Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial

Summary

Background

Despite important advances in treatment, the risk of recurrent ischaemic events is high both early and late after an acute coronary syndrome. We aimed to assess the effectiveness of ximelagatran and acetylsalicylic acid for prevention of death, non-fatal myocardial infarction, and severe recurrent ischaemia after a recent myocardial infarction.

Methods

In this placebo-controlled, double-blind, multicentre, multinational dose-guiding study we assessed 1883 patients who had had recent ST-elevation or non-ST-elevation myocardial infarction. Within 14 days after the index event we randomised the participants in the proportions 1/1/1/1/2 to oral ximelagatran at doses of 24 mg, 36 mg, 48 mg, or 60 mg twice daily, or placebo, respectively for 6 months. All patients received acetylsalicylic acid 160 mg once daily. The primary efficacy outcome was the dose response of ximelagatran by comparison with placebo for the occurrence of all-cause death, non-fatal myocardial infarction, and severe recurrent ischaemia. Analysis was by intention to treat.

Findings

Oral ximelagatran significantly reduced the risk for the primary endpoint compared with placebo from 16·3% (102 of 638) to 12·7% (154 of 1245) (hazard ratio 0·76, 95% Cl 0·59–0·98, p=0·036) for the combined ximelagatran groups versus placebo. There was no indication of a dose response between the ximelagatran groups. Major bleeding events were rare, 1·8 % (23 of 1245) and 0·9 % (six of 638) (hazard ratio 1·97, 95% Cl 0·80–4·84) in the combined ximelagatran and placebo groups, respectively. We recorded no serious clinically adverse outcomes judged related to the investigational drug.

Interpretation

Oral direct thrombin inhibition with ximelagatran and acetylsalicylic acid is more effective than acetylsalicylic acid alone in preventing major cardiovascular events during 6 months of treatment in patients who have had a recent myocardial infarction.

Published online Sept 1, 2003 http://image.thelancet.com/extras/03art6477web.pdf

Introduction

Platelet activation and thrombin generation are key mechanisms in the pathophysiology of acute coronary syndromes—eg, ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, and unstable angina.1, 2, 3, 4 Antithrombotic treatment, therefore, is one of the cornerstones in pharmacological treatment of acute coronary syndromes. Acute treatment typically includes reperfusion treatment in ST-elevation myocardial infarction; consideration of clopidogrel, glycoprotein IIb/IIIa inhibitors, and early revascularisation in non-ST-elevation myocardial infarction; and acetylsalicylic acid and anticoagulation with intravenous unfractionated or subcutaneous low-molecular-weight heparin in all acute coronary syndromes.1, 2, 3, 4 Soon after anticoagulation treatment stops, however, rebound ischaemia and myocardial infarction can occur.5, 6, 7, 8 During the subsequent months, morbidity and mortality remain high because of recurrent thrombotic events. Long-term acetylsalicylic acid is the mainstay of antiplatelet therapy, reducing the relative risk of myocardial infarction, stroke, or vascular death by about 25%.1, 2, 3, 4, 9 Additional antiplatelet treatment with clopidogrel is beneficial in patients with non-ST-elevation acute coronary syndromes.¹⁰ Long-term anticoagulation with oral vitamin K antagonists further reduces cardiovascular events in patients with ST-elevation myocardial infarction and non-ST-elevation myocardial infarction.11, 12 However, use of such drugs after myocardial infarction is restricted because of the many food-drug and drug-drug interactions needing regular coagulation monitoring and subsequent dose adjustments, and because of the risk of bleeding, especially when combined with acetylsalicylic acid. Such limitations have prompted development of new oral anticoagulants that are safer and more effective.

Ximelagatran (AstraZeneca, Mölndal, Sweden) is the first in a new class of oral direct thrombin inhibitors under investigation for prevention and treatment of thromboembolic events. After oral administration, ximelagatran is rapidly metabolised to its active form melagatran,¹³ which is mainly excreted through the kidneys. Melagatran is stable over time, and its metabolism is unaffected by age,¹⁴ sex, body weight,¹⁵ or ethnic origin.¹⁶ The bioconversion of ximelagatran and elimination of melagatran are independent of the hepatic cytochrome P450 enzyme system, providing a low potential for drug-drug interactions,¹⁷ and there are no known clinically relevant food or alcohol interactions.¹⁸ Melagatran's pharmacokinetics are unchanged and the pharmacodynamic properties show only minor additive effects when oral ximelagatran and acetylsalicylic acid are given concomitantly.¹⁹

In ESTEEM (efficacy and safety of the oral direct thrombin inhibitor ximelagatran in patients with recent myocardial damage), we aimed to compare the efficacy and safety of four doses of oral ximelagatran with placebo in patients given acetylsalicylic acid who had recently been admitted for ST-elevation myocardial infarction or non-ST-elevation myocardial infarction, and to investigate any dose-effect relation. Our endpoints were frequency of death, non-fatal myocardial infarction and severe recurrent ischaemia during 6 months of treatment.