The Harmonizing Outcomes with Revascularization and Stents
in Acute Myocardial Infarction Study (HORIZONS AMI)
This large-scale, open-label, prospective, randomized trial of ST-segment elevation
myocardial infarction (STEMI) patients undergoing a primary percutaneous coronary
intervention (PCI) strategy, comparing Angiomax® (bivalirudin) vs
unfractionated heparin (UFH) plus routine use of glycoprotein (GP) IIb/IIIa inhibitor
monotherapy, at 30 days resulted in:1
– 24% reduction in the primary end point of net adverse clinical events
(NACE)
– 41% reduction in the primary end point of major bleeding
– No difference in major adverse cardiovascular events (MACE)
– Reduced rate of both overall and cardiac mortality1
The multicenter, open-label, randomized trial of ST-segment elevation myocardial
infarction (STEMI) patients undergoing a primary percutaneous coronary intervention
(PCI) strategy. Of patients in the ANGIOMAX arm, the majority (93 percent) received
ANGIOMAX monotherapy. At one year, results showed that, compared with the control
treatment, ANGIOMAX:
– Reduced the incidence of cardiac-related death by 43 percent (2.1% vs.
3.8%, HR 0.57 [95% CI 0.38-0.84]; P=0.005)
– Reduced all-cause death by 31 percent (3.4% vs. 4.8%, HR 0.70 [95% CI
0.50-0.97]; P=0.029)
– Reduced the incidence of net adverse clinical events, a composite of major
adverse cardiac events or major bleeding, by 16 percent (15.7% vs. 18.3%, HR 0.84
[95% CI 0.71-0.98]; P=0.03)
– Reduced rates of major bleeding by 39 percent (5.8% vs. 9.2%, HR 0.61
[95% CI 0.48-0.78]); P<0.0001)
– Demonstrated no difference in rates of major adverse cardiac events (11.9%
vs. 11.9%, HR 1.00 [95% CI 0.83-1.21]; P=0.98)
Trial Design
HORIZONS AMI findings support ANGIOMAX use in STEMI patients undergoing primary
PCI
- Patients (N=3,602) were randomized to receive heparin + GP IIb/IIIa inhibitor or
ANGIOMAX1
- HORIZONS AMI primary results are consistent with those in the landmark trials, Randomized
Evaluation of PCI Linking ANGIOMAX to Reduced Clinical Events (REPLACE-2) and Acute
Catheterization and Urgent Intervention Triage StrategY (ACUITY)1-3†
* ANGIOMAX monotherapy included "provisional" GP IIb/IIIa inhibitor.
† The safety and effectiveness of ANGIOMAX have not been established
in patients with acute coronary syndromes (ACS) who are not undergoing PCI.4
Inclusion Criteria1
- STEMI >20 minutes and <12 hours in duration
- ST-segment elevation of ≥1 mm in ≥2 contiguous leads; or
- Presumably new left bundle branch block; or
- True posterior myocardial infarction (MI) with ST depression of ≥1 mm in ≥2
contiguous anterior leads
- Patients with cardiogenic shock or left main disease were not excluded
Exclusion Criteria
- Contraindication to any of the study medications
- Prior administration of thrombolytic therapy, bivalirudin, GP IIb/IIIa inhibitor,
low molecular weight heparin (LMWH), or fondaparinux for the present admission (prior
UFH allowed)
- Current use of warfarin
- History of bleeding diathesis or known coagulopathy (including heparin-induced thrombocytopenia),
or will refuse blood transfusions
- History of intracerebral mass, aneurysm, arteriovenous malformation, or hemorrhagic
stroke; stroke or transient ischemic attack within 6 months or any permanent neurologic
deficit; gastrointestinal or genitourinary bleed within 2 months, or major surgery
within 6 weeks; recent or known platelet count <100,000 cells/mm3
or Hgb <10 g/dL
- Planned elective surgical procedure that would necessitate interruption of thienopyridines
during the first 6 months after enrollment
Primary Endpoints (at 30 days)1
HORIZONS-AMI 30-Day End Point1
TVR=target vessel revascularization
Baseline Characteristics1
|
|
Bivalirudin*
(n=1,800) |
|
UFH + GP IIb/IIIa
(n=1,802) |
|
Age, years [range] |
59.8 [26.0-92.3] |
|
60.7 [21.6–91.6] |
|
Male |
77.1% |
|
76.1% |
|
Diabetes |
15.6% |
|
17.3% |
|
HTN† |
51.8% |
|
55.2% |
|
Hyperlipidemia |
43.4% |
|
42.7% |
|
Current smoking |
47.2% |
|
45.0% |
|
Prior MI |
10.4% |
|
11.4% |
|
Prior PCI |
10.5% |
|
11.0% |
|
Prior CABG |
3.3% |
|
2.6% |
|
Weight, kg [range] |
80 [71–90.3] |
|
80 [71–90] |
|
Chest pain – ED, hours [range] |
2.2 [1.3–4.0] |
|
2.1 [1.3–3.9] |
|
Killip class 2-4 |
8.5% |
|
8.5% |
|
LVEF, % [range] |
50 [45–60] |
|
50 [41–59] |
* In HORIZONS AMI: 93% of ANGIOMAX patients received ANGIOMAX monotherapy1
ANGIOMAX significantly reduced NACE* and major bleeding with no difference
in MACE†at 30 days in HORIZONS AMI1‡
these results were maintained at 1 year5
* NACE=MACE or major bleeding.1
† MACE=major adverse cardiovascular events: all-cause death, reinfarction,
ischemic target vessel revascularization, or stroke.1
‡ IN HORIZONS AMI, 93% of ANGIOMAX patients received ANGIOMAX
monotherapy, without provisional GP IIb/IIIa inhibitor.1
§ Data from Kaplan-Meier analyses based on log-rank estimates.
