Recombinant Nematode Anticoagulant Protein c2 in Patients With Non–ST-Segment Elevation Acute Coronary SyndromeThe ANTHEM–TIMI-32 Trial
Robert P. Giugliano, MD, SM, FACC*,2,*,
Stephen D. Wiviott, MD*,3,
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,1,
Carolyn H. McCabe, BS*,
Eugene Braunwald, MD, MACC*,4 for the ANTHEM–TIMI-32 Investigators
* TIMI Study Group, Boston, Massachusetts
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.
View larger version (15K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1 Mechanism of Action of rNAPc2
Tissue factor/activated factor VII (TF/fVIIa) inhibition by recombinant nematode anticoagulant protein c2 (rNAPc2) involves the following steps: 1) rNAPc2 binds tightly to zymogen factor X; 2) docking of the rNAPc2-fX complex to TF/fVIIa assembled on a procoagulant phospholipid surface; and 3) presentation of the reactive loop of rNAPc2 to the active site of fVIIa, resulting in a tightly bound quarternary inhibitory complex. c2 = rNAPc2; TF = tissue factor; VIIa = fVIIa; X = factor X.
|
|
View larger version (40K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 2 ANTHEM–TIMI-32 Design
The study had 2 phases: (A) a double-blind, randomized, placebo-controlled, ascending dose-ranging phase and (B) a single-arm, unblinded heparin de-escalation phase. In the dose-ranging phase (A), 203 patients with non-ST-segment elevation acute coronary syndrome (nSTE-ACS) managed with an early catheterization were randomized 4:1 to recombinant nematode anticoagulant protein c2 (rNAPc2) or matching placebo administered intravenously (IV) every 48 h for 1 to 3 doses in 8 panels of  25 patients each. In the heparin de-escalation phase (B), 26 patients received 10 µg/kg rNAPc2 and half-dose unfractionated heparin (UFH), followed by a second panel of 26 patients treated with 10 µg/kg rNAPc2 and no heparin. *Encouraged per current practice guidelines. 10 µg/kg dose panel repeated. ASA = aspirin; ECG = electrocardiogram; Enox = enoxaparin; GP = glycoprotein.
|
|
View larger version (22K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 3 Pharmacokinetics and Pharmacodynamics
(A) Increasing doses of recombinant nematode anticoagulant protein c2 (rNAPc2) were associated with increased plasma drug concentrations at 2 to 6 and 48 h. (B) rNAPc2 increased the international normalized ratio (INR) in a dose-related fashion at 2 to 6 and 48 h.
|
|
View larger version (13K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 4 rNAPc2 Suppresses New Thrombin Generation
Prothrombin fragment 1.2 (F1.2), a marker of new thrombin generation, was reduced signficantly at 2 to 6 and 48 h with  7.5 µg/kg recombinant nematode anticoagulant protein c2 (rNAPc2) compared with placebo. Lower-dose rNAPc2 (1 to 5 µg/kg) blunted the increase in F1.2 seen at 48 h in the placebo group.
|
|
View larger version (16K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 5 Hemorrhagic Events With rNAPc2
There was no difference between the rates of major plus minor hemorrhage among patients receiving recombinant nematode anticoagulant protein c2 (rNAPc2) versus placebo (3.7% vs. 2.5%, respectively), nor was there a trend across ascending doses (p = NS). All major and minor bleeding events were related to procedures; none were spontaneous. *3/4 major hemorrhages were CABG-related, 2 to 3 days after surgery. CABG = coronary artery bypass graft; Hgb = hemoglobin; ICH = intracranial hemorrhage; TIMI = Thrombolysis In Myocardial Infarction; UFH = unfractionated heparin.
|
|
|
