Direct Thrombin Inhibitors in Percutaneous Coronary Intervention
Hitinder S. Gurm
Michael A. Lincoff
Percutaneous coronary intervention (PCI), by virtue of the introduction of foreign bodies (wires, catheters, stents, etc.) and the obligate vascular injury (at the site of intervention), creates a pro-thrombotic milieu and therefore requires adjuvant pharmacotherapy to prevent thrombosis. Although unfractionated heparin has been and remains the most commonly used agent in most procedures, its use is associated with certain drawbacks. These include a variable anticoagulant effect and dose response in different patients (1), inability to inhibit clot-bound thrombin (2), a potential platelet aggregant effect (3,4), susceptibility to platelet factor 4 (PF4) (5), and the propensity to produce heparin-induced thrombocytopenia (HIT), with its attendant hazard of thrombosis (6). Given these factors, multiple agents have been evaluated as potential replacements for heparin in cardiovascular disease. This review focuses on direct thrombin inhibitors and their role in cardiovascular intervention.
Thrombin is derived from the cleavage of prothrombin after activation of the coagulation cascade. Thrombin, in turn, acts as a catalyst for the conversion of fibrinogen to fibrin, which subsequently cross-links to form the mesh that, with its entrapped cellular content, forms a thrombus. Thrombin also activates factors V and VIII, which in turn enhance the production of thrombin and stimulate factor XIII to form factor XIIIa, which stabilizes the fibrin cross links (7). Beyond these effects, thrombin is also a potent vasoconstrictor and a platelet aggregant and enhances leukocyte chemotaxis (8,9).
Given the unique role of thrombin in the coagulation cascade, its inhibition is central to successful antithrombotic pharmacotherapy (7,10). Thrombin is a serine protease with high substrate specificity (11). Antithrombotic agents can block its action via binding to three sites: (a) the active or the catalytic site, (b) exosite -1, which ensures proper orientation of substrates, and (c) exosite -2, the binding site for indirect thrombin inhibitors (heparin and anti thrombin -3 complex) (12, 13, 14).
Currently, three direct thrombin inhibitors (DTIs) are available for clinical use. These include lepirudin and bivalirudin, which bind in a bivalent fashion to both the catalytic site and exosite-1, and argatroban, which binds only to the catalytic site. Although lepirudin binds in an irreversible fashion to thrombin, the binding of bivalirudin to thrombin is reversible and is associated with the eventual cleavage of the amino terminal region of bivalirudin by thrombin at the catalytic site (15,16). This in turn weakens the bond between the exosite -1 and the remainder of bivalirudin segment, leading to their dissociation and resumption of normal thrombin activity. Although
this factor may be important in the recovery of normal hemostatic function after bivalirudin use, it also explains the loss of antithrombotic activity as may occur in the setting of stasis as seen in extracorporeal circuits or associated with prolonged dwelling time in the setting of brachytherapy.
this factor may be important in the recovery of normal hemostatic function after bivalirudin use, it also explains the loss of antithrombotic activity as may occur in the setting of stasis as seen in extracorporeal circuits or associated with prolonged dwelling time in the setting of brachytherapy.
BIVALIRUDIN
Bivalirudin is currently the only agent for which significant data exist with respect to its use in coronary and peripheral intervention. In patients undergoing PCI, it is administered intravenously as a bolus of 0.75 mg/kg, followed by an infusion of 1.75 mg/kg/hour for the duration of the procedure. It is distributed predominantly intravascularly and does not exhibit binding to plasma proteins (other than thrombin) or blood cells. The clearance of bivalirudin is via both proteolysis (80%) and renal excretion (20%). The half-life of bivalirudin is 25 minutes and is prolonged by renal insufficiency. Whereas the bolus does not need adjustment, the infusion should be reduced by 20% in patients with a calculated glomerular filtrate rate (GFR) of 30 to 59 mL/min and 60% in those with a lower GFR (17). In patients on dialysis, the half-life approximates 3.5 hours, and the infusion should be reduced by 90%. Approximately 25% of bivalirudin is cleared by hemodialysis. There is no known antidote for bivalirudin, but given its short half-life, this is not usually a concern except in patients with severe renal dysfunction.
Bivalirudin in Percutaneous Coronary Intervention
Early clinical experience with bivalirudin came from the Hirulog Angioplasty study that randomized 4,098 patients undergoing angioplasty for unstable or postinfarction angina to heparin or bivalirudin (18). No difference was observed in the primary endpoint of death in the hospital, myocardial infarction (MI), abrupt vessel closure, or rapid clinical deterioration of cardiac origin (11.4% versus 12.2%) although the group randomized to bivalirudin had a lower incidence of bleeding (3.8% versus 9.8%). The investigators subsequently published the results of the complete study based on 4,312 patients analyzed on an intention-to-treat basis and incorporating postprocedural myonecrosis (instead of angiographic variables) as an endpoint (19). This analysis demonstrated a reduction in the composite of death, MI, or repeat revascularization at 7 days (6.2% versus 7.9%), 90 days, or 6 months. The reduction in bleeding was maintained, thus suggesting a unique safety profile.
Although these results were instrumental in the approval of bivalirudin, the routine use of bivalirudin had to await further evaluation, in view of the large body of data that had come to support the use of platelet glycoprotein (GP) IIb/IIIa inhibitors in PCI. The Comparison of Abciximab Complications with Hirulog for Ischemic Events (CACHET) trial randomized 268 patients undergoing PCI to either heparin and abciximab or a bivalirudin-based strategy (20). Three bivalirudin strategies were tested in a sequential fashion: bivalirudin with routine abciximab, bivalirudin with provisional abciximab, and a low dose of bivalirudin with provisional abciximab. A reduction was observed in the composite of death, MI, repeat revascularization, or major bleeding by 7 days in the bivalirudin-based strategy (3.4% versus 10.6%). This pilot study suggested a role for a bivalirudin-based strategy with provisional rather than routine use of GP IIb/IIIa inhibitors.
This study was followed by the REPLACE-I trial, in which 1,056 patients were randomized to heparin or bivalirudin (21). GP IIb/IIIa inhibitor use was at the discretion of the investigator. No difference was observed in the incidence of the composite of death, MI, repeat revascularization before hospital discharge or within 48 hours between the two arms (5.6% versus 6.9%, p = 0.40). Major bleeding occurred in 2.1% of those randomized to bivalirudin versus 2.7% of those randomized to heparin. Although statistically nonsignificant, the reduction in ischemic events was seen both among patients who received GP IIb/IIIa inhibitors and in those who did not receive them. In contrast, the reduction in bleeding events was limited to patients not treated with GP IIb/IIIa inhibitors.
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