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Accepted for publication October 15, 2007.
* Address correspondence to Dr Mentzer, Wayne State University School of Medicine, 540 East Canfield, 1241 Scott Hall, Detroit, MI 48201 (Email: rmentzer{at}med.wayne.edu).
| Drs Mentzer, Chaitman, Menasché, and Nicolau disclose that they have a financial relationship with Sanofi-Aventis, Inc.
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Abstract |
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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.
The EXPEDITION (for Na+/H+ Exchange inhibition to Prevent coronary Events in acute cardiac condition) study addressed the efficacy and safety of inhibiting the sodium hydrogen exchanger (NHE) by cariporide in the prevention of death or nonfatal myocardial infarction (MI) in patients undergoing coronary artery bypass grafting (CABG). The premise was that inhibition of the NHE-1 isoform (NHE-1) limits intracellular Na accumulation and thereby limits Na/Ca exchanger mediated calcium overload to reduce infarct size.
With more than 1 million interventions per year worldwide, CABG is one of the most common surgical procedures performed today [1]. The benefits of CABG are partially offset by periprocedural ischemic events manifesting themselves as myocardial stunning or myocardial necrosis and can result in significant morbidity and mortality [2, 3]. Inadequate myocardial protection and ischemia/reperfusion injury remain major problems after CABG. Despite intensive research toward the development of more effective agents, a specific drug that unequivocally reduces the incidence or magnitude of perioperative myocardial necrosis after CABG is lacking [4]. Although many have been proposed, drugs that activate the sodium-proton exchange systems have received considerable attention.
Cariporide, a NHE-1 inhibitor, has been shown experimentally to reduce intracellular calcium overload and prevent myocardial injury associated with ischemia/reperfusion (provide reference or clarification). Ischemia/reperfusion has been shown to increase intracellcular Na concentration. This occurs in part as a result of increased Na entry through NHE-1. The increase in intracellular Na concentration contributes to a reversal of the driving force for the sodium-calcium exchanger to increase net entry of Ca through the sodium-calcium exchanger and thereby increase cytosolic calcium concentration, leading to intracellular calcium overload [5, 6]. These results served as the rationale for the GUARDIAN trail, a study performed to evaluate the efficacy of cariporide in reducing myocardial injury in patients with unstable angina and those undergoing either percutaneous coronary intervention or CABG [7]. Although it failed to meet the study endpoint, this trial did suggest the drug was safe and cardioprotective in patients undergoing CABG. The EXPEDITION trial was conducted to confirm whether treatment with cariporide could reduce the incidence of death or nonfatal MI in patients undergoing CABG.
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Material and Methods |
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The clinical study protocol and informed consent documents were reviewed and approved by the Institutional Review Board at each study center. Signed informed consent was obtained from each study participant before enrollment. The study was conducted in accordance with good clinical practice as indicated in the Declaration of Helsinki [8].
Treatment Regimen
On enrollment, central telephone randomization (ClinPhone, Princeton, New Jersey) was used to assign patients to receive either cariporide or matching placebo in a double-blind fashion. The study medication was given as a continuous intravenous infusion for a total of 49 hours, beginning 2 hours before induction of anesthesia. A 1-hour loading infusion of placebo or 180 mg cariporide was followed by a maintenance infusion over 48 hours (placebo or 40 mg/h cariporide for the first 24 hours and placebo or 20 mg/h cariporide for the second 24 hours; subjects weighing < 50 kg received placebo or 20 mg/h cariporide over the entire 48-hour period).
Study Endpoints
The primary objective of the study was to demonstrate that cariporide reduces the composite endpoint of all-cause mortality or nonfatal MI by day 5, day 30, and month 6. The safety and tolerability of cariporide was assessed descriptively by frequency of adverse events (AE), changes in laboratory variables and postsurgical functional recovery.
