Conclusion

The r-hirudin lepirudin is a DTI that provides rapid and effective anticoagulation and significantly reduces the risk of thrombosis in patients with HIT, including those with isolated thrombocytopenia. Less than 10% of all patient groups with HIT developed a new thrombosis after start of active treatment.

Lepirudin is given parenterally by iv infusion or sc injection. Recommended lepirudin dosage schedules have been established (Table 1). Lepirudin has a short half-life, which presents an advantage if invasive surgical procedures are indicated. However, its elimination strongly depends on renal function. The most important lessons learned after approval of the drug is that the approved dosage schedule is too high. The bolus should only be given in life- or limb-threatening thrombosis and also the starting maintenance dose should be greatly reduced (from 0.15 to 0.05-0.10 mg/kg/h), especially in elderly patients. Lepirudin can be used safely and effectively in patients with renal impairment by appropriate dosing according to serum creatinine and regular monitoring. Lepirudin also allows for a safe and uncomplicated transition to warfarin, provided that warfarin is initiated after recovery of the platelet count.

After start of treatment, lepirudin should be monitored every 4 h until a steady state is reached, then daily monitoring of aPTT is recommended with dosage adjustments made as needed to maintain the target aPTT value. Routine monitoring with ECT should be performed in high-dose situations, such as those required during CPB. All functional assays (aPTT, ECT) can give false high levels of anticoagulation in patients with prothrombin or fibrinogen deficiencies. In these patients a chromogenic assay (ECA) is more suitable to avoid underdosing.

The most common adverse event in the prospective clinical trials was bleeding. No antidote exists for the DTIs. Excess lepirudin can be removed by hemofiltration, and rFVIIa may also be used, but clinical data are limited.

Besides the 403 patients with HIT treated in prospective trials, an additional 1329 patients received lepirudin for HIT in a postmarketing surveillance study. Data on these patients, collected under routine clinical conditions, showed the lowest incidence of the clinical endpoints of death, new thrombosis, and amputations, with risk reductions exceeding those reported in the prospective clinical trials. Even more importantly, the incidence of major bleeding was low. These differences support the assumption that outcomes in patients with HIT can be substantially improved by immediately stopping heparin and starting lepirudin when HIT is strongly suspected on clinical grounds, without awaiting results of antibody testing, and that the bleeding risk has been reduced substantially as physicians have learned to handle this agent.

Postapproval observational studies also gave insights in the frequency of rare adverse effects associated with lepirudin treatment, such as anaphylaxis. The results of these trials and the DMP demonstrate that lepirudin is highly effective in reducing the risk of the potentially devastating complications of HIT.

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