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CLINICAL STUDIES

A multicenter, randomized study of argatroban versus heparin as adjunct to tissue plasminogen activator (TPA) in acute myocardial infarction: myocardial infarction with Novastan and TPA (MINT) study

Ik-Kyung Jang, MD, FACC^a, David F. M. Brown, MD^a, Robert P. Giugliano, MD, SM^a, H. Vernon Anderson, MD, FACC^*, Douglas Losordo, MD, FACC, Jose C. Nicolau, MD, Oscar P. Dutra, MD, Oscar Bazzino, MD, FACC^||, Victor Molina Viamonte, MD, FACC^¶, Roberto Norbady, MD^**, Alvaro Sosa Liprandi, MD, Thomas J. Massey, BS, Robert Dinsmore, MD^a, Richard P. Schwarz, Jr, PhD the MINT Investigators

^a Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
^* Texas Heart Institute, Houston, Texas, USA
St. Elizabeth Hospital, Boston, Massachusetts, USA
Instituto de Mol stias Cardiovascular, Sao Jose Do Rio Preto, Brazil
Instituto de Cardiologica, do Rio Grande do Sul, Porto Alegre, Brazil
^|| Hospital Italiano, Buenos Aires, Argentina
^¶ Institute de Cardiologica y Cirugia Cardiovascular, Hospital Espanol, Buenos Aires, Argentina
^** Hospital Frances, Buenos Aires, Argentina
Sanatorio Mitre, Buenos Aires, Argentina
Coromed Inc., Troy, New York, USA
Texas Biotechnology Corporation, Houston, Texas, USA

Manuscript received October 6, 1998; revised manuscript received January 25, 1999, accepted February 16, 1999.

Reprint requests and correspondence: Dr. Ik-Kyung Jang, Cardiology Division, Bulfinch 105, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114
jang.ik{at}mgh.harvard.edu

OBJECTIVES

This study examined the effect of a small-molecule, direct thrombin inhibitor, argatroban, on reperfusion induced by tissue plasminogen activator (TPA) in patients with acute myocardial infarction (AMI).

BACKGROUND

Thrombin plays a crucial role in thrombosis and thrombolysis. In vitro and in vivo studies have shown that argatroban has advantages over heparin for the inhibition of clot-bound thrombin and for the enhancement of thrombolysis with TPA.

METHODS

One hundred and twenty-five patients with AMI within 6 h were randomized to heparin, low-dose argatroban or high-dose argatroban in addition to TPA. The primary end point was the rate of thrombolysis in myocardial infarction (TIMI) grade 3 flow at 90 min.

RESULTS

TIMI grade 3 flow was achieved in 42.1% of heparin, 56.8% of low-dose argatroban (p = 0.20 vs. heparin) and 58.7% of high-dose argatroban patients (p = 0.13 vs. heparin). In patients presenting after 3 h, TIMI grade 3 flow was significantly more frequent in high-dose argatroban versus heparin patients: 57.1% versus 20.0% (p = 0.03 vs. heparin). Major bleeding was observed in 10.0% of heparin, and in 2.6% and 4.3% of low-dose and high-dose argatroban patients, respectively. The composite of death, recurrent myocardial infarction, cardiogenic shock or congestive heart failure, revascularization and recurrent ischemia at 30 days occurred in 37.5% of heparin, 32.0% of low-dose argatroban and 25.5% of high-dose argatroban patients (p = 0.23).

CONCLUSIONS

Argatroban, as compared with heparin, appears to enhance reperfusion with TPA in patients with AMI, particularly in those patients with delayed presentation. The incidences of major bleeding and adverse clinical outcome were lower in the patients receiving argatroban.

Abbreviations and Acronyms   AMI = acute myocardial infarction   aPTT = activated partial thromboplastin time   CABG = coronary artery bypass graft surgery   CHF = congestive heart failure   CPK = creatine phosphokinase   cTFC = mean corrected TIMI frame count   GUSTO Trial = Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries Trial   MI = myocardial infarction   MINT Trial = Myocardial Infarction with Novastan and TPA Trial   PTCA = percutaneous transluminal coronary angioplasty   TIMI = thrombolysis in myocardial infarction   TPA = tissue plasminogen activator

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