Bivalirudin

Abstract Bivalirudin, a synthetic analogue of hirudin, is a specific and reversible inhibitor of thrombin which binds directly with both fluid-phase and clot-bound thrombin. In patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA), results from a large well designed study and its reanalysis (n = 4312) indicate that bivalirudin is more effective than heparin in the prevention of ischaemic complications for up to 90 days after the start of treatment. In addition, among patients undergoing PTCA for post myocardial infarction (MI) bivalirudin may be more effective than heparin in preventing ischaemic complications for up to 180 days after treatment was started. Data from dose-finding studies indicate bivalirudin has potential in the treatment of patients with unstable angina not undergoing percutaneous coronary intervention (PCI); however, well designed comparative studies are needed before firm conclusions can be made. Among patients with acute ST elevation MI, randomised trials have demonstrated bivalirudin to be significantly more effective than heparin in improving early patency in patients receiving thrombolytic therapy with streptokinase. Data from the Hirulog and Early Reperfusion/Occlusion (HERO)-l trial (n = 412) indicate that bivalirudin recipients were significantly more likely to have Thrombin Inhibition in Myocardial Ischaemia (TIMI) grade 3 flow at 90 to 120 minutes than heparin recipients. In addition, data from the HERO-2 trial (n = 17073) show bivalirudin was significantly more effective than heparin in reducing adjudicated 96-hour reinfarction and 30-day investigator-reported death/reinfarction than heparin. Bivalirudin was as effective as heparin in reducing 30-day mortality. Data from a meta-analysis of four randomised trials among patients undergoing PTCA or treatment for acute coronary syndromes indicate that, at after 30 to 50 days of follow-up, bivalirudin was significantly more effective than heparin in reducing the incidence of nonfatal MI and the combined endpoint of death or nonfatal MI. The most significant adverse events associated with bivalirudin are bleeding complications. In individual trials, bivalirudin was as well tolerated as heparin with, in general, a reduced incidence of bleeding complications. Additionally, bivalirudin provides a more consistent, predictable anticoagulant response. In 4312 patients with unstable angina undergoing PTCA the incidence of retroperitoneal bleeding, blood transfusion and major haemorrhage was significantly lower in bivalirudin than heparin recipients. Data from the HERO-2 trial in patients with acute MI indicate that although bivalirudin recipients had a significantly higher incidence of mild or moderate bleeding than heparin recipients, there was no difference in intracranial haemorrhage, severe bleeding or transfusions. Data from a meta-analysis among 5674 patients with ischaemic heart disease show bivalirudin recipients were at a significantly lower risk of haemorrhagic events than heparin recipients. Conclusions: Bivalirudin is an effective alternative to heparin in the prevention of ischaemic complications in patients with unstable angina undergoing PTCA. In addition, the drug has shown potential in the treatment of patients with unstable angina not undergoing PCI. For patients with MI, it is clear that bivalirudin can replace heparin in the management of MI where streptokinase is used as the thrombolytic agent. Further data are required on the efficacy of bivalirudin in patients undergoing thrombolysis with newer thrombolytics. Pharmacodynamic Profile Bivalirudin is a specific and reversible inhibitor of thrombin and, unlike heparin, inhibits both fluid-phase and clot-bound thrombin and does not require anti-thrombin as a cofactor. The resultant complex is reversible, as bivalirudin is slowly cleaved by thrombin to leave a weak thrombin inhibitor binding competitively to the fibrin(ogen) recognition exosite of thrombin. In animal and in vitro studies bivalirudin has been shown to have dose-or concentration-dependent antithrombin properties with activity against clotbound thrombin. In addition, in vitro bivalirudin weakly inhibits activated protein C, improves vessel patency, and inhibits thrombin-induced plasminogen activator inhibitor-1 and factor Xa. In animal models, bivalirudin reduces thrombotic vascular stenosis, the time to thrombolysis, and platelet deposition. In healthy volunteers, intravenous (IV) bivalirudin produces a dose-dependent increase in activated partial thromboplastin time (aPTT), prothrombin time and thrombin time. In patients with acute coronary syndromes, a roughly linear correlation is observed between dose and aPTT values. There is little intraindividual and