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Newsletter
Inhibition of Na/H Exchange in Patients Undergoing Coronary Artery Bypass GraftingHong Liu, MD
Sodium-hydrogen exchange (NHE) is one of the principal mechanisms of regulating intracellular pH (pHi) during myocardial ischemia and reperfusion.4, 6 Seven NHE isoforms have been identified. NHE1 is located in the myocardial cell membrane. During ischemia, anaerobic metabolism produces large amounts of intracellular hydrogen ions (H) which activate the NHE1 in the cell membrane to regulate the pHi. In this buffering process, the cell imports one Na for each H excreted with a consequent increase in intracellular Na (Nai). When Nai increased to 2-3 times the normal concentration, it will stop and/or reverse the Na/Ca exchange (NCX), another cell membrane protein that normally extrudes Ca to maintain intracellular Ca (Cai) homeostasis. This process exchanges 3 Na for 1 Ca and causes significant increase in Cai and this overload of Cai is believed to be detrimental to the ischemic myocardium.1,6 NHE1 inhibitors have been developed and evaluated in order to break this unfavorable cascade leading to acute myocardial injury. A series of compounds ranging from the amiloride, a K-sparing diuretic and nonspecific NHE inhibitor to cariporide, a more specific NHE1inhibitor, have been tested in laboratory research and clinical trials.5,8 The laboratory studies have consistently suggested that NHE1 inhibition can be a successful myocardial protection method in different animal models and age groups.2,3,4,6,7 However, the clinical trials have not been as successful 9. The GUARDIAN (Guard During Ischemia Against Necrosis) trial was the first clinical trial designed to evaluate the efficacy and safety of the NHE inhibitor cariporide in patients at acute risk for myocardial necrosis.9 The primary objectives were to determine whether cariporide reduces the combined incidence of all-cause mortality and MI at 36 days and to assess the drug's safety and tolerability. Subjects who had unstable angina or a non-Q-wave MI and were scheduled to undergo high-risk percutaneous transluminal coronary angioplasty or CABG were randomized to receive placebo or one of three doses of cariporide: 20, 80, or 120 mg. Although the results of this trial failed to demonstrate an overall clinical benefit, there was a significant reduction in the primary end point from 16.7% to 12.8% in the bypass surgery subgroup. Further, analysis of the relationship between cariporide plasma levels and efficacy demonstrated a steep reduction in the risks of death and MI when the drug reached a threshold concentration of 550 ng/mL. Notably, 67% of subjects who received the 120 mg dose of cariporide (compared to 20% and 0% of subjects in the 80 and 20 mg groups, respectively) achieved this concentration, suggesting that the efficacy of cariporide could be improved by higher doses or a modified dosing schedule. Because cariporide was administered before global ischemia and during subsequent reperfusion in the CABG subgroup of this trial, the GUARDIAN investigators suggested that further studies of cariporide be performed in the ischemia-reperfusion situation typified by CABG with doses of 120 mg.9 Consistent with this suggestion, EXPEDITION (sodium-hydrogen EXchange inhibition to Prevent coronary Events in acute cardiac conditions), a follow up clinical trial was initiated. The EXPEDITION trial is a double-blind, placebo-controlled, parallel-group, phase III study of intravenous cariporide in the CABG population. The primary objective is to determine the effect of cariporide on the combined incidence of all-cause mortality and nonfatal MI by day five after CABG in subjects at increased risk for myocardial necrosis. The secondary objective is to determine whether any effect of cariporide on the composite endpoint of all-cause mortality and nonfatal MI by day 5 is maintained until day 30. Tertiary objectives are to evaluate the drug effects on composite clinical outcomes including all-cause mortality and nonfatal MI between 49 hours after the start of study medication and six months, the incidence of cardiovascular death, nonfatal MI, and low-cardiac-output syndrome i.e events related to LV dysfunction at within six months, infarct size assessed by creatine kinase-MB (CK-MB), and the immediate post-surgical functional recovery (postoperative status, time to extubation, length of intensive care unit stay, length of hospital stay). The safety and tolerability of cariporide will also be evaluated by the frequency of adverse events and changes in blood pressure, heart rate, 12-lead electrocardiogram (ECG), and laboratory parameters (clinical chemistry, hematology). In summary, preclinical studies have suggested that NHE inhibition is most effective when applied before or shortly after the onset of ischemia. Thus, patients undergoing CABG, in whom the timing of the occlusion is known and pretreatment is possible, present as a patient population that could be expected to benefit most readily from NHE inhibition. Reference:
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