Study Procedures
Upon enrollment, a complete physical examination, 12-lead electrocardiogram, standard laboratory assessment, and total creatine kinase–myocardial band (CK-MB) isoenzyme measurements were performed. During the treatment and follow-up phase, electrocardiograms were performed 24, 48, and 72 hours after surgery and also on day 5, day 30, and month 6 follow-up visits. Serial serum CK-MB values were obtained 4, 8, 12, 18, 24, 36, and 48 hours after intensive care unit arrival and whenever an ischemic event was suspected. The diagnosis of Q-wave MI was determined by electrocardiogram criteria of a two-step Q-wave change as defined by the Minnesota code with the Nova-code adjustment [9]. In the absence of a new Q wave, CK-MB elevation more than tenfold the upper limits of normal (ULN) range of the investigator’s local laboratory within 24 hours of CABG was considered indicative of a non–Q-wave MI. If MI was suspected more than 24 hours after CABG, a CK-MB elevation greater than two times the ULN with chest pain or an elevation greater than three times ULN was considered indicative of MI. In addition, CK-MB values and electrocardiograms from all patients were screened for the presence of previously unreported "database-identified MI."
Statistical Procedures
Efficacy analyses were performed on all randomly allocated patients. Safety analyses were performed on all patients who received any amount of cariporide. An unadjusted 
2 statistic was used for the primary efficacy analysis. The secondary endpoint analysis used survival analysis methodology (Gehan-Wilcoxon test and Kaplan-Meier curves). Descriptive analyses are provided and p values given where appropriate. The planned sample size of 7,000 assumed a 12% primary event rate at day 5 for the placebo group and a 20% relative risk reduction in the cariporide treatment arm, a two-sided type 1 error rate of 5%, and power approximately 90%. The protocol specified rules for the conduct of the interim analyses by the Data Safety Management Board to allow stopping the study early for overwhelming evidence of efficacy or for futility [10, 11]. Rules for early termination for efficacy required a nominal significance level of 0.00001 with demonstration of reduction in risk for both components of the primary endpoint (death or nonfatal MI by day 5). The Data Safety Management Board also assessed the overall safety profile to determine study continuation, modification, or termination based on evidence that cariporide conveyed undue risk.
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Results |
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Baseline Demographics
Baseline characteristics were well balanced between the two groups (Table 1). Eighty percent of patient procedures were considered elective CABG, 11% elective repeat surgery, and 9% urgent CABG. Compliance with study drug administration was high and also balanced between the treatment groups. Main reasons for premature discontinuations were technical reasons (3% in both arms). Early death or termination due to renal insufficiency accounted for termination in less than 1% of subjects in either group. Adverse events (AEs) resulted in premature termination in 0.9% versus 1.2% of subjects in the placebo and cariporide group, respectively (p = 0.32).
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Regarding the effect on MI, a reduction in both Q-wave MI (RRR = 23.5%; p = 0.013) and non–Q-wave MI (RRR = 20.6%; p = 0.002) was observed (Table 3). It is noteworthy that in this population at increased risk of myocardial injury, the incidence of Q-wave MI at day 5 in the placebo group was quite high, 6.5%. As a measure of the extent of the infarction, the peak CK-MB ratio was assessed in prespecified categories and confirmed a smaller extent of injury in cariporide-treated patients (p = 0.027). Patients in the cariporide group had a higher incidence of no or minor myocardial injury (CK-MB 
ULN, or as high as five times ULN, respectively), and fewer large infarcts. Patients with cardiovascular death were captured as a separate group in the analysis and demonstrated the imbalance against the cariporide group already noted for the overall population.
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An analysis of focal persistent CVE occurring during the observation period was reviewed by a blinded panel of neurologic and cardiac surgery experts (Table 5). Nearly all of these CVEs were of an ischemic nature. A higher frequency of embolic strokes occurred in the cariporide group (41 versus 21 events). However, in about half of the cases, a pathoanatomical classification was not possible owing to limited information.
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In total, there were 152 deaths reported in the placebo group and 185 in the cariporide group (Table 6). All deaths were reported on a "death" endpoint form and were centrally adjudicated by the Endpoint Validation Committee. Additionally, any death possibly related to the study treatment was documented as a SAE. The central classification by the Endpoint Validation Committee demonstrated that the imbalance in the death in the cariporide group appeared to be mainly due to an increase in "noncardiovascular death" (1.7% in the placebo versus 2.3% in the cariporide). The most common primary cause of death was cardiac. Deaths due to ischemic, arrhythmic, and pump failures were slightly higher in the cariporide group. Shock, sepsis, or multiorgan failures were overall infrequent, yet observed twice as often in the cariporide-treated group (14 versus 28 deaths). Other causes of death were rare and equally distributed among both treatment groups. This analysis included deaths that occurred after the 6-month observation periods; thus, the number of events cannot be directly compared with those given at 6 months.
