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Bivalirudin for Non-ST-segment Elevation Acute Coronary Syndrome: A Discussion on the Results of the ACUITY Trial
Sarah A. Spinler, PharmD, FCCP, BCPS
May, 2007
Bivalirudin, an injectable direct thrombin inhibitor, was recommended in the 2005 percutaneous coronary intervention (PCI) guidelines of the American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions (ACC/AHA/SCAI) as an alternative to unfractionated heparin or enoxaparin, in patients at low risk for death, myocardial infarction (MI) or recurrent ischemia, undergoing PCI, and instead of UFH or enoxaparin in patients with heparin-induced thrombocytopenia undergoing PCI.1 In practice, bivalirudin has been most often used for elective PCI in patients with a history of a "positive" stress test. New information from the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial may impact the selection of pre-PCI anticoagulant in patients at high-risk for death or MI presenting with non-ST-segment elevation acute coronary syndrome (ACS). In the ACUITY trial, 13,819 patients with NSTE ACS at moderate to high-risk of death or MI (expected to undergo coronary angiography within the first 48 to 72 hours of hospital admission) were randomized to one of three antithrombotic treatment strategies: 1) heparin (UFH or enoxaparin) plus a glycoprotein (GP) IIb/IIIa inhibitor, 2) bivalirudin plus GP IIb/IIIa inhibitor, or 3) bivalirudin alone. The primary end point was "net clinical outcome" at 30 days, which was a quadruple end point consisting of the composite ischemic end point (death, MI or unplanned revascularization for ischemia) plus non-coronary artery bypass graft surgery (CABG) major bleeding. In the trial, 56% of the patients underwent revascularization with PCI and 11% with CABG while 32% received management with medications for ischemia alone. The quadruple end point occurred in 11.7% of the heparin plus GP IIb/IIIa group, 11.8% of the bivalirudin plus GP IIb/IIIa group, and 10.1% of the bivalirudin alone group (p value for noninferiority < 0.001, p value for superiority = 0.93 UFH/enoxaparin plus a GP IIb/IIIa inhibitor versus bivalirudin plus a GP IIb/IIIa inhibitor, and p value for noninferiority < 0.001, p value for superiority = 0.015 for UFH/enoxaparin plus a GP IIb/IIIa inhibitor versus bivalirudin alone). The non-CABG major bleeding rates were lower in patients treated with bivalirudin (alone) compared to those receiving UFH/enoxaparin plus a GP IIb/IIIa inhibitor or the combination of bivalirudin and a GP IIb/IIIa inhibitor (3.0% versus 5.7% versus 5.3%) (p value for noninferiority = 0.001, p value for superiority = 0.38 UFH/enoxaparin plus a GP IIb/IIIa inhibitor versus bivalirudin plus a GP IIb/IIIa inhibitor, and p value for noninferiority < 0.001, p value for superiority < 0.001 for UFH/enoxaparin plus a GP IIb/IIIa inhibitor versus bivalirudin alone). Additional analyses suggested similar results across a variety of subgroups (including patients age > 65 years, women, patients with diabetes mellitus, those with elevated troponin concentrations, ST-segment changes, different strata of TIMI risk score, those undergoing PCI, medical management or CABG surgery, patients crossed-over at the time of randomization to another therapy that differed from pre-randomized treatment, and patients proceeding early (< 3 hours) or late (> 19.7 hours to angiography or intervention).2 Results of the PCI sub-study of 13,819 patients indicated similar results in the 30-day net clinical outcome with bivalirudin alone compared to heparin plus a GP IIb/IIIa inhibitor (12% versus 13%, p=0.057) and a significant reduction in major bleeding (4% versus 7%, p<0.0001).3 Unpublished results from 1-year follow-up indicate similar outcomes between the bivalirudin alone group versus the heparin plus GP IIb/IIIa inhibitor group for the ischemic composite end point [HR=1.05, 95% CI 1.05 (0.95-1.17)], and mortality [HR=1.05, 95% CI 1.05 (0.77-1.18)].4 The hazard ratio for the effect of major bleeding on 1-year mortality was 2.89 (2.24-3.72, p<0.0001).4
With similar efficacy and a lower bleeding rate, on the surface, bivalirudin alone appears the preferred therapy. However, several issues surround the study design and application to practice. The main issue surrounds the non-inferiority margin of 25% used in the trial. This means that bivalirudin could be 25% "worse" than heparin plus GPI treated and still be called "noninferior". In fact, the upper boundary of the 95% CI for the ischemic composite end point comparing bivalirudin alone with heparin plus a GP IIb/IIIa inhibitor was 1.24.2 Other contemporary NSTE ACS trials, such as A to Z and SYNERGY, have used lower margins of 10%-15%. The reader is referred to a review article specifically focused on the noninferiority margin selected in ACUITY.5 In addition, patients received a very short duration of randomized treatment (about 5.5 hours) prior to coronary angiography.2 More than 60% of patients received on average more than 14 hours of