• Lee A Fleisher, Mark F Newman, Lisa B St Aubin, Anne B Cropp, C Bill Billing, Sharon Bonney, William C Mackey, Don Poldermans, Roman Corbalan, Adamastor H Pereira, Pierre Coriat, and Perioperative Myocardial Ischemic Injury Investigators.
• Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA 19104, USA. fleishel@uphs.upenn.edu
• J. Cardiothorac. Vasc. Anesth. 2005 Oct 1;19(5):570-6.

ObjectivesTo determine whether a novel Na+/H+ exchange ion inhibitor, zoniporide, is associated with reduced perioperative myocardial ischemic injury in high-risk surgery patients.DesignRandomized double-blind placebo-controlled multidose trial.SettingMulticenter worldwide (105 centers) trial.ParticipantsPatients with known or multiple risk factors for coronary artery disease undergoing noncardiac vascular surgery.InterventionsFour 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.Measurements And Main ResultsA 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.ConclusionsThe 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.

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