Editor's Note: Commentary based on Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218-30.

Background

Timely reperfusion with primary percutaneous coronary intervention (PCI) is the mainstay of treatment in patients with ST-segment elevation myocardial infarction (STEMI).1 Since the coagulation cascade and platelet activation play a key role in arterial thrombosis which follows plaque rupture, adequate antithrombotic pharmacotherapy is pivotal in the acute and long-term treatment of STEMI patients.2 Several different intravenous anticoagulant agents have been developed and are available for use during primary PCI, including unfractionated heparin (UFH), enoxaparin, and bivalirudin.1 Bivalirudin is an intravenous direct thrombin inhibitor, rapidly reversible (with a half-life of 25 minutes), and also inhibits collagen- and thrombin-induced platelet aggregation.3 In the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial, bivalirudin reduced the rate of major bleeding and death at 30 days, with a survival benefit that extended to three years, compared with UFH and routine use of glycoprotein IIb/IIIa inhibitors (GPIs), at the expense of four-fold increase in acute stent thrombosis.4,5 The EUROMAX (European Ambulance Acute Coronary Syndrome Angiography) trial was designed to test whether the benefit of bivalirudin treatment persists in the contemporary pattern of STEMI treatment, characterized by pre-hospital initiation of treatment, prolonged infusion post-PCI, optional use of GPIs, use of the novel potent P2Y12 inhibitors prasugrel and ticagrelor, and increased use of radial-artery PCI access.6

Methods

EUROMAX was an international, randomized, open-label trial which enrolled STEMI patients (n=2218) with symptoms onset >20 minutes and ≤12 hours, presenting either via ambulance or to centers where PCI was not performed, scheduled for angiography and eventually primary PCI. Patients were randomized in a 1:1 fashion to receive either bivalirudin or a control strategy of either UFH (100 IU/Kg without GPIs or 60 IU/Kg with GPIs) or enoxaparin (intravenous bolus of 0.5 mg/kg). In particular, in patients assigned to bivalirudin, bolus (0.75 mg/kg) and high dose of infusion (1.75 mg/kg per hour) were started in the ambulance and maintained until the end of primary PCI. At the end of the procedure, bivalirudin infusion was to be continued for at least 4 hours, and both the infusion of a reduced dose (0.25 mg/kg per hour) as well as of the high dose used during PCI were allowed. In the control group, the use of GPIs was left to physician preference and was categorized as either routine (started before PCI) or bailout. In the bivalirudin group, bailout use of GPIs was allowed. All devices and procedural decisions were at the discretion of the physician. Aspirin and an oral P2Y12 inhibitor were administered as soon as possible after first medical contact. The primary endpoint at 30 days was a composite of all-cause death or non-coronary artery bypass grafting (CABG) associated major bleeding, and the principal secondary outcome was a composite of all-cause death, reinfarction, or non-CABG major bleeding.6

Results

The median time between study drug initiation and coronary angiography was 50 minutes and the median duration of bivalirudin infusion was 268 minutes. GPIs were used in 11.5% of patients in the bivalirudin group and 69.1% in the control group. After PCI, 93% of bivalirudin-treated patients received a prolonged (two hours or longer) infusion of bivalirudin, with 22.5% receiving the PCI dose. A loading dose of P2Y12receptor inhibitor was administered in 98% of patients, which was clopidogrel in 50% of cases. Radial artery access was used in almost half of patients. At 30 days, bivalirudin as compared with UFH plus optional GPIs reduced the primary endpoint (5.1% vs 8.5%; relative reduction [RR]: 0.60; 95% confidence interval [CI]: 0.43-0.82; P=0.001), as well as the principal secondary outcome (6.6% vs. 9.2%; RR: 0.72; 95% CI: 0.54-0.96; P=0.02). The benefit was primarily driven by a 57% relative reduction in protocol-defined non-CABG-related major bleeding, without any effect on all-cause and cardiac death, reinfarction, ischemia-driven revascularization, and stroke. Stent thrombosis was more frequent in the bivalirudin group than in the control group (1.6% vs. 0.5%; P=0.02), driven by a six-fold increase in acute (≤24 hours) stent thrombosis (1.1% vs 0.2%; RR 6.11; 95% CI: 1.37-27.24; P=0.007). Of note, results were consistent among multiple subgroups, such as arterial-access site, type of P2Y12 receptor inhibitor, and use of GPIs.6

Conclusions

Bivalirudin, started during transport for primary PCI, improved 30-day clinical outcomes with a reduction in major bleeding, but with no effect on mortality and at the expense of an increase in acute stent thrombosis.