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Comment |
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The results of EXPEDITION revealed (1) compelling evidence that the incidence of intraoperative myocardial necrosis in patients undergoing CABG occurs more frequently than previously appreciated; (2) a reduction in the primary endpoint of all-cause death or nonfatal MI was achieved with cariporide; and (3) the reduction in the primary endpoint was due almost exclusively to a reduction in nonfatal MI; however, this benefit was offset by a higher incidence of CVEs ad mortality in patients receiving cariporide.
The finding that incidence of myocardial necrosis after CABG is greater than generally appreciated may be due in part to the lack of consensus regarding the definition of a postoperative MI and the assumption that it is not necessary to perform routine postoperative CK-MB measurements as modest elevations are not associated with increased mortality rates. Clearly, myocardial damage associated with heart surgery can be induced by different mechanisms. With respect to CK-MB levels, there have been different thresholds for identifying MI after CABG [14]. By utilizing these definitions or modifications, the findings in EXPEDITION are consistent with observations that incidence of any MI after CABG ranged between 12% and 19% [7, 15, 16].
The observation that CK-MB release after CABG is greater than generally accepted is particularly important because there is increasing evidence the CK-MB release exceeding 10 times ULN is associated with reduced survival over time. Thus, there is considerable evidence that even mild to moderate elevations of CK-MB release levels after CABG are associated with decreased survival over time [17–19]. Based on these findings, one might expect that the reduction in the incidence and magnitude of MI observed with cariporide treatment in EXPEDITION would have resulted in an improvement in the 6-month survival. Possibly, the 6-month follow-up was too short to appreciate fully the impact of varying degrees of myocardial necrosis on mortality.
There is a large body of experimental and clinical evidence that NHE inhibition can be cerebroprotective [20–29]. The challenge is to reconcile these studies with the findings in EXPEDITION. Because NHE-1 inhibition may limit cells ability to regulate intracellular pH in response to acidification, the timing and duration of administration of NHE inhibitors such as cariporide may be critical. It is well known that severe acidosis is associated with worsening of cerebral infarction whereas milder acidosis can be protective. Conversely, the absence of acidosis may exaggerate mechanisms of ischemic injury [22]. The timing and duration of administration of certain NHE inhibitors such as cariporide may be critical. Alternatively, it may be that the CVEs observed in EXPEDITION were unique to the specific molecular structure of cariporide and are not characteristic of NHE-1 inhibitors in general.
The increase in thromboembolic strokes with cariporide could indicate that the agent has a procoagulant effect. That seems unlikely because NHE-1 contributes to the platelet activation process through coupling with calcium influx after stimulation of platelets by various agonists, and inhibition of platelet NHE-1 can inhibit platelet aggregation [30, 31]. Possibly, an abrupt withdrawal of cariporide could lead to a rebound effect and result in rapid activation of the exchanger and platelet hyperactivity. Alternatively, prolonged NHE-1 blockade in the brain could result in NHE-1 upregulation. In this setting, cessation of cariporide administration could result in the brain being more susceptible to ischemic injury [32].
The variability in the literature regarding the stroke rate after CABG is due partly to reliance on registry data, definition of serious CVE, and coexisting risk factors such as renal insufficiency, recent MI, carotid artery disease, hypertension, diabetes mellitus, age greater than 75 years, severe left ventricular dysfunction, low cardiac output, and atrial fibrillation [26, 27, 32]. For these reasons, it is important that any clinical study that evaluates the risk of stroke after an intervention demonstrate that (1) the patient population under investigation has the same risk profiles; (2) the study is adequately powered and conducted in a double-blind, randomized fashion; and (3) the neurologic outcomes are evaluated in the context of both the degree of disability and death. Because EXPEDITION met these criteria, it was able to detect the small neurologic consequences of the cariporide treatment.
