients with known or multiple risk factors for coronary artery disease undergoing noncardiac vascular surgery.


METHODS
Four parallel groups received 1 of 3 doses of zoniporide or placebo, delivered as a 60-minute loading dose immediately before surgery, and followed by a continuous intravenous infusion for up to 7 days.


RESULTS
A total of 824 subjects were randomized into the study from 105 centers worldwide. Of these, 784 subjects received study drug infusion in the 3-mg/kg/d, 6-mg/kg/d, and 12-mg/kg/d groups and the placebo group, and 769 satisfied the criteria for the primary efficacy analysis population. This is 68% of the planned sample size of 1125 subjects. Anesthetic management and perioperative cardiac medications were at the discretion of the attending anesthesiologists, surgeons, and cardiologists. The proportion of subjects who experienced the composite endpoint event (death, myocardial infarction, congestive heart failure, arrhythmia) by postsurgical day 30 was 18.5% in the 12-mg/kg/d group, compared with 15.7% in the placebo group, resulting in a relative risk (RR) of 1.17% (95% confidence interval [CI], 0.80-1.72; p = NS) favoring placebo. The proportions in the lower 2 zoniporide dose groups were slightly lower than in the placebo group, although the sample size is inadequate to reach any firm conclusions.


CONCLUSIONS
The results fail to demonstrate the efficacy of zoniporide in reducing the proportion of patients at high risk undergoing noncardiac vascular surgery who experience a composite cardiovascular endpoint, which led the corporate sponsor to stop enrollment early on the basis of a futility analysis of the chance of demonstrating efficacy with a larger sample size.
Fleisher
Lee A
LA
Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA 19104, USA. fleishel@uphs.upenn.edu
Newman
Mark F
MF
St Aubin
Lisa B
LB
Cropp
Anne B
AB
Billing
C Bill
CB
Bonney
Sharon
S
Mackey
William C
WC
Poldermans
Don
D
Corbalan
Roman
R
Pereira
Adamastor H
AH
Coriat
Pierre
P
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001145:Arrhythmias, Cardiac / Q000517:prevention & control; D001208:Asia; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005060:Europe; D005260:Female; D006146:Guanidines / Q000627:therapeutic use*; D006333:Heart Failure / Q000517:prevention & control; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000517:prevention & control*; D019990:Perioperative Care; D011183:Postoperative Complications / Q000145:classification / Q000517:prevention & control; D011720:Pyrazoles / Q000627:therapeutic use*; D012307:Risk Factors; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013020:South America; D016896:Treatment Outcome; D014481:United States; D014656:Vascular Surgical Procedures
D006146:Guanidines; D011720:Pyrazoles; D017923:Sodium-Hydrogen Exchangers; C424422:zoniporide