Commentary/Perspective

The EUROMAX trial confirmed that the use of the direct thrombin inhibitor bivalirudin improves outcomes compared to UFH plus optional GPIs in the modern era of STEMI treatment. The benefit achieved with the use of bivalirudin is due to a significant reduction of major bleeding, which occurred despite the high use of radial access and more potent antiplatelet agents. However, bivalirudin use did not reduce mortality and ischemic outcomes, and there was a significant increase in stent thrombosis. In particular, acute (<24 hours) stent thrombosis was increased, while subacute stent thrombosis (after 24 hours and within 30 days) was similar in bivalirudin- and heparin-treated patients, findings that were consistent with the results of the HORIZONS-AMI trial. This increase in the rate of stent thrombosis occurred despite the use of the more prompt and potent antiplatelet agents (prasugrel and ticagrelor) and the use of a prolonged bivalirudin infusion after PCI. Indeed only half of patients received a prasugrel/ticagrelor loading dose and 78% received the low-dose bivalirudin infusion after PCI.6Importantly, acute stent thrombosis occurred in only 0.4% of patients (1/274) who received a prolonged PCI-dose bivalirudin infusion, a strategy which appears to overcome the delay in P2Y12 inhibitors effect and which therefore warrants further investigations.7 Recently, two single-center randomized trials, namely the HEAT PPCI (How Effective are Antithrombotic Therapies in PPCI) and the BRAVE 4 (The Bavarian Reperfusion Alternatives Evaluation) trials, questioned the real effectiveness of bivalirudin when compared with UFH monotherapy with only bailout GPIs use.8,9 Both trials showed that heparin alone has similar efficacy and safety compared with bivalirudin in primary PCI. However, both trials have limitations, such as the absence of post-PCI bivalirudin infusion in HEAT PPCI and a small under-powered sample size in BRAVE 4. Moreover, a recent pre-specified post-hoc analysis of the EUROMAX trial showed that pre-hospital bivalirudin reduced the composite outcome of death or major bleeding also compared with heparin with only bailout GPIs, an effect largely driven by marked reductions in major bleeding.10 These data support the role of bivalirudin as a valid antithrombotic treatment option in STEMI patients treated with primary PCI, even though strategies to reduce the rate of early stent thrombosis are still warranted.

References

1. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:e78-140.
2. Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med 2013;368:2004-13.
3. Arsenault KA, Hirsh J, Whitlock RP, Eikelboom JW. Direct thrombin inhibitors in cardiovascular disease. Nat Rev Cardiol 2012;9:402-14.
4. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218-30.
5. Stone GW, Witzenbichler B, Guagliumi G, et al. Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3-year results from a multicentre, randomised controlled trial. Lancet 2011;377:2193-204.
6. Steg PG, van 't Hof A, Hamm CW, et al. Bivalirudin started during emergency transport for primary PCI. N Engl J Med 2013;369:2207-17.
7. Clemmensen P, van't Hof A, Deliargyris EN, et al. Predictors associated with acute stent thrombosis after primary PCI: The EUROMAX Trial. J Am Coll Cardiol2014;63(12S):A27.
8. Adeel S, Stables R, et al. Unfractionated Heparin versus Bivalirudin in Primary Percutaneous Coronary Intervention: A Unique Randomized Controlled Trial with Consecutive, Unselected Patient Enrollment (using Delayed Consent), Designed to Reflect Real-World, Contemporary Practice. American College of Cardiology Scientific Session, Washington, DC, March 31, 2014.
9. Schulz S, Richardt G, Laugwitz KL, et al. Prasugrel plus bivalirudin vs. clopidogrel plus heparin in patients with ST-segment elevation myocardial infarction. Eur Heart J. 2014 May 9. [Epub ahead of print].
10. Zeymer U, van 't Hof A, Adgey J, et al. Bivalirudin is superior to heparins alone with bailout GP IIb/IIIa inhibitors in patients with ST-segment elevation myocardial infarction transported emergently for primary percutaneous coronary intervention: a pre-specified analysis from the EUROMAX trial. Eur Heart J. 2014 May 21 [Epub ahead of print].

Keywords: Coronary Angiography, Coronary Artery Bypass, Enoxaparin, Hirudins, Peptide Fragments, Radial Artery, Recombinant Proteins, Stents, Stroke, Thrombosis, Ticlopidine

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