On the basis of EXPEDITION, it is unlikely that cariporide will be used clinically because the treatment was associated with an unanticipated higher mortality rate and incidence of CVEs. However, the importance of this study should not be underestimated; EXPEDITION clearly demonstrated that the incidence of myocardial necrosis after CABG is high and targeted pharmacologic interventions can be effective in reducing MI. In this regard, the use of NHE inhibitors could lead to significant improvement in medium- and long-term survival among patients undergoing heart surgery as well as those at risk of MI at any time. The challenge becomes to elucidate the mechanisms underlying the neurologic toxic effects associated with cariporide and to ascertain whether the phenomenon is unique to cariporide or NHE inhibition in general. The next step will be to pharmacologically dissociate the central nervous system adverse event of cariporide from its demonstrated cardioprotective properties or develop an NHE-1 inhibitor that does not exhibit neurotoxicity.
In summary, EXPEDITION demonstrated that pharmacologically induced myocardial protection designed to reduce the incidence of myocardial necrosis after CABG is feasible and that this class of agents holds considerable promise in the quest to identify a drug treatment that will reduce the overall incidence of myocardial necrosis in patients at risk of ischemia/reperfusion injury.
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Appendix |
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Gabriel Aldea, MD (Seattle, WA), Keith Allen, MD (Indianapolis, IN), G. Hossein Almassi, MD (Milwaukee, WI), Ezra Amsterdam, MD (Sacramento, CA), H. V. Anderson, MD (Houston, TX), Jerome Anderson, MD (Oklahoma City, OK), Lon Annest, MD (Tacoma, WA), John M. Armitage, MD (Fredericksburg, VA), Alan J. Bank, MD (St. Paul, MN), Yvon Baribeau, MD (Manchester, NJ), Claus Bartels, MD (Lubeck, Germany), Joseph E. Bavaria (Philadelphia, PA), Howard Berlin, MD (Hollywood, FL), Marc Bloom, MD (Tampa, FL), Steven Boiling, MD (Ann Arbor, MI), Roberto Bolli, MD (Louisville, KY), Morton Bolman, MD (Minneapolis, MN), Steven Boyce, MD (Washington, DC), John Braxton, MD (Portland, ME), Gerald Buckberg, MD (Los Angeles, CA), Paul Burns, MD (Baltimore, MD), Robert G. Carlson, MD (Sarasota, FL), John C. Chen, MD (Honolulu, HI), Eric Chi, MD (Bridgewater, NJ), David Churchill, MD (Fayetteville, AR), Barry Clemson, MD (Peoria, IL), Arthur Coffey, MD (Indianapolis, IN), Lawrence Creswell, MD (St. Louis, MO), Ronald Curran, MD (Evanston, IL), Doug Dawley, MD (Portland, OR), Thomas Deal, MD (Clearwater, FL), Hanumant Deshmukh, MD (Chicago, IL), Todd Dewey, MD (Dallas, TX), Louis Dibos, MD (Baltimore, MD), Verdi J. DiSesa, MD (Chicago, IL), Fred Edwards, MD (Jacksonville, FL), Richard M. Engelman, MD (Springfield, MA), Marc J. Enjalbert, MD (Quebec, Ontario), Vic Ferraris, MD (Lexington, KY), John Fetter, MD (Duluth, MN), David Fullerton, MD (Chicago, IL), Deepak Gangahar, MD (Lincoln, NE), Jose Garcia, MD (Philadelphia, PA), H. Edward Garrett, Jr, MD (Memphis, TN), Alexander S. Geha, MD (Chicago, IL), Joel Gellmann, MD (Baltimore, MD), Jeffrey P. Gold, MD (Bronx, NY), Bruce