Monitoring

The PT (INR), ACT, aPTT, and TT all rise linearly with increases in the dose of bivalirudin. The ACT can be used to monitor bivalirudin in patients undergoing PTCA, PCI, OPCAB, or PTA, while the aPTT has been used in patients treated for HIT and other non-interventional indications if desired. However, monitoring is optional due to the linear pharmacokinetics of bivalirudin. Dosing in PCI generally results in ACTs above 300 or 350 although dosing is not adjusted based on the ACT, while at lower doses within the range of aPTT monitoring (used for certain non-approved indications), the target range usually is a 1.5- to 2.5-fold increase in the baseline aPTT (Chew et al., 2001).

The ACT and aPTT have limitations, however, and questions regarding their adequacy for monitoring DTI therapy remain, particularly for anticoagulation during CPB (Pötzsch et al., 1997; Koster et al., 2000, 2003a; Despotis et al., 2001; de Denus and Spinier, 2002). As a result, other tests have been developed for monitoring these anticoagulants. One of these, the ecarin clotting time (ECT; see Chapter 19) has been recommended for monitoring during on-pump cardiac surgery.

Koster et al. (2003a) found that an ECT ranging between 400 and 450 s provided acceptable anticoagulation during CPB, noting a close relationship between the ECT (but not the ACT) and bivalirudin concentrations. Nevertheless, a bivalirudin dosing protocol has now been developed that utilizes ACT (rather than ECT) monitoring, which has also provided acceptable monitoring during prospective evaluation for CPB anticoagulation (Dyke et al., 2006) (see Chapter 19). The bivalirudin infusion rate in the EVOLUTION-ON cardiac surgery trial was usually not adjusted according to the ACT; rather, the ACT was used to assure that the protocol-specified dosing achieved an acceptable level of anticoagulation, although physicians could give extra bivalirudin boluses at their discretion (see Chapter 19).

As with other anticoagulants, monitoring may not be reliable if the patient has a lupus anticoagulant, hypofibrinogenemia, elevated fibrinogen-fibrin degradation products, or if the plasma contains heparin (Reid and Alving, 1993). Acquired coagulopathies are often seen in critically ill patients (a patient group sometimes treated with bivalirudin), and associated low fibrinogen or prothrombin levels may lead to difficulties in judging appropriate drug levels. In these situations, other tests including high-performance liquid chromatography, immunoassays, and chromo-genic assays may be superior. Although such assays have been used to measure levels of various DTIs (Griessbach et al., 1985; Bichler et al., 1991; Spannagl et al., 1991; Walenga et al., 1991), these assays are not widely available.

Reid and Alving (1993) developed a quantitative thrombin time (QTT) in which bivalirudin (or hirudin) levels are measured using patient plasma (or whole blood) mixed with human fibrinogen solution, with the clotting time measured after adding human thrombin. The concentration of bivalirudin (or hirudin) is then determined by comparison with a standard curve that is generated by adding known concentrations of bivalirudin to pooled normal plasma.

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