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CLINICAL RESEARCH

Recombinant Nematode Anticoagulant Protein c2 in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome

The ANTHEM–TIMI-32 Trial

Robert P. Giugliano, MD, SM, FACC^_*,_*, Stephen D. Wiviott, MD^_*, Peter H. Stone, MD, FACC, Daniel I. Simon, MD, PhD, FACC, Marc J. Schweiger, MD, FACC, Alain Bouchard, MD, FACC^||, Massoud A. Leesar, MD, FACC^#, Michael A. Goulder, BSc^_**, Steven R. Deitcher, MD, Carolyn H. McCabe, BS^_*, Eugene Braunwald, MD, MACC^_* for the ANTHEM–TIMI-32 Investigators

^_* TIMI Study Group
Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts
University Hospitals–Case Medical Center, Cleveland, Ohio
Baystate Medical Center, Springfield, Massachusetts
^|| Baptist Medical Center-Princeton, Birmingham, Alabama
^# University of Louisville, Louisville, Kentucky
^_** Nottingham Clinical Research, Nottingham, United Kingdom
Nuvelo, Inc., San Carlos, California

Manuscript received January 3, 2007; revised manuscript received January 31, 2007, accepted February 12, 2007.

^_* Reprint requests and correspondence: Dr. Robert P. Giugliano, TIMI Study Group, 350 Longwood Avenue, First Floor Offices, Boston, Massachusetts 02115 (Email: rgiugliano{at}partners.org).

Objectives: We sought to evaluate the safety and efficacy of recombinant nematode anticoagulant protein c2 (rNAPc2) in patients with non–ST-segment elevation acute coronary syndrome (nSTE-ACS).

Background: Recombinant NAPc2 is a potent inhibitor of the tissue factor/factor VIIa complex that has the potential to reduce ischemic complications mediated by thrombin generation.

Methods: A total of 203 patients were randomized 4:1 to double-blinded intravenous rNAPc2 or placebo every 48 h for a total of 1 to 3 doses in 8 ascending panels (1.5 to 10 µg/kg). All patients received aspirin, unfractionated heparin (UFH), or enoxaparin and early catheterization; clopidogrel and glycoprotein IIb/IIIa blockers were encouraged. Two subsequent open-label panels evaluated 10 µg/kg rNAPc2 with half-dose UFH (n = 26) and no UFH (n = 26). The primary end point was the rate of major plus minor bleeding. Pharmacokinetics, pharmacodynamics, continuous electrocardiography, and clinical events were assessed.

Results: Recombinant NAPc2 did not significantly increase major plus minor bleeding (3.7% vs. 2.5%; p = NS) despite increasing the international normalized ratio in a dose-related fashion (trend p 0.0001). Higher-dose rNAPc2 (7.5 µg/kg) suppressed prothrombin fragment F1.2 generation compared with placebo and reduced ischemia by >50% compared to placebo and lower-dose rNAPc2. Thrombotic bailout requiring open-label anticoagulant occurred in 5 of 26 patients treated without UFH, but none in the half-dose UFH group (19% vs. 0%; p = 0.051).

Conclusions: In patients with nSTE-ACS managed with standard antithrombotics and an early invasive approach, additional proximal inhibition of the coagulation cascade with rNAPc2 was well tolerated. rNAPc2 doses 7.5 µg/kg suppressed F1.2 and reduced ischemia, though some heparin may be necessary to avoid procedure-related thrombus formation. (Anticoagulation With rNAPc2 to Eliminate MACE/TIMI 32; http://www.clinicaltrial.gov/ct/show/NCT00116012?order=1; NCT00116012 [ClinicalTrials.gov] )

Abbreviations and Acronyms   CABG = coronary artery bypass graft   F1.2 = prothrombin fragment 1.2   GP = glycoprotein   INR = international normalized ratio   nSTE-ACS = non–ST-segment elevation acute coronary syndrome   PCI = percutaneous coronary intervention   rNAPc2 = recombinant nematode anticoagulant protein c2   TF/fVIIa = tissue factor/activated factor VII   TIMI = Thrombolysis In Myocardial Infarction   UFH = unfractionated heparin