S. Goldenberg, MD (Passaic, NJ), Steven Goldman, MD (Tuscon, AZ), Frederick Grover, MD (Denver, CO), John W. Hammon, MD (Winston Salem, NC), Prof Axel Haverich (Hannover, Germany), Robert Hebeler, MD (Dallas, TX), William L. Higgs, MD (Mobile, AL), William L. Holman, MD (Birmingham, AL), Peter Horneffer, MD (Baltimore, MD), Richard Hui, MD (Belleville, IL), Valluvan Jeevanandam, MD (Chicago, IL), Andreas Jessel, MD (Bridgewater, NJ), G. Kimble Jett, MD (Towson, MD), Alan M. Johnson, MD (Asheville, NC), Robert G. Johnson, MD (St. Louis, MO), Scott Johnson, MD (San Antonio, TX), Kushagara Katariya, MD (Miami, FL), David Kawanishi, MD (Mission Viejo, CA), Dean J. Kereiakes, MD (Cincinnati, OH), Siavosh Khonsari, MD (Los Angeles, CA), Shukri F. Khuri, MD (West Roxbury, MA), Michael King, MD (Minneapolis, MN), John Knight, MD (Bedford Park, Australia), Jeffrey Kramer, MD (Haddon Heights, NJ), Karl H, Krieger, MD (New York, NY), Irving Kron, MD (Charlottesville, VA), John Laschinger, MD (Towson, MD), Omar Lattouf, MD (Atlanta, GA), Kenneth Lehmann, MD (Seattle, WA), John Lemmer, MD (Portland, OR), George Litman, MD (Akron, OH), Marc R. Litt, MD (Jacksonville, FL), Mario Lopez, MD (Port Charlotte, FL), James E. Lowe, MD (Durham, NC), John Luber, MD (Tacoma, WA), Gary Luckasen, MD (Bryn Mawr, PA), Prof Philippe Menasche (Paris, France), Robert Michler, MD (Columbus, OH), Thomas Militano, MD (Tacoma Park, MD), Jeffrey Milliken, MD (Orange, CA), Marc Moon, MD (St. Louis, MO), James Morris, MD (Charleston, SC), Gregory Muehlebach, MD (Kansas City, MO), Mary Lee Myers, MD (London, Ontario), Donald E. Netherland, MD (Pensacola, FL), Imran Niazi, MD (Milwaukee, WI), Prof Jose Nicolau (Sao Paulo, Brazil), Nancy Nussmeier, MD (Houston, TX), Grant Van S. Parr, MD (Morristown, NJ), William F. Penny, MD (San Diego, CA), Ganga Prabhaker, MD (Morgantown, WV), Michael Reardon, MD (Houston, TX), Todd Rosengart, MD (Evanston, IL), Eli M. Rath, MD (Cincinnati, OH), Sibu Saha, MD (Lexington, KY), Jorge F. Saucede, MD (Little Rock, AR), Hartzell Schaff, MD (Rochester, MN), Peter M. Scholz, MD (New Brunswick, NJ), Nanette Schwann, MD (Philadelphia, PA), Steven Sedlis, MD (New York, NY), Frank Selike, MD (Boston, MA), Norman Silverman, MD (Detroit, MI), Prof Maarten Simoons (Rotterdam, Netherlands), David Snowden, MD (Fort Wayne, IN), William Spotnitz/Garcia, MD (Philadelphia, PA), Vaughn Starnes, MD (Los Angeles, CA), Christopher D. Stone, MD (Kenosha, WI), Cary Stowe, MD (Orlando, FL), John M. Streitz, MD (Duluth, MN), James Stringham, MD (Salt Lake City, UT), Valavanur Subramanian, MD (New York, NY), Szabolos Szenpetery, MD (Norfolk, VA), Stephen A. Tahta, MD (Missoula, MT), Lars Thulin, MD (Lund, Sweden), James C. Todd, MD (Salisbury, MD), Melwin Tonkon, MD (Santa Ana, CA), Kevin Tveter, MD (Grand Forks, ND), Cliff Van Meter, MD (New Orleans, LA), Arthur Wallace, MD (San Francisco, CA), Raymond Waters, MD (Hudson, FL), Prof Richard Weisel (Toronto, Ontario),Graham Wetherly, MD (Boise, ID), Theodore Wingard, MD (Jacksonville, FL), Neal Worrall, MD (Spokane, WA), Lawence Yellen, MD (San Diego, CA), and Robert Zeff, MD (Des Moines, IA).
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