Elsevier

The Lancet

Volume 374, Issue 9696, 3–9 October 2009, Pages 1149-1159
The Lancet

Articles
Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year results of a randomised controlled trial

https://doi.org/10.1016/S0140-6736(09)61484-7Get rights and content

Summary

Background

In the HORIZONS-AMI trial, patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) who were treated with the thrombin inhibitor bivalirudin had substantially lower 30-day rates of major haemorrhagic complications and net adverse clinical events than did patients assigned to heparin plus a glycoprotein IIb/IIIa inhibitor (GPI). Here, we assess whether these initial benefits were maintained at 1 year of follow-up.

Methods

Patients aged 18 years or older were eligible for enrolment in this multicentre, open-label, randomised controlled trial if they had STEMI, presented within 12 h after the onset of symptoms, and were undergoing primary PCI. 3602 eligible patients were randomly assigned by interactive voice response system in a 1:1 ratio to receive bivalirudin (0·75 mg/kg intravenous bolus followed by 1·75 mg/kg per h infusion; n=1800) or heparin plus a GPI (control; 60 IU/kg intravenous bolus followed by boluses with target activated clotting time 200–250 s; n=1802). The two primary trial endpoints were major bleeding and net adverse clinical events (NACE; consisting of major bleeding or composite major adverse cardiovascular events [MACE; death, reinfarction, target vessel revascularisation for ischaemia, or stroke]). This prespecified analysis reports data for the 1-year follow-up. Analysis was by intention to treat. Patients with missing data were censored at the time of withdrawal from the study or at last follow-up. This trial is registered with ClinicalTrials.gov, number NCT00433966.

Findings

1-year data were available for 1696 patients in the bivalirudin group and 1702 patients in the control group. Reasons for participant dropout were loss to follow-up and withdrawal of consent. The rate of NACE was lower in the bivalirudin group than in the control group (15·6% vs 18·3%, hazard ratio [HR] 0·83, 95% CI 0·71–0·97, p=0·022), as a result of a lower rate of major bleeding in the bivalirudin group (5·8% vs 9·2%, HR 0·61, 0·48–0·78, p<0·0001). The rate of MACE was similar between groups (11·9% vs 11·9%, HR 1·00, 0·82–1·21, p=0·98). The 1-year rates of cardiac mortality (2·1% vs 3·8%, HR 0·57, 0·38–0·84, p=0·005) and all-cause mortality (3·5% vs 4·8%, HR 0·71, 0·51–0·98, p=0·037) were lower in the bivalirudin group than in the control group.

Interpretation

In patients with STEMI undergoing primary PCI, anticoagulation with bivalirudin reduced the rates of net adverse clinical events and major bleeding at 1 year compared with treatment with heparin plus a GPI. This finding has important clinical implications for the selection of optimum treatment strategies for patients with STEMI.

Funding

Cardiovascular Research Foundation, with unrestricted grant support from Boston Scientific Corporation and The Medicines Company.

Introduction

Glycoprotein IIb/IIIa inhibitors (GPIs) are frequently used in the USA and Europe in patients with ST-segment elevation myocardial infarction (STEMI) who are undergoing primary percutaneous coronary intervention (PCI) to reduce ischaemic complications.1, 2, 3 These agents, however, increase the rates of haemorrhagic events and of thrombocytopenia,4, 5, 6, 7 both of which have been strongly associated with early and late mortality.8, 9, 10, 11, 12 The direct thrombin inhibitor bivalirudin, when used instead of heparin plus a GPI during PCI, reduces the rates of major and minor bleeding and thrombocytopenia across a broad range of patients with coronary artery disease.13, 14, 15, 16, 17 In the large-scale prospective HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial, patients with high-risk STEMI undergoing primary PCI were randomly assigned to receive bivalirudin alone or heparin plus a GPI. Patients in the bivalirudin group had lower 30-day rates of major bleeding and thrombocytopenia, similar rates of composite ischaemic events, and improved survival compared with those in the heparin plus GPI group.17 Whether the beneficial effects of bivalirudin seen at 30 days are preserved, increased, or diminished at 1 year is not known. We report the prespecified analysis of 1-year outcomes from the HORIZONS-AMI trial.

Section snippets

Participants

The study design of the HORIZONS-AMI trial has been reported elsewhere.17, 18 Briefly, consecutive patients aged 18 years or older were eligible for enrolment if they presented within 12 h after the onset of symptoms with STEMI of 1 mm or more in two or more contiguous leads, new left bundle branch block, or true posterior myocardial infarction. Exclusion criteria included contraindications to any of the study drugs; previous administration of fibrinolytic therapy, bivalirudin, GPI,

Results

Between March 25, 2005, and May 7, 2007, 3602 eligible patients at 123 centres in 11 countries were randomly assigned to receive bivalirudin (n=1800) or control (n=1802). Figure 1 shows the trial profile. Following emergency angiography, the primary management strategy was primary PCI in 92·9% of patients (bivalirudin, n=1679; control, n=1666), deferred PCI in 0·1% (bivalirudin, n=2; control, n=0), CABG in 1·7% (bivalirudin, n=24; control, n=38), and medical management in 5·4% (bivalirudin,

Discussion

In this large-scale, prospective, randomised controlled trial of patients with STEMI undergoing primary PCI, procedural anticoagulation with the direct thrombin inhibitor bivalirudin reduced the rates of net adverse clinical events and major bleeding at 1 year compared with treatment with heparin plus routine use of a GPI. All-cause mortality and cardiac mortality at 1 year were also substantially reduced in patients assigned to bivalirudin compared with those assigned to heparin plus a GPI.

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