Anticoagulation With rNAPc2 to Eliminate MACE/TIMI 32 - ANTHEM–TIMI-32


The goal of the trial was to evaluate the safety and efficacy of a novel inhibitor of the tissue factor/factor VIIa complex, recombinant nematode anticoagulant protein c2 (NAPc2), among patients with non–ST-segment elevation acute coronary syndrome (NSTE ACS).

Study Design

Study Design:

Patients Enrolled: 255
Mean Follow Up: 6 months
Mean Patient Age: Median age, 58 years
Female: 32

Patient Populations:

Age 18-75 years, hospitalization with moderate- to high-risk NSTE ACS with ischemic discomfort at rest lasting ≥5 minutes consistent with ACS within 48 hours of randomization, and management with an early invasive strategy (≤72 hours)


STEMI, ACS due to a distinct nonatherosclerotic mechanism, increased bleeding risk, fibrinolytics within 24 hours, planned CABG within 7 days, creatinine >4 mg/dl, anemia, aminotransferase >3 times normal, allergy to aspirin, history of heparin-induced thrombocytopenia, pregnancy, or other conditions placing the patient at increased risk

Primary Endpoints:

Composite of TIMI major or minor hemorrhage through 7 days

Drug/Procedures Used:

Patients were randomized in a 4:1 double-blind manner to varying doses of rNAPc2 (n = 163; 1.5-10 µg/kg) or placebo (n = 40). Patients received concomitant therapy with aspirin, enoxaparin, or unfractionated heparin (UFH).

An additional 52 patients underwent randomization in an open-label manner to rNAPc2 with half-dose UFH (n = 26; 10 µg/kg) or rNAPc2 with no heparin (n = 26; 10 µg/kg). Patients underwent angiography within 72 hours with or without revascularization.

Principal Findings:

The index event was NSTE myocardial infarction (NSTEMI) in 53% of patients. More than half of the patients (59%) had an intermediate Thrombolysis in Myocardial Infarction (TIMI) risk score of 3-4. Diabetes was present in 34% of patients and prior percutaneous coronary intervention (PCI) in 43%.

Type of heparin used was enoxaparin in 72% of patients and UFH in 33%. The majority of patients received clopidogrel (82%) and glycoprotein IIb/IIIa inhibitors (53%). PCI was performed in 49% of patients and coronary artery bypass grafting (CABG) in 10%.

The primary endpoint of TIMI major or minor bleeding did not differ between rNAPc2 and placebo (3.7% vs. 2.5%; p = NS). There were four major bleeds, all of which were in the highest dose rNAPc2 group. International normalized ratio increased in a dose-related manner in the rNAPc2 groups (trend p ≤ 0.0001). Prothrombin fragment F1.2 generation was lower in the higher-dose rNAPc2 groups compared with placebo (≥7.5 µg/kg; p < 0.01).

There was no difference in occurrence of ischemia by 7 days on continuous Holter monitoring between the rNAPc2 and placebo groups (18% vs. 21%; p = NS). In the higher-dose rNAPc2 groups (7.5 or 10 µg/kg), there was a trend for ischemia to occur less often than in the placebo group (9.3% vs. 21%). The composite of death, MI, or clinical recurrent ischemia by 42 days occurred in 11% of the rNAPc2 groups and 10% of the placebo group (p = NS).

In the open-label portion of the study comparing rNAPc2 with half-dose UFH versus rNAPc2 with no heparin, thrombotic bailout requiring open-label anticoagulant was higher in those treated without UFH (19% vs. 0%; p = 0.051). Three patients treated with rNAPc2 developed mild thrombocytopenia.


Among patients with NSTE ACS, treatment with recombinant NAPc2, a novel inhibitor of the tissue factor/factor VIIa complex, was not associated with a difference in TIMI major or minor bleeding compared with placebo.

While ischemia did not differ for the pooled rNAPc2 compared with placebo comparison, ischemia on Holter was reduced with the higher doses of rNAPc2 (7.5 and 10 µg/kg). However, given the major bleeding observed in the highest dose rNAPc2 group, larger studies would be needed to more fully evaluate the safety and efficacy of high-dose rNAPc2.

In the open-label portion of the study, use of rNAPc2 without heparin during PCI was associated with higher rates of thrombotic bailout; four of the five which had intracoronary thrombus formed during PCI.

Several trials such as EASY and EPOS have explored performance of PCI without heparin, but those studies were conducted in patients with stable angina, not NSTE ACS, as was done in the current trial. The increase in thrombotic complications during PCI without heparin in the present study suggests that patients with ACS have greater thrombin generation during PCI and require more potent inhibitors of thrombin formation.


Giugliano RP, Wiviott SD, Stone PH, et al. Recombinant nematode anticoagulant protein c2 in patients with non-ST-segment elevation acute coronary syndrome: the ANTHEM-TIMI-32 trial. J Am Coll Cardiol 2007;49:2398-407.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Stable Ischemic Heart Disease, ACS and Cardiac Biomarkers, Anticoagulation Management and ACS, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and SIHD, Lipid Metabolism, Novel Agents, Interventions and ACS, Chronic Angina

Keywords: Myocardial Infarction, Acute Coronary Syndrome, Platelet Aggregation Inhibitors, Angina, Stable, Heparin, Ticlopidine, Prothrombin, Percutaneous Coronary Intervention, Thrombosis, Enoxaparin, Thromboplastin, Peptide Fragments, Factor VIIa, Electrocardiography, Ambulatory, Coronary Artery Bypass, Diabetes Mellitus, Thrombocytopenia, Platelet Glycoprotein GPIIb-IIIa Complex

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