|| Non-CABG.
ANGIOMAX resulted in lower rates of overall and cardiac mortality at 30-days1
and 1-year in HORIZONS AMI 5
* IN HORIZONS AMI, 93% of ANGIOMAX patients received ANGIOMAX monotherapy, without
provisional GP IIb/IIIa inhibitor.1
† Data from Kaplan-Meier analyses based on log-rank estimates.
Please see important
safety information and
bleeding definitions.
Similar Rates of Stent Thrombosis Between Treatment Groups at 30 Days and 1 Year
- Of the 28 patients with acute stent thrombosis, 2 died (one in each treatment group).
Of the 50 patients with subacute stent thrombosis, 17 died within 30 days (3 in
the bivalirudin group and 14 in the heparin group)7
- Rates of subacute stent thrombosis favored bivalirudin, resulting in similar overall
rates of stent thrombosis between treatment groups at 30 days and 1 year7
* Protocol definition of stent thrombosis, CEC adjudicated.
† In HORIZONS AMI, 93% of bivalirudin patients received monotherapy,
without provisional GP IIb/IIIa inhibitor.
ARC=Academic Research Consortium; CEC=clinical events committee..
In HORIZONS AMI, more deaths were attributed to 30-day major bleeding—association
between 30-day events and 30-day mortality in HORIZONS AMI1,7
More deaths were attributable to major bleeding than stent thrombosis
* Time-updated covariate-adjusted Cox model.
Attributable deaths = N deaths among patients with the time updated event (attribute)
X (adj. HR – 1)/adjusted HR.
† 6.5% of 93 total deaths.
‡ 29.0% of 93 total deaths.
Reduction in 1-Year Overall Mortality demonstrated with ANGIOMAX, Regardless of
Stent Type5
* In HORIZONS AMI, 93% of bivalirudin patients received monotherapy, without provisional
GP IIb/IIIa inhibitor.
Safety Considerations
ANGIOMAX with provisional use of glycoprotein IIb/IIIa inhibitor is indicated for
use as an anticoagulant in patients undergoing percutaneous coronary intervention
(PCI), and in patients with or at risk for heparin-induced thrombocytopenia and
thrombosis syndrome (HIT/HITTS) undergoing PCI. ANGIOMAX is intended for use with
aspirin and has been studied only in patients receiving concomitant aspirin. ANGIOMAX
is contraindicated in patients with active major bleeding or hypersensitivity to
ANGIOMAX or its components. The most common (≥10%) adverse events for ANGIOMAX were back pain, pain, nausea, headache,
and hypotension. An unexplained fall in blood pressure or hematocrit, or any unexplained
symptom, should lead to serious consideration of a hemorrhagic event and cessation
of ANGIOMAX administration. Please see complete prescribing information.
1Stone 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.
2Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin
and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned
glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2
randomized trial. JAMA. 2003;289:853-863.
3Stone GW, McLaurin BT, Cox DA, et al; for the ACUITY
Investigators. Bivalirudin for patients with acute coronary syndromes. N Engl J Med.
2006;355:2203-2216.
4ANGIOMAX Prescribing Information. The Medicines Company;
Parsippany, NJ, December 6, 2005
5Mehran R; HORIZONS-AMI Trial Investigators. A prospective,
randomized comparison of bivalirudin vs. heparin plus glycoprotein IIb/IIIa inhibitors
during primary angioplasty in acute myocardial infarction—one year results [oral
presentation]. Presented at: Transcatheter Cardiovascular Therapeutics (TCT); October
12-17, 2008;
Washington, DC.
6Mauri L, Hsieh WH, Massaro JM, Ho KKL, D’Agostino R,
Cutlip DE. Stent thrombosis in randomized clinical trials of drug-eluting stents.
N Engl J Med. 2007;356:1020-1029.
7Data on file. The Cardiovascular Research Foundation,
New York, NY.