ACC 2009: HORIZONS AMI: Give Early Heparin Bolus to All STEMI Patients to Reduce Stent Thrombosis

March 31, 2009

March 31, 2009 (Orlando, Florida) — New data from the HORIZONS AMI trial suggest that inadequate very early antithrombin and antiplatelet therapy is one of the strongest drivers of early stent thrombosis in STEMI patients undergoing primary PCI with stenting, with the take-home message to give all patients a heparin bolus and 600 mg of clopidogrel as soon as possible--either in the ambulance or as soon as they arrive in the emergency department. Cigarette smoking was one of strongest drivers of late stent thrombosis.

"We can do a few simple things to bring stent thrombosis rates down. Get heparin and a potent antiplatelet agent into the patients as fast as possible, and reinforce the importance of stopping smoking," commented HORIZONS investigator Dr George Dangas (Columbia University Medical Center, New York).

The HORIZONS AMI trial, the largest trial of primary PCI ever conducted, involved 3602 STEMI patients within 12 hours of symptom onset undergoing primary PCI who were randomized to treatment with heparin plus a GP IIb/IIIa inhibitor or to bivalirudin alone. The primary results showed that bivalirudin monotherapy resulted in less major bleeding, comparable rates of ischemia, and improved survival compared with heparin plus a GP IIb/IIIa inhibitor at 30 days and one year.

The current analysis of stent thrombosis in the trial, presented today by Dangas during the i2 Summit at the American College of Cardiology 2009 Scientific Sessions, was based on the 3203 patients who received a stent. Dangas reported that there were 107 cases of definite or probable stent thrombosis (3.3%) by one year. This could be broken down into an incidence of 0.9% in the first 24 hours (acute), 1.6% between one and 30 days (subacute), and 1% between one month and one year (late). "The 3.3% figure at one year sounds high, but these are patients with acute ST-elevation MI who are getting a stent, and these rates are not different from those seen in other studies of similar patients," he said.

He added that acute, subacute, and late stent thrombosis appear to be related to different factors, with lack of potent adjunctive pharmacological therapy one of the driving factors for acute and subacute events, while cigarette smoking made a large contribution to late stent thrombosis.

Early Heparin Bolus

The most important factor influencing acute stent thrombosis appeared to be use of early nonrandomized heparin before patients had been randomized to the study drug. Patients who received such treatment had significantly lower rates of stent thrombosis within the first 24 hours regardless of which treatment group they were assigned to.

HORIZONS AMI: Effect of Prerandomization Heparin on Incidence of Acute Stent Thrombosis

Group Prerandomization heparin (%) No prerandomization heparin (%) HR (95% CI) p
Bivalirudin 0.9 2.6 3.07 0.006
Heparin+GP IIb/IIIa blocker 0.1 0.8 9.64 0.02

Dangas noted that about half the patients in the study received a prerandomization bolus of heparin. "This is something that just makes sense to do. Often bivalirudin or IIb/IIIa blockers are not stored in the emergency department, and many doctors like to get something in quick, so they give a heparin bolus. Every center has their own way of doing things--in Europe, heparin is often given in the ambulance, while in the US it is given in the ER. And we saw that this practice seems to have a big benefit on acute stent thrombosis. This cheap and easy strategy seems to have an important effect," he said.

A 600-mg loading dose of clopidogrel also appeared to be important in reducing stent thrombosis, particularly subacute stent thrombosis in the bivalirudin group. Dangas commented: "Again, this simple intervention of 600-mg clopidogrel seemed to have an effect. Early upfront intense antiplatelet therapy is of prime importance in these patients." He added: "So we have a clear message from this data: Give potent antiplatelet therapy and a bolus of heparin as soon as possible to ST-elevation-MI patients. This is a practical and viable solution."

Bivalirudin: Different Effect Early and Late

While stent thrombosis within one year occurred with similar frequency in both randomized treatment arms, acute stent thrombosis was more common with bivalirudin, especially within the first five hours, whereas stent thrombosis between 24 hours and one year was more common in the heparin–GP-IIb/IIIa-blocker arm.

HORIZONS AMI: Stent Thrombosis in Bivalirudin vs Heparin/GP-Iib/Iiia-Blocker Arms, Differential Effect With Time

Time Bivalirudin (%) Heparin+IIb/IIIa blocker (%) HR p
0–24 h 1.5 0.3 5.93 0.0002
1 d–1 y 2.2 3.0 1.73 0.06


On this observation, Dangas noted that optimizing adjunctive pharmacotherapy appears to be particularly important to reduce acute and subacute stent thrombosis with bivalirudin and that more use of early heparin and high doses of clopidogrel or the newer, more potent, antiplatelet agents approaching the market could further improve outcomes with bivalirudin. He also suggested that a prolonged bivalirudin infusion of about four to six hours may reduce acute stent thrombosis, but this would need further investigation to make sure it did not increase bleeding risk.

"It is really the first five hours that are important," Dangas commented. "The delay in the onset of action of clopidogrel could be key here, especially in ST-elevation-MI patients who may have decreased absorption. This is why we need superactive, more potent antiplatelet agents."

Other factors that affected acute and subacute stent thrombosis in HORIZONS AMI were vessel flow, lesion characteristics, and number and length of stents, while patient-related factors including cigarette smoking were predictors of late stent thrombosis. The type of stent implanted (drug eluting or bare metal) did not affect the risk of stent thrombosis during any time interval up to one year.

HORIZONS AMI: Independent Predictors of Acute Stent Thrombosis

Factor HR for stent thrombosis p
Pre-PCI TIMI flow 0-1 6.10 0.01
Lesion ulceration 4.80 0.01
Bivalirudin (vs heparin+GP IIb/IIIa) 4.65 0.005
Number of stents 1.50 0.02
Prerandomization heparin 0.27 0.002

HORIZONS AMI: Independent Predictors of Subacute Stent Thrombosis

Factor HR for stent thrombosis p
Insulin-treated diabetics 4.43 0.0002
History of CHF 4.16 0.003
Pre-PCI TIMI flow 0-1 2.21 0.04
Final TIMI flow 0-1 3.72 0.03
Stent/lesion-length ratio 1.44 <0.0001
Clopidogrel loading dose 600 mg (vs 300 mg) 0.49 0.01

HORIZONS AMI: Independent Predictors of Late Stent Thrombosis

Factor HR for stent thrombosis p
Current smoking 4.05 0.001
Insulin-treated diabetics 3.17 0.06
History of prior MI 3.15
Poststent dilation balloon used 2.75 0.008

The HORIZONS AMI trial was sponsored by the Medicines Company. Dangas has received speaker's bureau fees from AstraZeneca, Abbott, Sanofi Aventis, Bristol-Myers Squibb, Medtronic, Boston Scientific, and the Medicines Company and consulting fees from Cordis.