Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction - HORIZONS-AMI

Description:

The goal of the trial was to evaluate treatment with bivalirudin compared with heparin plus glycoprotein (GP) IIb/IIIa inhibitors among patients undergoing primary percutaneous coronary intervention (PCI) for acute ST-elevation myocardial infarction (STEMI).

Hypothesis:

Bivalirudin during primary PCI will result in similar ischemic events and less bleeding.

Study Design

  • Randomized

Patients Enrolled: 3,602
Mean Follow Up: 1, 2, and 3 years
Mean Patient Age: 60
Female: 23

Patient Populations:

  • Clinical symptoms consistent with acute MI lasting >20 minutes but <12 hours in duration
  • ST-segment elevation of ≥1 mm in ≥2 contiguous leads, or presumably new left bundle branch block, or true posterior MI with ST depression of ≥1 mm in ≥2 contiguous anterior leads

Exclusions:

  • Prior administration of thrombolytic therapy, bivalirudin, GP IIb/IIIa inhibitors, low molecular weight heparin, or fondaparinux for this admission
  • Current use of Coumadin
  • Systemic (intravenous) paclitaxel or Taxol use within 12 months
  • History of bleeding diathesis or known coagulopathy
  • History of intracerebral mass, aneurysm, arteriovenous malformation, or hemorrhagic stroke
  • Stroke or transient ischemic attack within the past 6 months, or any permanent residual neurologic defect
  • Gastrointestinal or genitourinary bleeding within the last 2 months, or major surgery within 6 weeks
  • Recent history or known current platelet count <100,000 cells/mm3 or hemoglobin <10 g/dl
  • Extensive peripheral vascular disease
  • Planned elective surgical procedure that would necessitate interruption of thienopyridines during the first 6 months post-enrollment
  • Noncardiac comorbid conditions present with life expectancy <1 year or that may result in protocol
  • Coronary stent implantation within the past 30 days
  • Known hypersensitivity or contraindication to heparin, both abciximab and eptifibatide, aspirin, both clopidogrel and ticlopidine, bivalirudin, paclitaxel, stainless steel, and/or contrast media

Primary Endpoints:

  • Composite of major adverse ischemic cardiac events plus major bleeding at 30 days
  • Major bleeding events at 30 days

Secondary Endpoints:

  • Mortality (cardiac and all-cause)
  • Revascularization
  • Stroke
  • Stent thrombosis
  • Blood transfusion
  • Thrombocytopenia
  • TIMI major and minor bleeding
  • GUSTO major and minor bleeding

Drug/Procedures Used:

Patients undergoing planned primary PCI for acute STEMI were randomized to treatment during PCI with bivalirudin (n = 1,800) or heparin plus a GP IIb/IIIa inhibitor (n = 1,802). The investigator was not blinded to treatment assignment. Choice of GP IIb/IIIa inhibitor was at the discretion of the investigator. GP IIb/IIIa inhibitors could be used in the bivalirudin arm as bailout therapy. In a factorial design, patients were also randomized to use of a paclitaxel-eluting stent or bare-metal stent (see the HORIZONS-AMI Stent trial for these results).

Concomitant Medications:

Periprocedure, patients received at least 324 mg of aspirin and 300-600 mg of clopidogrel. If a patient received heparin prior to randomization, and was then randomized to bivalirudin, this was started 30 minutes later (always before PCI). Antithrombin agents were discontinued at the completion of PCI, although they could be continued at low dose if clinically indicated.

A GP IIb/IIIa inhibitor could be administered in the bivalirudin arm according to operator discretion for no-reflow or large thrombus. Post-procedure, patients were treated with aspirin indefinitely (at least 80 mg daily) and clopidogrel (75 mg daily) for at least 6 months.

At discharge, aspirin was used in 97% of the heparin and GP IIb/IIIa inhibitor group versus 98% of the bivalirudin group, thienopyridine in 93% versus 94%, and statins in 94% versus 94%, respectively.

Principal Findings:

The index event was an anterior MI in 43% of patients. Unfractionated heparin (UFH) had been used prior to randomization in 66% of patients in the trial. The primary management strategy was primary PCI in 93% of patients, medical therapy in 5%, and bypass surgery in 2%. A GP IIb/IIIa inhibitor was used in 7.2% of patients in the bivalirudin arm (abciximab in 50% and eptifibatide in 44%). Closure device was used in 28% of cases.

Of the co-primary endpoints, the composite of death, MI, ischemic target vessel revascularization, stroke, or major bleeding at 30 days was significantly lower in the bivalirudin alone group compared with the GP IIb/IIIa inhibitor + UFH group (9.2% vs. 12.1%, relative risk [RR] 0.76, 95% confidence interval [CI] 0.63-0.92, p = 0.005), driven by a decrease in major bleeding (4.9% vs. 8.3%, RR 0.60, 95% CI 0.46-0.77, p < 0.001). Using the TIMI definition of major or minor bleeding, there was also a decrease in the bivalirudin group (5.9% vs. 9.6%, p < 0.001).

There was no difference in major adverse cardiac events (MACE) at 30 days (5.4% in the bivalirudin group vs. 5.5% in the GP IIb/IIIa inhibitor + UFH group, p = 0.95). Results were consistent when restricted to the cohort of patients who underwent PCI. Cardiac death was significantly lower in the bivalirudin group (1.8% vs. 2.9%, p = 0.035). There was no significant difference in stent thrombosis at 30 days between the groups (2.5% with bivalirudin vs. 1.9% with GP IIb/IIIa inhibitor + UFH, p = 0.30), but rates of acute stent thrombosis within 24 hours were higher in the bivalirudin group (1.3% vs. 0.3%, p < 0.001).

