Document Detail


Sodium-hydrogen exchange inhibition by cariporide to reduce the risk of ischemic cardiac events in patients undergoing coronary artery bypass grafting: results of the EXPEDITION study.
MedLine Citation:
PMID:  18355507     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: The EXPEDITION study addressed the efficacy and safety of inhibiting the sodium hydrogen exchanger isoform-1 (NHE-1) by cariporide in the prevention of death or myocardial infarction (MI) in patients undergoing coronary artery bypass graft surgery. The premise was that inhibition of NHE-1 limits intracellcular Na accumulation and thereby limits Na/Ca-exchanger-mediated calcium overload to reduce infarct size. METHODS: High-risk coronary artery bypass graft surgery patients (n = 5,761) were randomly allocated to receive either intravenous cariporide (180 mg in a 1-hour preoperative loading dose, then 40 mg per hour over 24 hours and 20 mg per hour over the subsequent 24 hours) or placebo. The primary composite endpoint of death or MI was assessed at 5 days, and patients were followed for as long as 6 months. RESULTS: At 5 days, the incidence of death or MI was reduced from 20.3% in the placebo group to 16.6% in the treatment group (p = 0.0002). Paradoxically, MI alone declined from 18.9% in the placebo group to 14.4% in the treatment group (p = 0.000005), while mortality alone increased from 1.5% in the placebo group to 2.2% with cariporide (p = 0.02). The increase in mortality was associated with an increase in cerebrovascular events. Unlike the salutary effects that were maintained at 6 months, the difference in mortality at 6 months was not significant. CONCLUSIONS: The EXPEDITION study is the first phase III myocardial protection trial in which the primary endpoint was achieved and proof of concept demonstrated. As a result of increased mortality associated with an increase in cerebrovascular events, it is unlikely that cariporide will be used clinically. The findings suggest that sodium hydrogen exchanger isoform-1 inhibition holds promise for a new class of drugs that could significantly reduce myocardial injury associated with ischemia-reperfusion injury.
Authors:
Robert M Mentzer; Claus Bartels; Roberto Bolli; Steven Boyce; Gerald D Buckberg; Bernard Chaitman; Axel Haverich; John Knight; Philippe Menasché; M Lee Myers; Jose Nicolau; Maarten Simoons; Lars Thulin; Richard D Weisel;
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Publication Detail:
Type:  Journal Article; Multicenter Study; Randomized Controlled Trial    
Journal Detail:
Title:  The Annals of thoracic surgery     Volume:  85     ISSN:  1552-6259     ISO Abbreviation:  Ann. Thorac. Surg.     Publication Date:  2008 Apr 
Date Detail:
Created Date:  2008-03-21     Completed Date:  2008-04-16     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  15030100R     Medline TA:  Ann Thorac Surg     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  1261-70     Citation Subset:  AIM; IM    
Affiliation:
Wayne State University School of Medicine, 540 East Canfield, 1241 Scott Hall, Detroit, MI 48201, USA. rmentzer@med.wayne.edu
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Confidence Intervals
Coronary Angiography
Coronary Artery Bypass / methods,  mortality*
Coronary Disease / mortality,  radiography,  surgery*
Dose-Response Relationship, Drug
Double-Blind Method
Drug Administration Schedule
Female
Follow-Up Studies
Guanidines / administration & dosage*
Hospital Mortality / trends
Humans
Infusions, Intravenous
Male
Middle Aged
Myocardial Ischemia / prevention & control*
Postoperative Complications / prevention & control
Preoperative Care / methods
Probability
Reference Values
Risk Assessment
Severity of Illness Index
Sodium-Hydrogen Antiporter / drug effects*,  metabolism
Sulfones / administration & dosage*
Survival Analysis
Treatment Outcome
Chemical
Reg. No./Substance:
0/Guanidines; 0/Sodium-Hydrogen Antiporter; 0/Sulfones; 0/cariporide
Investigator
Investigator/Affiliation:
Gabriel Aldea / ; Keith Allen / ; G Hossein Almassi / ; Ezra Amsterdam / ; H V Anderson / ; Jerome Anderson / ; Lon Annest / ; John M Armitage / ; Alan J Bank / ; Yvon Baribeau / ; Joseph E Bavaria / ; Howard Berlin / ; Marc Bloom / ; Steven Boiling / ; Morton Bolman / ; John Braxton / ; Paul Burns / ; Robert G Carlson / ; John C Chen / ; Eric Chi / ; David Churchill / ; Barry Clemson / ; Arthur Coffey / ; Lawrence Creswell / ; Ronald Curran / ; Doug Dawley / ; Thomas Deal / ; Hanumant Deshmukh / ; Todd Dewey / ; Louis Dibos / ; Verdi J DiSesa / ; Fred Edwards / ; Richard M Engelman / ; Marc J Enjalbert / ; Vic Ferraris / ; John Fetter / ; David Fullerton / ; Deepak Gangahar / ; Jose Garcia / ; H Edward Garrett / ; Alexander S Geha / ; Joel Gellmann / ; Jeffrey P Gold / ; Bruce S Goldenberg / ; Steven Goldman / ; Frederick Grover / ; John W Hammon / ; Robert Hebeler / ; William L Higgs / ; William L Holman / ; Peter Horneffer / ; Richard Hui / ; Valluvan Jeevanandam / ; Andreas Jessel / ; G Kimble Jett / ; Alan M Johnson / ; Robert G Johnson / ; Scott Johnson / ; Kushagara Katariya / ; David Kawanishi / ; Dean J Kereiakes / ; Siavosh Khonsari / ; Shukri F Khuri / ; Michael King / ; Jeffrey Kramer / ; Karl H Krieger / ; Irving Kron / ; John Laschinger / ; Omar Lattouf / ; Kenneth Lehmann / ; John Lemmer / ; George Litman / ; Marc R Litt / ; Mario Lopez / ; James E Lowe / ; John Luber / ; Gary Luckasen / ; Robert Michler / ; Thomas Militano / ; Jeffrey Milliken / ; Marc Moon / ; James Morris / ; Gregory Muehlebach / ; Donald E Netherland / ; Imran Niazi / ; Nancy Nussmeier / ; Grant Van S Parr / ; William F Penny / ; Ganga Prabhaker / ; Michael Reardon / ; Todd Rosengart / ; Eli M Rath / ; Sibu Saha / ; Jorge F Saucede / ; Hartzell Schaff / ; Peter M Scholz / ; Nanette Schwann / ; Steven Sedlis / ; Frank Selike / ; Norman Silverman / ; David Snowden / ; William Spotnitz Garcia / ; Vaughn Starnes / ; Christopher D Stone / ; Cary Stowe / ; John M Streitz / ; James Stringham / ; Valavanur Subramanian / ; Szabolos Szenpetery / ; Stephen A Tahta / ; James C Todd / ; Melwin Tonkon / ; Kevin Tveter / ; Cliff Van Meter / ; Arthur Wallace / ; Raymond Waters / ; Graham Wetherly / ; Theodore Wingard / ; Neal Worrall / ; Lawence Yellen / ; Robert Zeff /

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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