Inhibition of the Sodium-Hydrogen Exchanger With Cariporide to Prevent Myocardial Infarction in High-Risk Ischemic Situations

Abstract

Background-The transmembrane sodium/hydrogen exchanger maintains myocardial cell pH integrity during myocardial ischemia but paradoxically may precipitate cell necrosis. The development of cariporide, a potent and specific inhibitor of the exchanger, prompted this investigation of the potential of the drug to prevent myocardial cell necrosis. Methods and Results-A total of 11 590 patients with unstable angina or non-ST-elevation myocardial infarction (MI) or undergoing high-risk percutaneous or surgical revascularization were randomized to receive placebo or 1 of 3 doses of cariporide for the period of risk. The trial failed to document benefit of cariporide over placebo on the primary end point of death or MI assessed after 36 days. Doses of 20 and 80 mg every 8 hours had no effect, whereas a dose of 120 mg was associated with a 10% risk reduction (98% CI 5.5% to 23.4%, Pϭ0.12). With this dose, benefit was limited to patients undergoing bypass surgery (risk reduction 25%, 95% CI 3.1% to 41.5%, Pϭ0.03) and was maintained after 6 months. No effect was seen on mortality. The rate of Q-wave MI was reduced by 32% across all entry diagnostic groups (2.6% versus 1.8%, Pϭ0.03), but the rate of non-Q-wave MI was reduced only in patients undergoing surgery (7.1% versus 3.8%, Pϭ0.005). There were no increases in clinically serious adverse events. Conclusions-No significant benefit of cariporide could be demonstrated across a wide range of clinical situations of risk.The trial documented safety of the drug and suggested that a high degree of inhibition of the exchanger could prevent cell necrosis in settings of ischemia-reperfusion. (Circulation. 2000;102:3032-3038.)

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

“…Clinical trials in humans, however, have not found a benefit to NHE1 inhibition. The GUARDIAN trial did not show an overall benefit for NHE1 inhibition by cariporide in acute coronary syndromes, a small benefit was only observed in the subgroup of patients that underwent high risk coronary artery bypass surgery [21,164].…”

Interfering with pH regulation in tumours as a therapeutic strategy

“…However, owing to the diffuse presence of NHE1 in many tissues and its fundamental role in crucial physiological processes, there is a potential risk of life-threatening side effects associated with this class of agents. In fact, Sanofi has stopped the clinical development of cariporide owing to the unexpected incidence of stroke in a large Phase III clinical trial 85 . To exploit the benefits of NHE1 inhibition in the treatment of cancer, it would be crucial to develop agents that selectively target NHE1 in tumours and do not target the enzyme in healthy tissues.…”

Mice With a Null Mutation in the NHE1 Na + -H + Exchanger Are Resistant to Cardiac Ischemia-Reperfusion Injury

“…36 -38 In the present study, we used a combined genetic and pharmacological approach to assess the hypothesis that blocking the activity of NHE1 protects against cardiac I/R injury. Given the use of NHE1 inhibitors in clinical trials for a number of cardiovascular diseases, 39 it is important to determine, by some means other than pharmacological inhibition, that ablation of NHE1 activity is cardioprotective. To accomplish this, we performed ischemia-reperfusion studies of the isolated perfused heart using a mouse model in which the Nhe1 gene (gene locus symbol Slc9a1) was disrupted.…”