At 12 months, the composite outcome of death, MI, ischemic target vessel revascularization, stroke, or major bleeding was still significantly lower in the bivalirudin group compared with the GP IIb/IIIa inhibitor + UFH group (15.7% vs. 18.3%, HR 0.84, 95% CI 0.71-0.98, p = 0.03), again driven by a significantly reduced incidence of major bleeding in the bivalirudin arm (5.8% vs. 9.2%, HR 0.61, 95% CI 0.48-0.78, p < 0.0001). 

MACE at 1 year was similar between the two groups (11.9% vs. 11.9%, p = 0.98). However, mortality was significantly lower in the bivalirudin arm (3.4% vs. 4.8%, HR 0.69, 95% CI 0.50-0.97, p = 0.029), mainly due to a reduction in cardiac mortality (2.1% vs. 3.8%, p = 0.005).

There was also a significant reduction in the incidence on non&ndash;Q-wave MI in the bivalirudin arm at 1 year (1.4% vs. 2.7%, HR 0.53, 95% CI 0.32-0.86, p = 0.01), but not in the incidence of Q wave (2.2% vs. 2.1%, p = 0.81) or all (3.6% vs. 4.4%, p = 0.22) MIs. The incidence of stroke was similar between the two arms (1.1% vs. 1.2%, p = 0.99). Stent thrombosis at 1 year was similar between the two arms (3.2% vs. 3.5%, p = 0.59).

At 2 years, there was still no difference in MACE between the bivalirudin and GP IIb/IIIa inhibitor + UFH arms (18.7% vs. 18.8%, p = 0.99). However, there was still a significant reduction in mortality (4.6% vs. 6.1%, p = 0.05), and MI (5.1% vs. 6.9%, p = 0.04) in the bivalirudin arm. Stent thrombosis was similar (4.3% vs. 4.6%, p = 0.73). Non-CABG major bleeding was also significantly lower in the bivalirudin arm at 2 years (6.4% vs. 9.6%, p < 0.001).

At 3 years, there was a significant reduction in mortality (5.9% vs. 7.7%, p = 0.03), cardiovascular mortality (2.9% vs. 5.1%, p = 0.001), and MI (6.2% vs. 8.2%, p = 0.04) in the bivalirudin arm. Definite or probable stent thrombosis was similar (4.5% vs. 5.1%, p = 0.49). Non-CABG major bleeding was also significantly lower in the bivalirudin arm at 3 years (6.9% vs. 10.5%, p < 0.001), although bleeding between 30 days and 3 years was similar.

Interpretation:

Among patients undergoing planned primary PCI for acute MI, use of bivalirudin was associated with a reduction in the composite endpoint of death, MI, target vessel revascularization, stroke, or major bleeding at 30 days compared with heparin plus GP IIb/IIIa inhibitors. This finding was driven by a reduction in major bleeding, with no difference in MACE.

At 12 months, there was still a significantly reduced incidence of the composite endpoint, but in addition to bleeding, a significant reduction in mortality and non–Q-wave MI was noted. There was an increase in early (<24 hours) stent thrombosis with the use of bivalirudin; however, there was no difference between study arms at the end of 1 year.

While the initial 30-day results of the present study were similar to those of the ACUITY trial, which showed a reduction in the composite primary endpoint with bivalirudin among patients with acute coronary syndromes, driven by a reduction in bleeding, but without a change in cardiac events, the 1-year results of HORIZONS-AMI are striking, and may require revision of guidelines and practice. A major limitation of the trial was the open-label design, with physicians aware of what study drug the patient had received.

Two- and three-year follow-up data indicate that bivalirudin is associated with a significant reduction in MI and all-cause mortality, as compared with GP IIb/IIIa inhibitors. The mechanism for the continued separation of these curves over long-term follow-up is unclear, since stent thrombosis rates were similar between the two arms. It is possible that bleeding is associated with other deleterious actions such as transfusions and termination of dual antiplatelet therapy, and other medications such as beta-blockers.

References:

Presented by Dr. Gregg Stone at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2010), Washington, DC, September 25, 2010.

Also presented by Dr. Gregg Stone at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2009), San Francisco, CA, September 25, 2009.

Also presented by Dr. Roxana Mehran at TCT 2008, Washington, DC, October 2008.

Stone GW, Witzenbichler B, Guagliumi G, et al., on behalf of the HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218-2230.

Presented by Dr. Gregg W. Stone, at TCT 2007, Washington, DC.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, ACS and Cardiac Biomarkers, Anticoagulation Management and ACS, EP Basic Science, Heart Failure and Cardiac Biomarkers, Interventions and ACS

Keywords: Risk, Myocardial Infarction, Acute Coronary Syndrome, Stroke, Follow-Up Studies, Platelet Aggregation Inhibitors, Heparin, Immunoglobulin Fab Fragments, Hirudins, Platelet Membrane Glycoprotein IIb, Stents, Percutaneous Coronary Intervention, Paclitaxel, Metals, Thrombosis, Recombinant Proteins, Bundle-Branch Block, Peptide Fragments, Confidence Intervals


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