Pharmacodynamics

Bivalirudin produces an immediate effect after iv administration. It causes prolongation of the prothrombin time (PT)/international normalized ratio (INR), activated clotting time (ACT), the activated partial thromboplastin time (aPTT), and the thrombin time (TT) (Fox et al., 1993; Lidon et al., 1993; Sharma et al., 1993; Topol et al., 1993). Although there is some interindividual variability, a dose of bivalirudin given as an infusion of 0.20 mg/kg/h increased the aPTT from 27 to 62 s in one study, while an infusion rate of 1.0 mg/kg/h resulted in an average aPTT of 98 s in another group of patients (Lidon et al., 1993).

The INR is also prolonged somewhat during bivalirudin infusion. In 54 healthy volunteers, a dose of 0.05-0.6 mg/kg of bivalirudin given over 15 min iv increased the INR to between 1.25 and 2.43 (Fox et al., 1993). In a study by Lidon and coworkers (1993), the PT was prolonged to between 12 and 16 s with a dose of 0.20 mg/kg/h, while Francis and colleagues (2004) recently reported the mean INR on monotherapy to be 1.50 (range 1.23-2.18) in 52 patients with suspected HIT treated with bivalirudin. Two abstracts also mention a slight prolongation in the INR (Bufton et al., 2002a,b). Although the increase in the INR seems not to be as great as with the DTI argatroban, physicians need to be aware of DTI-coumarin interactions during overlapping therapy (see Chapter 12).

Two studies have demonstrated differences among the DTIs with respect to their ability to prolong the PT (or INR). Gosselin et al. (2004) performed an in vitro study comparing bivalirudin, lepirudin, and argatroban using pooled normal plasma and 14 PT reagents commercially available in the United States, whereas Warkentin and colleagues (2005) used two reagents (of widely differing international sensitivity index [ISI] values) and compared four DTIs (lepirudin, bivali-rudin, argatroban, and melagatran). Both groups reported that argatroban had the

Activated partial thromboplastin time, aPTT (s)

FIGURE 3 Effects of four DTIs on the INR-aPTT relationship. Pooled normal plasma was supplemented with serial twofold increases in the concentrations of each DTI. The asterisk (*) indicates the identical molar concentration (0.5 mmol/L) for each DTI. For a 1.5-3.0-fold increase in the aPTT (the range shown by the vertical dotted lines), the DTIs differ considerably in their ability to prolong the INR, as follows: argatroban > melagatran > bivalirudin > lepirudin. Abbreviations: aPTT, activated partial thromboplastin time; DTI, direct thrombin inhibitor; INR, international normalized ratio. Source: From Warkentin and Koster, 2005, with modifications.

Activated partial thromboplastin time, aPTT (s)

FIGURE 3 Effects of four DTIs on the INR-aPTT relationship. Pooled normal plasma was supplemented with serial twofold increases in the concentrations of each DTI. The asterisk (*) indicates the identical molar concentration (0.5 mmol/L) for each DTI. For a 1.5-3.0-fold increase in the aPTT (the range shown by the vertical dotted lines), the DTIs differ considerably in their ability to prolong the INR, as follows: argatroban > melagatran > bivalirudin > lepirudin. Abbreviations: aPTT, activated partial thromboplastin time; DTI, direct thrombin inhibitor; INR, international normalized ratio. Source: From Warkentin and Koster, 2005, with modifications.

greatest effect on the INR while lepirudin exhibited the least. Gosselin et al. also found that bivalirudin's effect on the INR was dependent on its concentration and the reagent used, with INR values ranging from 1.10 to 1.53 (Gosselin et al., 2004). Warkentin and Koster found similar results, and noted that PT (INR) prolongation corresponded to the DTI molar concentrations required to prolong the aPTT, i.e., if a higher molar concentration of the DTI is needed to prolong the aPTT, then its effect on PT (INR) prolongation will be relatively greater (Warkentin and Koster, 2005; Warkentin et al., 2005) (Fig. 3).

Bivalirudin decreases fibrinopeptide A levels (a marker of fibrinogen cleavage) in patients with coronary artery disease (Cannon et al., 1993; Ren et al., 1997). It may also increase the bleeding time in some patients (Topol et al., 1993).

Bivalirudin does not inhibit platelet activation or aggregation directly, but it has been shown to inhibit thrombin-mediated platelet aggregation without affecting adenosine 5'-diphosphate (ADP) or collagen-mediated platelet activation (Weitz and Maraganore, 2001; Wiggins et al., 2002; Wittkowsky, 2002) (Fig. 4). Bivalirudin has also been shown to be effective in blocking thrombin activation of both protease-activated receptor (PAR)1 and PAR4-dependent platelet aggregation (Leger et al., 2006).

Recently, Schneider et al. (2006) demonstrated that bivalirudin inhibited thrombin-induced activation of platelets to a greater extent than heparin or heparin plus eptifibatide. Bivalirudin has also been shown to be effective (when used in combination with aspirin and clopidogrel) in suppressing thrombin generation and activity (Keating et al., 2005a). These antiplatelet effects, as well as bivalirudin's a ro 50'

Therapeutic concentration of bivalirudin (2-20 p,g/L) I-1

Platelet agonist -O- ADP -o- Collagen Thrombin

Bivalirudin concentration (^g/L)

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