Recombinant hirudin as a periprocedural antithrombotic in coronary angioplasty for unstable angina pectoris

Abstract

Percutaneous transluminal coronary angioplasty is often complicated by thrombotic abrupt vessel closure in patients with unstable angina pectoris. The present multicentre trial was performed to determine the feasibility of two-dose regimens of recombinant hirudin (r-hirudin) compared to standard heparin in patients undergoing coronary angioplasty for unstable angina, and to investigate the effects of the different treatment regimen on markers of coagulation activation. At five participating centres, 61 patients were randomly enrolled in one of two sequential groups of r-hirudin (group 1: 0.3 mg.kg-1 i.v. bolus, 0.12 mg.kg-1.h-1 i.v. infusion; 21 patients; group 2: 0.5 mg.kg-1 i.v. bolus, 0.24 mg.kg-1.h-1 i.v. infusion; 19 patients) or in a heparin control group (150 IU.kg-1 i.v. bolus, 20 IU.kg-1.h-1 i.v. infusion; 21 patients). Antithrombotic therapy was started immediately before coronary angioplasty and continued for 24 h. This was followed by a low-dose anticoagulant infusion for another 24 h (r-hirudin: 0.04 mg . kg-1 . h-1; heparin: 7 IU . kg-1 . h-1). Activated partial thromboplastin time, r-hirudin plasma concentrations by both immunological and functional assay, thrombin-hirudin complex, thrombin-antithrombin III complex, soluble fibrin, and prothrombin fragment 1 + 2 were closely monitored. The median partial thromboplastin time prolongations at 24 h vs baseline were found to be 1.9-fold and 2.3-fold in r-hirudin group 1 and dose group 2, respectively, and 3.0-fold in the heparin group. There was a dose-dependent correlation between partial thromboplastin time and the r-hirudin plasma levels (r = 0.61). In five of 21 patients of dose group 1, three of 19 patients of dose group 2, and 10/21 patients of the heparin group, partial thromboplastin time values exceeding the predefined target range prompted an interruption of the infusion. One major bleeding complication occurred in dose group 2. The functional assay for the estimation of r-hirudin plasma concentrations showed excellent correlations to the immunological technique (r = 0.99). Differences between the thrombin-hirudin complex levels could not be observed. Increased concentrations of thrombin-antithrombin III complex, soluble fibrin, and prothrombin fragment 1 + 2 were seen 4-8 h after coronary angioplasty and after reduction of the high-dose therapy in dose group 1 when compared with dose group 2 and the heparin group, respectively. Based on coagulation tests the present study showed the feasibility of a periprocedural antithrombotic regimen with r-hirudin for patients undergoing coronary angioplasty for unstable angina. In addition to the partial thromboplastin time the determination of r-hirudin plasma levels by a chromogenic substrate assay considerably improves the monitoring of therapy. The lower dose r-hirudin regimen seems to be suboptimal as periprocedural anticoagulation in coronary angioplasty patients as indicated by markers of thrombin generation and thrombin activity.

Increased platelet responsiveness following coronary stenting Heparin as a possible aetiological factor in stent thrombosis

“…Even in patients scheduled to receive antiplatelet therapy after stenting, heparin is still administered at the time of the procedure. Further reductions in the thrombotic complications of angioplasty and stenting might therefore accrue from the use of alternative antithrombin agents such as hirudin [40] , or if heparin continues to be used, from the use of low molecular weight rather than unfractionated heparins. …”

Anticoagulation in Patients with Heparin-Induced Thrombocytopenia undergoing Percutaneous Coronary Angiography and Interventions

“…Despite the fact that the event-free survival at 7 month was not significant (#1 67.3%, #2 63.5% and #3 68%; P=0.61) the administration of hirudin yielded to a significant lower rate in early cardiac events (#1 11.0%, #2 7.9% and #3 5.6%; combined relative risk with hirudin 0.61; 95% CI, 0.41 to 0.9; P=0.023). Two smaller trials demonstrated the feasibility of hirudin in patients with unstable angina pectoris undergoing PCI [110,111]. The OASIS and OASIS-2 trials demonstrated the superiority of recombinant hirudin compared to heparin in terms of preventing of cardiovascular death, myocardial infarction and refractory angina in patients presenting with unstable angina pectoris or NSTEMI [112,113].…”

Emerging Anticoagulant Drugs

“…79 -81 Generally, treatment is monitored with the activated partial thromboplastin time (aPTT), which should be determined before treatment, 4 hours after the start of intravenous hirudin therapy, 4 hours after every dosage change, and then at least once daily. 78 Unfortunately, there are problems when the aPTT is used to monitor hirudin therapy, including variability in responsiveness between patients 82 and the lack of a linear correlation with plasma hirudin levels. At higher doses, use of the ecarin clotting time may be more appropriate, because its correlation with plasma hirudin levels is more linear.…”