Si

Note: Many of the approaches discussed in this chapter have not been formally studied, none has been approved yet. Treatment examples are given based on a limited number ^

of cases successfully treated with the respective regimen. The different anticoagulants thus cannot be uncritically applied in the dosage given here. The choice of anticoagulant 5>'

should depend on the experience of the center and the anticoagulant monitoring available. Doses for danaparoid as given by the manufacturer. 3'

aMonitoring the condition of the dialyzer after a HD session as well as the time required for termination of bleeding of the fistula should be included as well. I

bDosage given in anti-Xa units (bolus).

cDosage in brackets for patients with body weight <55 kg.

dData given in U/mL.

ePeak activity determined after approximately 30 min of HD; this level is not required throughout the whole HD session. 'Determination 30-60 min before start of the respective HD session.

9lf fibrin deposition in the dialyzer or clots in the extracorporeal circuit occur, addition of 1500 anti-Xa units as a single bolus. hDosage given in anti-Xa units/h (infusion).

'To achieve the same anti-Xa activity, smaller doses may be required in hemodialysis as compared to hemofiltration. 'Maintenance dosage dependent on actual anti-Xa activity; determination every 12 h (provided that no bleeding or clotting occurs). kDosage given in mg/kg body weight for hemodialysis performed with polysulfone high-flux hemodialyzers.

'The dosage required to reach the target range may vary, for example due to residual renal function or the type of dialyzer used (cf. text).

mlf larger doses are needed to achieve the target range or to avoid clotting of the extracorporeal circuit, changing to another type of dialyzer may be helpful.

"In our center aPTT is determined with the BCS coagulometer and Pathromtin SL as aPTT reagent (both Dade-Behring, Liederbach, Germany).

"According to the literature alternative tests such as Ecarin Clotting Time (ECT) or Activated Clotting Time (ACT) also appear suitable for monitoring.

plt is unclear which test is best-suited to monitor anticoagulation with r-hirudin, as no test has been prospectively evaluated in HD patients so far.

qA peak aPTT of 100 s should not be exceeded.

'Determination in plasma by chromogenic assays.

sData given in ng/mL.

'The agent has not yet been formally studied in continuous hemodialysis procedures.

"This approach has been successfully performed in a number of patients in our center without adverse events.

"Dosage given for anuric patients; in case of polyuria a higher dosage may be required; the required daily dosage may vary significantly between patients. wAs patients requiring continuous procedures often are at an increased risk of bleeding, a lower aPTT is to be preferred (50-70 s). "To be initially controlled every 4-6 h to avoid overdosage especially in patients at bleeding risk.

Abbreviations: aPTT, activated partial thromboplastin time; conc., concentration; HD, hemodialysis; HF, hemofiltration; Xa, clotting factor Xa.

■b vi between 1.5 and 2.5, which was associated with only a moderately increased bleeding risk (Greinacher et al., 2000). Control of r-hirudin treatment by the aPTT is problematic: there is considerable assay variability among patients and different aPTT reagents (Nurmohamed et al., 1994; Hafner et al., 2000; Lube-now and Greinacher, 2000). In contrast to the foregoing tests, correlation between aPTT and plasma r-hirudin concentration is not linear over a broad concentration range. Instead, linear correlation is observed only with r-hirudin concentrations up to 0.5 mg/mL (Nowak and Bucha, 1996), a concentration often insufficient for HD. Above this concentration, the correlation between aPTT and r-hirudin concentration is poor (Nowak and Bucha, 1996; Hafner et al., 2000), especially for aPTT values of more than 70 s (Lubenow and Greinacher, 2000). Nevertheless, because of its wide availability, aPTT monitoring of r-hirudin treatment is likely to remain common. If available, ECT or chromogenic assays are preferred. A frequent problem in ICU patients with HIT and renal failure are low prothrombin levels, which can cause falsely high values in the aPTT and ECT during therapy with lepirudin or argatroban (risk of underdosing).

3. The elimination of r-hirudin is markedly prolonged in renal impairment. Nowak et al. (1992) reported elimination half-lives of up to 316 h in HD patients. Vanholder et al. (1997) found a prolongation of r-hirudin half-life by a factor of 31 in HD patients compared with healthy controls. Both studies showed a correlation between the residual creatinine clearance and the r-hirudin clearance, in that a minor improvement in creatinine clearance resulted in a shorter elimination half-life of r-hirudin. This was confirmed in a study of HD patients repetitively anticoagulated with r-hirudin (Bucha et al., 1999a). As with HD patients treated with danaparoid, r-hirudin-treated patients remain anticoagulated during the interdialytic interval (Nowak et al., 1997). Because various organs may metabolize hirudin (Grötsch and Hropot, 1991), other factors affecting metabolic clearance of hirudin may be present in patients with end-stage renal failure.

