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CLINICAL STUDY

The Na⁺/H⁺ exchange inhibitor eniporide as an adjunct to early reperfusion therapy for acute myocardial infarction¹

Results of the evaluation of the safety and cardioprotective effects of eniporide in acute myocardial infarction (ESCAMI) trial

Uwe Zeymer, MD^*,*, Harry Suryapranata, MD, Jean Pierre Monassier, MD, Grzegorz Opolski, MD, John Davies, MD^||, Gundars Rasmanis, MD^¶, Gerard Linssen, MD^#, Ulrich Tebbe, MD^**, Rolf Schröder, MD, FACC, Rolf Tiemann, Thomas Machnig, MD, Karl-Ludwig Neuhaus, MD^* for the ESCAMI Investigators

^* Medizinische Klinik II, Klinikum Kassel, Kassel, Germany
Ziekenhuis De Weezenlande, Zwolle, The Netherlands
Hopital Emile Muller, Mulhouse, France
Department and Clinic of Cardiology of the Medical Academy in Warsaw, Warszawa, Poland
^|| Royal Gwent Hospital, Gwent, United Kingdom
^¶ Huddinge Hospital, Huddinge, Sweden
^# Twenteborg Ziekenhues, Amelo, The Netherlands
^** Klinikum Lippe-Detmold, Detmold, Germany
Universitätsklinikum Benjamin Franklin, Berlin, Germany
Merck KGaA, Darmstadt, Germany

Manuscript received February 15, 2001; revised manuscript received July 18, 2001, accepted August 15, 2001.

^* Address for correspondence: Dr. Uwe Zeymer, Klinikum Kassel, Medizinische Klinik II, Mönchebergstrasse 41-43, D-34125 Kassel, Germany
Uwe.Zeymer{at}t-online.de

OBJECTIVES

We conducted an international, prospective, randomized, double-blind, placebo-controlled phase 2 trial in patients undergoing thrombolytic therapy or primary angioplasty for acute ST-elevation myocardial infarction (MI) to investigate the effect of eniporide on infarct size and clinical outcome.

BACKGROUND

Experimental studies suggest that the activity of the Na⁺/H⁺ exchange (NHE) plays an important role in the unfavorable sequels of myocardial ischemia and reperfusion. Eniporide specifically inhibits the NHE-1 isoform and has been shown to limit infarct size in experimental models.

METHODS

The primary efficacy end point was the infarct size measured by the cumulative release of alpha-hydroxybutyrate dehydrogenase (alpha-HDBH) (area under the curve [AUC] 0 to 72 h). In stage 1, 50, 100, 150 or 200 mg eniporide given as a 10-min infusion before start of reperfusion therapy were compared with placebo in 430 patients, and in stage 2, 100 and 150 mg eniporide were compared with placebo in 959 patients.

RESULTS

In stage 1, the administration of 100 mg and 150 mg eniporide resulted in smaller infarct sizes (mean alpha-HBDH AUC in U/ml x h, placebo: 44.2, 100 mg eniporide: 40.2, 150 mg eniporide: 33.9), especially in the angioplasty group. In contrast, in stage 2 there was no difference in the enzymatic infarct size between the three groups (placebo: 41.2, 100 mg eniporide: 43.0, 150 mg eniporide: 41.5). Overall there was no effect of eniporide on clinical outcome (death, cardiogenic shock, heart failure, life-threatening arrhythmias). However, there was a significant reduction of the incidence of heart failure in patients reperfused late (>4 h).

CONCLUSIONS

In this large study administration of the NHE-1 inhibitor eniporide, before reperfusion therapy in patients with acute ST elevation MI, did not limit infarct size or improve clinical outcome.

Abbreviations and Acronyms   alpha-HDBH = alpha-hydroxybutyrate dehydrogenase   AMI = acute myocardial infarction   AUC = area under the curve   CK = creatine kinase   CK-MB = creatine kinase isoenzyme   ESCAMI = Evaluation of the Safety and Cardioprotective Effects of Eniporide in Acute Myocardial Infarction study   MI = myocardial infarction   NHE = Na+/H+ exchange   PTCA = percutaneous transluminal coronary angioplasty

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