Pharmacologic and Pharmacokinetic Considerations in Anticoagulant Selection

The lack of prospective comparative studies between danaparoid, lepirudin, and argatroban precludes definitive conclusions about relative efficacy and safety. However, there are several pharmacological and pharmacokinetic differences that physicians should consider when determining which drug might be preferred in

TABLE 3 Main Characteristics of Danaparoid Sodium

Mechanism of action, pharmacokinetics

Monitoring

Undesirable effects

Comments

Catalyzes the inactivation of factor Xa by AT, and of thrombin (IIa) by AT and HCII Bioavailability after sc injection ~100%; peak anti-Xa levels, 4-5 h after injection (Danhof etal., 1992) Mean plasma distribution time following iv bolus, ~2.3 h Plasma ty2 of anti-Xa activity, 17-28 h (mean, 25 h); ty2 of anti-IIa activity, 2-4 h (Danhof etal., 1992)

Anti-Xa levels during treatment by an amidolytic assay using danaparoid reference curve Monitoring recommended in patients with: (1) significant renal impairment; (2) body weight < 45 kg or >110 kg; (3) life- or limb-threatening thrombosis; (4) unexpected bleeding; (5) critically ill or unstable patient

XR with HIT antibodies: in vitro XR usually not associated with adverse effects; patients should be monitored for in vivo XR (unexplained platelet count fall, progressive new TECs); in vivo XR is estimated to occur in ~3% of patients (Magnani and Gallus, 2006) Bleeding complications in compassionate-release study (Ortel and Chong, 1998): fatal (0.9%), major nonfatal bleeding (6.5%); no major bleeds in RCT (Chong etal., 2001) Skin hypersensitivity: rare

Anticoagulant effect depends on adequate AT levels Does not significantly prolong the aPTT, ACT, PT/INR (does not interfere with monitoring of overlapping oral anticoagulants) Reduce dosage if serum creatinine >265 mmol/L No antidote: in case of overdosage, stop the drug and treat bleeding with blood products as indicated

Abbreviations: ACT, activated clotting time; aPTT, activated partial thromboplastin time; AT, antithrombin III; HCII, heparin cofactor II; HIT, heparin-induced thrombocytopenia; iv, intravenous; PT/INR, prothrombin time/ international normalized ratio; RCT, randomized controlled trial; sc, subcutaneous; TEC, thromboembolic complication; t1/2, drug half-life; XR, cross-reactivity .

an individual patient (Tables 3-5). For example, in a patient with vital organ or limb ischemia or infarction, who might need urgent surgical intervention, an agent with a short half-life may be desirable. But, in a patient with venous thromboem-bolism in whom an uncomplicated overlap with (longer-term) warfarin anticoagulation is anticipated or who requires outpatient treatment by subcutaneous (sc) injections, danaparoid use is advantageous. Argatroban (which undergoes hepatobiliary clearance) is suited for patients with renal insufficiency, as dose reduction is generally not required (cf. lepirudin). Conversely, lepirudin may be more suitable than argatroban for patients with hepatobiliary dysfunction, including reduced liver perfusion due to cardiac insufficiency.

As the key therapeutic goal of anticoagulation during acute HIT is to achieve effective inhibition of thrombin or its generation, the ability to determine accurately the drug anticoagulant levels is an important issue. In the case of danapar-oid, drug levels can be measured directly (via antifactor Xa levels), whereas in most medical centers, the anticoagulant levels of the DTIs are measured indirectly, using the activated partial thromboplastin time (aPTT). This can cause underdosing in patients with prothrombin deficiency, as a "therapeutic" aPTT may not necessarily indicate adequate dosing of the DTI (see Chapter 14). Other factors to consider include drug availability to, and prior experience of, the physician and availability and turnaround time of laboratory monitoring.

TABLE 4 Main Characteristics of the r-Hirudin, Lepirudin

Mechanism of action, pharmacokinetics

Monitoring

Undesirable effects

Comments

Direct, noncovalent, irreversible inhibitor of free and clot-bound thrombin Bioavailability after sc injection, ~100%; peak effect, 2-3 h Mean plasma distribution time after iv bolus, ~2 h Mean plasma tv2, 1.3 h; ty2 greatly prolonged in renal failure (~200 h in nephrectomized patients)

aPTT during treatment; a more precise monitoring is possible by the ECT (see Chapters 14, 16, and 19) Daily aPTT monitoring is recommended in all patients (see comments re: antihirudin antibodies) Monitoring by ECT recommended:

1. During CPB

2. Unexpected bleeding Monitoring by quantitative hirudin EIA or ECA recommended: when prothrombin levels are decreased (Lindhoff-Last et al., 2000; see Chapter 14)

Development of antihirudin antibodies in ~40% of patients. In about 3% of patients, these antibodies enhance the anticoagulant effect of hirudin, and require a substantial dose reduction Anaphylactic reactions: ~0.015% (first exposure) ~0.15% (reexposure) associated with iv bolus injection (Greinacher et al., 2003) Reduce dosage if serum creatinine >90 mmol/L (see Chapter 14) Allergic reactions:

very rare Skin hypersensitivity:

very rare Bleeding complications in HIT patients in prospective studies: major bleeding in two prospective studies, 13.4, 17% (see Chapter 14)

~40% of patients develop antihirudin antibodies on day 5 or later of treatment; in only ~5 % of these patients is a dose reduction or increase needed; risk of anaphylactic reactions post-iv bolus No major effect on PT/INR (Greinacher etal., 2000) No antidote: In case of overdosage, stop the drug and treat bleeding with blood products as indicated (hemofiltration with a high-flux membrane is a possible treatment for life-threatening bleeding)

Abbreviations: aPTT, activated partial thromboplastin time; CPB, cardiopulmonary bypass; ECA, ecarin chromo-genic assay; ECT, ecarin-clotting time; EIA, enzyme-immunoassay; HIT, heparin-induced thrombocytopenia; iv, intravenous; PT/INR, prothrombin time/international normalized ratio; sc, subcutaneous; t1/2, drug half-life.

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