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Title:   Intracoronary Stenting Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 3.¹

Objective:  To compare bivalirudin and unfractionated heparin (UFH) for anticoagulation in patients with stable or unstable angina undergoing percutaneous coronary intervention (PCI) with placement of a stent after pretreatment with 600 mg of clopidogrel.

Drug names: Bivalirudin, unfractionated heparin, clopidogrel

Drug types: Anticoagulants

Patient population: Patients aged >18 years with stable or unstable angina who were undergoing PCI and had been pretreated with 600 mg of clopidogrel >=2 hours before the procedure were eligible for the trial.

Study design: Patients with stable or unstable angina who were scheduled for PCI and had received aspirin 325 to 500 mg were treated with clopidogrel 600 mg >=2 hours before the procedure. Patients were randomized in a double-blind manner after the decision was made to perform PCI. Study drugs were administered before the guide wire crossed the lesion. Patients randomized to bivalirudin received a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/hour for the duration of the procedure. Patients randomized to UFH received a bolus of 140 U/kg followed by a placebo infusion for the duration of the procedure. Either a bare metal or drug-eluting stent was implanted, depending on the preference of the physician.

Following the procedure, patients received aspirin 80 to 325 mg/day indefinitely and clopidogrel 75 to 150 mg/day until discharge followed by 75 mg/day. Clopidogrel therapy continued for >=1 month in patients who received bare metal stents and >=6 months in patients who received drug-eluting stents. Other cardiovascular drugs were provided as deemed necessary by the treating physician.

End points: The primary end point was the combined incidence of death from any cause, myocardial infarction (MI), and urgent target-vessel revascularization within 30 days of randomization and major bleeding during hospitalization. The secondary end point was the combined incidence of death from any cause, MI, and urgent target-vessel revascularization.

Results: A total of 2289 patients were randomized to bivalirudin treatment and 2281 to UFH treatment. Baseline characteristics were similar between the 2 groups. The primary end point occurred in 8.3% of patients in the bivalirudin group and 8.7% of patients in the UFH group (relative risk 0.94, 95% confidence interval [CI] 0.77–1.15, P = 0.57). The secondary end point occurred in 5.9% of patients in the bivalirudin group and 5.0% of patients in the UFH group (relative risk 1.16, 95% CI 0.91–1.49, P = 0.23). There was no significant difference in the occurrence of the primary end point in any of the prespecified subgroups, which were defined by age, sex, presence of diabetes, creatinine level, and type of angina (stable vs unstable). Major bleeding occurred significantly less often in bivalirudin-treated patients (3.1% vs 4.6%, relative risk 0.66, 95% CI 0.49–0.90, P = 0.008).

Conclusions: In patients with unstable angina undergoing PCI with placement of a stent who have been pretreated with 600 mg clopidogrel, anticoagulation with bivalirudin does not provide a net clinical benefit compared with anticoagulation with UFH. Bivalirudin therapy is, however, associated with a lower rate of major bleeding.

Place in therapy: In previous trials of patients with acute coronary syndromes undergoing PCI, bivalirudin has consistently been shown to be as effective as UFH with a lower risk of bleeding. The REPLACE-2 trial randomized 6010 patients undergoing urgent or elective PCI to treatment with bivalirudin with provisional use of a glycoprotein IIb/IIIa inhibitor (GPI) or to treatment with UFH with planned use of a GPI.¹ Clopidogrel in a loading dose of 300 mg followed by 75 mg/day was encouraged but not required. A GPI was administered to 7.2% of bivalirudin-treated patients. At 30 days, the composite of death, MI, urgent revascularization, or in-hospital major bleeding occurred in 9.2% of the bivalirudin group and 10.0% of the UFH group, a nonsignificant difference. Major bleeding occurred significantly less often in bivalirudin-treated patients (2.4% vs 4.1%, P < 0.001).

The ACUITY trial randomized 13,819 moderate- and high-risk patients with acute coronary syndromes to treatment with heparin (either UFH or enoxaparin) plus a GPI, bivalirudin plus a GPI, or bivalirudin alone; 7789 of these patients underwent PCI.² Approximately two-thirds of patients in each of the 3 groups received a thienopyridine before PCI. At 30 days the rates of the composite of death, MI, urgent revascularization, or major bleeding were not significantly different among the 3 treatment groups. Major bleeding occurred at similar rates in the heparin plus GPI and bivalirudin plus GPI groups, but was significantly lower in the bivalirudin alone group compared with the heparin plus GPI group (4% vs 7%, P < 0.0001).

Bivalirudin was evaluated in the treatment of patients with ST-elevation MI in the HORIZONS-AMI trial, in which 3602 patients undergoing primary PCI were randomized to receive bivalirudin alone or UFH plus a GPI.³ All patients received clopidogrel in a loading dose of 300 or 600 mg or ticlopidine in a loading dose of 500 mg, each followed by 75 mg/day for at least 6 months. At 30 days, there was no difference between treatment groups in the incidence of death, MI, urgent revascularization, or stroke (5.4% in the bivalirudin group vs 5.5% in the UFH plus GPI group). Major bleeding occurred significantly less often in the bivalirudin group (4.9% vs 8.3%, relative risk 0.60, 95% CI 0.46–0.77, P < 0.001). Bivalirudin therapy was associated with a 38% reduction in the risk of death from cardiac causes and a 34% reduction in the risk of death from any cause. There were no differences between treatment groups in the rates of MI, urgent revascularization, or stroke.

In UA/NSTEMI patients undergoing PCI, pretreatment with a 600-mg loading dose of clopidogrel has been shown to reduce the rate of periprocedural MI compared with a 300-mg loading dose.⁴ As the higher loading dose comes into wider clinical use, it is important to know how it affects the efficacy and safety of concomitantly administered medications. This trial demonstrates that bivalirudin can be given safely with a 600-mg clopidogrel loading dose, with a low rate of major bleeding. Although it provides no efficacy benefit over UFH, bivalirudin may be an appropriate anticoagulant agent for patients undergoing PCI who are at high risk of bleeding.

References:

1. Lincoff AM, Bittl JA, Harrington RA, et al; REPLACE-2 Investigators. 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.
2. Stone GW, White HD, Ohman EM, et al; Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial investigators. Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial. Lancet. 2007;369:907-919.
3. Stone GW, Witzenbichler B, Guagliumi G, et al; HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med. 2008;358:2218-2230.
4. Patti G, Colonna G, Pasceri V, Pepe LL, Montinaro A, Di Sciascio G. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation. 2005;111:2099-2106.