Antithrombotic actions of the thrombin inhibitor, argatroban, in a canine model of coronary cyclic flow: comparison with heparin

Abstract

The antithrombotic action of argatroban, a synthetic thrombin inhibitor, was studied in a canine model of coronary cyclic flow having some of the characteristics of acute unstable angina. Heparin was studied as a reference anticoagulant. Localized endothelial damage was induced in the circumflex coronary artery of anaesthetized open‐chest foxhounds and a critical stenosis was applied by use of a Lexan constrictor placed around the artery at the site of endothelial damage. An electro‐magnetic flow probe was placed distal to the lesion, and cyclic flow variations (CFVs) were observed, as thrombi formed at the site of the arterial lesion and were dislodged. Test compounds were administered by i.v. infusion commencing 1 h after the appearance of CFVs, and maintained for 1 h. On termination of the treatments, coronary flow was observed for a further 60 min. A series of blood samples were taken at predetermined times throughout each experiment in order to determine the coagulation parameters, thrombin time (TT) activated partial thromboplastin time (aPTT) and for the determination of fibrinopeptide A (FpA) levels before, during and post‐treatment. Argatroban and heparin showed antithrombotic effects in this model. Argatroban dose‐dependently increased the minimum coronary flow at the nadir of the CFVs from 5.4 ± 1.7 to 9.1 ± 2.1 ml min−1 (30 μg kg−1 min−1, P = 0.041) and from 2.9 ± 0.9 to 16.3 ± 4.5 ml min−1 (100 μg kg−1 min−1, P = 0.023, n = 8 dogs at each dose level). Heparin (5 and 15 iu kg−1 min−1) also increased minimum flow, but the increase was not statistically significant at the 5% level, although the P value in animals treated with 15 iu kg−1 min−1 (P = 0.0521, n = 6 dogs) fell just outside this limit. Although neither compound significantly decreased the overall CFV frequency, argatroban (100 μg kg−1 min−1) significantly (P < 0.01) decreased the number of large amplitude CFVs (minimum coronary flow < 10 ml min−1) by 63%, and heparin (15 iu kg−1 min−1) caused a 50% decrease in this parameter (P < 0.05). The thrombin times were increased by a factor greater than 10 during antithrombotic treatment, irrespective of the compound or doses used. Heparin treatment induced 17 and > 30 fold increases in aPTT at 5 and 15 iu kg−1 min−1 respectively. However, argatroban produced only 2 and 3 fold increases in aPTT at 30 and 100 μg kg−1 min−1, despite significant antithrombotic effects. FpA levels were reduced in the presence of both argatroban and heparin. These data show that, when administered as an intravenous infusion, argatroban is a potent antithrombotic agent in a canine model of coronary cyclic flow.

Comparison of Anticoagulant Effects and Safety of Argatroban and Heparin in Healthy Subjects

“…These results are similar to those of early animal studies that reported much greater prolongation of aPTT for heparin than for argatroban. 12,28 In these three studies, plasma argatroban concentrations were correlated linearly with dose, and therefore the concentration-response relationships were easily derived. Thus it may be possible to predict the anticoagulant response of argatroban, given either its dose or plasma concentration.…”

“…10 Thrombus formation is inhibited by argatroban in various animal models. 11,12 In Japan, argatroban is approved for use in peripheral arterial occlusive disease, acute cerebral thrombosis, and hemodialysis in patients with antithrombin III deficiency, and is being evaluated as an anticoagulant in a variety of other conditions. In early Japanese clinical trials, however, the agent's efficacy and safety profiles are difficult to evaluate fully.…”

American College of Veterinary Emergency and Critical Care (ACVECC) Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE) guidelines: Small animal

“…Three studies (all LOE 3, Good) suggested that anticoagulants were inferior to antiplatelet agents in the setting of provoked arterial thrombosis . Multiple studies (19 LOE 3, Good; 1 LOE 3, Fair) also suggest efficacy of anticoagulants for arterial thrombosis in dogs, however …”

Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE): Domain 2—Defining rational therapeutic usage

“…In a femoral arterial thrombosis model, Prosdocimi et al demonstrated that UFH was inferior to aspirin and other platelet aggregation inhibitors, albeit at a lower UFH dosage than in the other 2 studies . Although direct comparisons suggest superiority of antiplatelet agents for arterial thrombosis in dogs, multiple studies (19 LOE 3, Good, 1 LOE 3, Fair) suggest efficacy of anticoagulants including UFH, low molecular weight heparin (LMWH), and direct inhibitors of Xa and thrombin for arterial thrombosis in dogs . Of these, 1 study suggested that heparin may protect against renal arterial thrombosis following renal transplantation in dogs better than aspirin, although the clinical applicability of that study is limited.…”