HORIZONS-AMI_trial

Infarction

Purpose

To compare the safety and efficacy of heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI).

Reference

Stone GW, Witzenbichler B, Guagliumi G, et al. for the

HORIZONS-AMI Trial Investigators. Bivalirudin during Primary PCI in Acute Myocardial Infarction. N Engl J Med 2008;358:2218–2230.

HORIZONS-AMI: Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial

Infarction - TRIAL DESIGN -

Design

Prospective, open-label, randomized, multicenter trial.

Patients

3602 patients aged ≥18 years old who had STEMI of ≥1 mm in two or more contiguous leads, new left bundle-branch block, or true

posterior MI presenting ≤12 hours after symptom onset. Exclusion criteria included contraindications for or previous administration of the study medications, and any comorbidity that might limit life

expectancy to <1 year or interfere with compliance with the protocol.

Follow-up and primary endpoints

Two primary 30-day endpoints: major bleeding unrelated to CABG; and the combination of major bleeding or a composite of major adverse cardiovascular events (death, reinfarction, target-vessel revascularization for ischemia, and stroke).

HORIZONS-AMI: Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial

Infarction

- TRIAL DESIGN continued -

Treatment

Bivalirudin: 0.75 mg/kg/h bolus followed by 1.75 mg/kg/h infusion.

Heparin: 60 IU/kg body weight bolus, with subsequent boluses

targeted to achieve an activated clotting time of 200–250 seconds.

Glycoprotein IIb/IIIa inhibitor: abciximab, at 0.25 mg/kg bolus, followed by 0.125 µg/kg/min infusion up to a maximum of 10 µg/min; or double-bolus epifibatide, at 180 µg/kg bolus followed by 2.0 µg/kg/min infusion, with the second bolus given 10 minutes after the first, and no maximum dose pre-specified.

HORIZONS-AMI: Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction - TRIAL DESIGN continued - Median age (years)‏ Baseline characteristics Heparin plus glycoprotein IIb/IIIa inhibitor (n=1802) 60.7 76.1 11.4 11.0 2.6 42.0 15.1 41.5 Bivalirudin alone (n=1800) 59.8 77.1 10.4 10.5 3.3 39.3 16.5 42.5 Male sex (%)‏ Prior myocardial infarction (%)‏ Prior PCI (%)‏ Prior coronary artery bypass grafting (%)‏ Infarct-related artery (%)‏ Left anterior descending Left circumflex Right Stone et al. N Eng J Med 2009;358:2218–2230. HORIZONS-AMI: Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial

Infarction - RESULTS -

Compared with heparin plus a glycoprotein IIa/IIIa inhibitor, bivalirudin led, at 30 days, to a significantly reduced rate of the following:

•Net adverse clinical events (9.2% vs. 12.1%, respectively; relative risk [RR], 0.76; p=0.005)‏

•Major bleeding (4.9% vs. 8.3%, respectively; RR, 0.60; p<0.001)‏

•Death from cardiac causes (1.8% vs. 2.9%, respectively; RR, 0.62; p=0.03) •Death from all causes (2.1% vs. 3.1%, respectively; RR, 0.66; p=0.047)‏

There were no significant differences in the rate of major adverse

cardiovascular events (5.4% vs. 5.5%, respectively; p=0.95), death from non-cardiac causes (0.2% vs. 0.3%, respectively; p=0.75), reinfarction, target-vessel revascularization, and stroke.

Although rates of stent thrombosis at 30 days were not significantly different, stent thrombosis at ≤24 h was significantly more common with bivalirudin, at 1.3% vs. 0.3%, respectively; p<0.001)‏

HORIZONS-AMI: Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial

Infarction

- RESULTS continued -

Time-to-event curves through 30 days on Kaplan-Meier estimates Net adverse clinical events 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 0 No. at risk Bivalirudin alone Heparin plus GP IIb/IIIa Major bleeding 12 11 Heparin plus GP IIb/IIIa 12.2% 10 9 8 Bivalirudin alone 9.3% Major bleeding (%) 7 6 5 4 3 2 HR, 0.75; 95% CI, 0.62–0.92; p=0.006 Heparin plus GP IIb/IIIa 8.4% Net adverse clinical events (%) Bivalirudin alone 5.0% 1 0 30 0 HR, 0.59; 95% CI, 0.45–0.76; p<0.0001 5 10 15 Days 1626 1578 20 25 5 10 15 Days 1668 1606 20 25 30 1800 1802 1660 1635 1633 1591 1620 1569 1607 1552 14 1482 1800 1802 1697 1651 1675 1617 16 1598 1653 1581 1590 1511 Stone et al. N Eng J Med 2009;358:2218–2230. HORIZONS-AMI: Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial

Infarction

- RESULTS continued -

Time-to-event curves through 30 days on Kaplan-Meier estimates 8 7 6 Major 5 adverse cardiovascular 4 events (%) 3 2 1 0 0 No. at risk Bivalirudin alone Heparin plus GP IIb/IIIa Major adverse cardiovascular events HR, 0.62; 95% CI, 0.40–0.96; p=0.03 5.5% Biv a lirudin alone 5.5% Death from cardiac and non-cardiac causes 5 Heparin plus GP IIb/IIIa Biv a lirudin alone 4 HR, 0.62; 95% CI, 0.40–0.96; p=0.03 3 2 2.9% Death (%) Cardiac 1.8% Heparin plus GP IIb/IIIa 1 Noncardiac 0 0.3% 0.2% 15 20 25 30 5 10 15 Days 20 25 30 0 5 10 Days 1620 1569 1607 1552 14 1482 1800 1802 1697 1651 1675 1617 1668 1606 16 1598 1653 1581 1590 1511 1800 1802 1660 1635 1633 1591 1626 1578 Stone et al. N Eng J Med 2009;358:2218–2230. HORIZONS-AMI: Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial

Infarction - SUMMARY -

In patients with STEMI undergoing primary PCI, at 30 days bivalirudin alone reduced the following in comparison with heparin plus routine use of glycoprotein IIb/IIIa inhibitor:

•Net adverse clinical events, owing to a significant reduction in major bleeding

•Rates of death from cardiac causes and from all causes

An increase in stent thrombosis with bivalirudin ≤24 hours after PCI was partially offset by a reduction in stent thrombosis between 24 hours and 30 days. There was also no increase in the overall reinfarction rate.