interindividual variation in aPTT values with 99.1% of patients maintaining values within a 40-second range in one study. Peak prolongation of values occurred 2 hours after the start of the infusion in one study. Activated clotting times (ACTs) also show a dose-dependent effect. Bivalirudin is as effective as heparin in reducing plasma levels of fibrinopeptide A. In patients undergoing cardiac catheterisation, bivalirudin produces an exponential dose-dependent decrease in fibrinopeptide A levels with the most consistent decreases seen at dosages of 1 mg/kg/h. In addition, when combined with abciximab there is some evidence to suggest it may be more effective than heparin plus abciximab in preventing platelet activation. Mean aPTT values are higher in patients with severe renal impairment and in those requiring haemodialysis than in patients with normal to moderate impairment. In addition, mean ACTs are prolonged in patients with moderate or severe renal function compared with those with mild impairment or normal renal function. Pharmacokinetic Profile In patients undergoing percutaneous transluminal coronary angioplasty (PTCA) and in healthy male adult volunteers, IV bivalirudin exhibits linear pharmacokinetics. Maximum plasma concentrations ($ C_{max} $) are dose-proportional and are reached after 2 minutes in those receiving IV bolus injections. Bivalirudin has a small mean volume of distribution (0.156 L/kg) and does not bind to plasma proteins, platelet factor 4 or red blood cells. Bivalirudin is rapidly cleared from plasma by a combination of renal mechanisms and proteolytic cleavage. Renal clearance is the primary route for elimination of unchanged bivalirudin which accounts for 20% of total clearance. About 80% of bivalirudin is degraded by proteolytic cleavage, including cleavage by thrombin with its protease, to individual amino acids and small, largely inactive peptide fragments. Bivalirudin has an elimination half-life (t1/2) of 25 minutes and a total body clearance rate of 0.204 L/kg/h following IV infusion in individuals with normal renal function undergoing PCI. Renal clearance is the primary route for clearance of unchanged drug and bivalirudin clearance is 1.8-fold greater than the glomerular filtration rate suggesting that renal secretion occurs in addition to filtration. In individuals with moderate renal impairment, clearance of bivalirudin is reduced both in otherwise healthy volunteers and in patients with unstable angina undergoing PTCA. Cmax and t1/2 increase progressively and total body clearance decreases as the degree of renal impairment increases in severity. Dosage adjustments are therefore recommended in patients with a glomerular filtration rate of <3.6 L/h. In patients undergoing PTCA, coadministration of bivalirudin with unfractionated heparin, warfarin or thrombolytics was associated with an increased risk of bleeding compared with that in patients not receiving these concomitant medications. Coadministration of bivalirudin with abciximab, ticlopidine or low molecular weight heparin has not revealed any clinically significant interactions. Therapeutic Use Percutaneous Coronary Interventions (PCI). Bivalirudin is as effective as heparin in improving angiographic and procedural outcomes according to data from a randomised, double-blind study. Data from a prospectively randomised population indicate that in patients with documented evidence of an MI bivalirudin may be more effective than heparin in preventing ischaemic outcomes. In addition, according to a reanalysis, bivalirudin is more effective than heparin in preventing ischaemic complications in patients with unstable angina undergoing PTCA. In the Bivalirudin Angioplasty Study (n = 4312), 11.4% of bivalirudin recipients reached the primary endpoint (death in-hospital, MI, abrupt vessel closure or rapid clinical deterioration of cardiac origin) compared with 12.2% of heparin recipients; in a prospective subgroup analysis of 741 study participants with a documented MI, significantly fewer bivalirudin than heparin recipients experienced procedural failure (5.1 vs 10.8%). A recent reanalysis of this study demonstrated that bivalirudin recipients had signif....

Medienart:	E-Artikel

Erscheinungsjahr:	2002
Erschienen:	2002

Enthalten in:	Zur Gesamtaufnahme - volume:62
Enthalten in:	Drugs - 62(2002), 5 vom: Apr., Seite 841-870

Sprache:	Englisch

Beteiligte Personen:	Carswell, Christopher I. [VerfasserIn] Plosker, Greg L. [VerfasserIn]

Links:	Volltext [lizenzpflichtig]

BKL:	44.40 44.38
Themen:	Abciximab Bivalirudin Percutaneous Coronary Intervention Streptokinase Unstable Angina

doi:	10.2165/00003495-200262050-00008

funding:
Förderinstitution / Projekttitel:

PPN (Katalog-ID):	SPR033188807