Direct thrombin inhibitors. Thrombin is the final enzyme in the clotting cascade, representing a reasonable target of most of the current clinical anticoagulants. The rationale for the clinical use of direct xxxxx- bin inhibitors is their ability to inactivate fibrin-bound thrombin, in contrast to both UFH and LMWH – AT complexes. They are also unaffected from other limitations of current therapeutic strategies like acquired or inherited AT deficiency, they demonstrate a better bioavailability profile, and avoid the problem of HIT.
Direct thrombin inhibitors. 6.6.1.1 Parenteral direct thrombin inhibitors Xxxxxxx, lepirudin (a recombinant hirudin), argatroban and bivalirudin are all parenterally administered direct thrombin inhibitors. The rationale for their clinical use as well as their benefits over UFH and LMWH has been analyzed before. Hirudin and (its recombinant analogue) lepirudin are mainly used for the treatment of HIT. Lepirudin has also been evaluated for the treatment of acute coronary syndromes (both unstable angina and non-ST elevation myocardial infarction) but results were disappointing; a benefit was indeed observed in terms of death, re-infarction and revascularization reduc- tion, but this was on the expense of increased moderate or major bleeding, attributed to its narrow therapeutic window243, 244. Similarly, in the case of STEMI patients, randomized trials failed to support a substantial benefit from the use of either hirudin or lepirudin, although in this case an increased risk of bleeding was not observed243, 245. Argatroban has also been FDA approved for the treatment of HIT. It has a short in vivo half- life and dose adjustments are not required in the presence of renal failure. As in the case of hirudin/lepirudin, a randomized trial failed to prove a benefit from using it in the setting of acute myocardial infarction patients246. Bivalirudin has also a short plasma half-life (of about 25 minutes) and undergoes predomi- nantly non-organ elimination (proteolysis), inclining for a rather safe profile in terms of bleed- ing complications. It is the first agent of this class that has been approved as an effective anticoagulant in the setting of interventional cardiology. In the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) study (involving 14000 patients with moderate or high risk ACS undergoing PCI) bivalirudin (as the only anticoagulant) proved as effective as the combination of UFH or enoxaparin with GPIIb/IIIa in terms of ischemic complications at 30 days, while significantly reducing the bleeding complications, with the greater benefit observed in those aged more than 75 years247. The efficacy of bivalirudin in the setting of STEMI was further studied in the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS AMI) trial, where bivalirudin plus provisional use of GPIIb/IIIa was tested against standard therapy, in a series of 3600 patients. Both at the 30-day and 12-month time points, bivalirudin proved safer in terms ...