prerandomized treatment prior to study enrollment and were "crossed over" to study medications.2 It could be expected that patients discontinued anticoagulant therapy following angiography. Therefore although patients were randomized, there was potential for the prerandomization therapy to impact study outcomes and some could question whether or not the short duration of treatment was long enough to impact outcomes. Also, there was a trend towards higher composite ischemic events in patients who were not pretreated with a thienopyridine (clopidogrel) prior to PCI (16.4% versus 14.3%, HR 1.20, 95% CI 1.01-1.44 at one year).4 This suggests that centers who do not administer clopidogrel precatheterization, may not want to select bivalirudin. However, one must keep in mind that this was not a pre-specified end point and were subgroup results of a study subgroup (PCI)! Finally, 9.1% of patients randomized to open-label bivalirudin required "bail out" administration of a GP IIb/IIIa inhibitor during the procedure and their outcomes included with the bivalirudin alone treatment group.2 This may raise drug costs in this group. The results of the ACUITY economic analysis presented at the TCT meeting in October 2006 demonstrated lower hospitalization costs in the bivalirudin alone arm compared to a heparin plus a GP IIb/IIIa inhibitor group.6 Overall drug costs appeared to be higher in the bivalirudin alone group. This is likely secondary to the fact that the majority of costs of a GP IIb/IIIa inhibitor such as eptifibatide are incurred starting in the cath lab and for 12-24 hours following PCI while the costs of bivalirudin in this study were incurred prior to the start of PCI through the end of the procedure. Since 32% of patients had medical management,2 their anticoagulants (and GP IIb/IIIa inhibitor if they received one prior to PCI), were discontinued at the conclusion of angiography. Perhaps a more relevant cost comparison will be in the PCI subgroup. The cost of a major bleed was $7278, and major bleeding was a significant independent predictor of in-hospital costs (p<0.001).6
So what does it all mean? In all likelihood, the revised ACC/AHA guidelines for NSTE ACS, due to be released very soon, will include a recommendation for selecting bivalirudin as one of several anticoagulant treatment options for patients with NSTE ACS likely to undergo coronary angiography and PCI. It is likely that no one anticoagulant will suit all patients in every U.S. practice site. Therefore, practitioners should be familiar with the study designs, patient demographics, and results for recent NSTE ACS studies and develop protocols for dosing each agent that is on formulary. The reader is referred to the AHA and American College of Clinical Pharmacy Expert Opinion Paper on PCI Pharmacotherapy that reviews dosing and other clinical trials in more detail.7 We are finding out that bleeding is becoming a more important end point to be aware of and vigilant to prevent as it impacts mortality and hospital costs.
References:
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Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al. ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention-Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol. 2006 Jan 3;47(1):216-35.
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Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203-16. Supplementary Appendix available on line at http://content.nejm.org/cgi/data/355/21/2203/DC1/1.
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Stone GW, White HD, Ohman EM, et al. 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 Mar 17;369(9565):907-19.
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Stone GW. A prospective, randomized trial of bivalirudin in acute coronary syndromes: final one-year results from the ACUITY trial. Presentation at the American College of Cardiology Meeting. New Orleans, LA, March 2007. Available from: http://clinicaltrialresults.org.
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Kaul S, Diamond GA. Making sense of noninferiority: a clinical and statistical perspective on its application to cardiovascular clinical trials. Prog Cardiovasc Disease 2007;49:284-99.
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Cohen DJ. Cost effectiveness in acute coronary syndromes: the ACUITY economic study. Presented at Transcatheter Cardiovascular Therapeutics meeting. Washington, DC, October 2006. Available from: http://clinicaltrialresults.org.
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Levine GN, Berger PB, Cohen DJ, et al. Newer pharmacotherapy in patients undergoing percutaneous coronary interventions: a guide for pharmacists and other healthcare professionals: expert opinion from the American Heart Association's Diagnostic and Interventional Catheterization Committee and Council on Clinical Cardiology, and the American College of Clinical Pharmacy's Cardiology Practice Research Network. Pharmacother 2006;26(11): 1537-56.
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