In patients suffering from acute renal failure, further deterioration or partial recovery of renal function frequently occurs (Fischer et al., 1999). Hence, r-hirudin anticoagulation should be closely monitored in these patients for timely dose adjustments. Preferably, r-hirudin should be given in repeated small boluses, rather than administered continuously, to minimize bleeding risk (Fischer et al., 1999; Kern et al., 1999). For the same reason, use of r-hirudin permeable high-flux hemodialyzers for patients with HD-dependent acute renal failure is recommended, especially as the patients often need vessel punctures, biopsies, or surgical interventions.

Given the prolonged half-life of r-hirudin in renal impairment, use of polyethylene glycol-hirudin (molecular mass 17 kDa), which has an even greater elimination half-life compared with uncoupled r-hirudin (Pöschel et al., 2000), does not seem appropriate for HD, as bleeding risk likely would be increased.

4. Pharmacokinetics of r-hirudin are also influenced by the type of dialyzer used. The pharmacology of r-hirudin (molecular mass ~7 kDa; volume of distribution 0.20-0.25 L/kg b.w.; low protein binding) should favor its elimination by high flux hemodialyzers with a nominal cutoff point of approximately 60 kDa. Indeed, most high-flux hemodialyzers are permeable to r-hirudin, whereas most of the low-flux hemodialyzers tested appear to be r-hirudin-impermeable (Bucha et al., 1999b; Frank et al., 1999, 2002; Benz et al., 2007; Koster et al.,

2000). However, high-flux hemodialyzers vary considerably in their capacity to filter r-hirudin (Fischer, 2002; Willey et al., 2002). Further, a specific type of hemophan low-flux dialyzer has been reported to show high permeability for r-hirudin (Nowak et al., 1997), whereas a specific type of polysulfone high-flux dialyzer, with a cutoff point of approximately 50 kDa, did not filter r-hirudin from the circulation (Vanholder et al., 1997). Thus, knowledge of the actual filtration characteristics for r-hirudin of a given type of hemodialyzer improves safety of treatment with r-hirudin in HD. 5. r-Hirudin overdosing or unexpected drug accumulation can lead to severe bleeding (Fischer et al., 2000; Kern et al., 1999; Müller et al., 1999). In this situation, r-hirudin can be removed from the circulation using hemofiltration (Bauersachs et al., 1999; Fischer et al., 2000; Mon et al., 2006). However, several hours may be needed to lower r-hirudin plasma levels by 50%, even at high ultrafiltration rates. Thus, careful r-hirudin dosing is of utmost importance. Recent case reports have shown application of recombinant factor VIIa to be of additional value in patients suffering from renal insufficiency and postoperative bleeding upon lepirudin anticoagulation (Hein et al., 2005; Oh et al., 2006). In the presence of AHAb, hemofiltration may no longer suffice to eliminate r-hirudin (Fischer et al., 2003). Here, plasmapheresis may be the only means to clear r-hirudin from the circulation. Preliminary studies in animals suggest that a possible future treatment might be use of certain AHAb with r-hirudin-neutralizing capacity (Liebe et al., 2001).

Table 2 lists dosing recommendations for use of lepirudin for HD. The recommendations should be considered as guidelines and not followed uncritically in any individual patient. In summary, r-hirudin is a valid alternative anticoagulant for HD procedures in HIT patients, but it should be used with caution and careful monitoring.

Argatroban

Argatroban (Novastan®; Argatra®; MD-805) is a potent arginine-derived, synthetic, catalytic site-directed thrombin inhibitor lacking antiplatelet and antifibrino-lytic activities (Koide et al., 1995; Matsuo et al., 1992). This agent is approved as alternative anticoagulant for HIT in the United States, Canada and a number of European countries (see Chapter 15). It does not cross-react with HIT antibodies. Apart from an even better relative ability to inhibit fibrin-bound versus soluble thrombin (Berry et al., 1996; Lunven et al., 1996), the principal advantages of argatroban over heparin are similar to r-hirudin (Markwardt, 1991; Matsuo et al., 1992). However, argatroban is metabolized primarily by the liver, and its half-life is only moderately extended in patients with renal insufficiency, i.e., a half-life of 64 ± 35 min in patients with creatinine clearance of 0-29 mL/min versus 47 ± 22 min in patients with creatinine clearance >80 mL/min (p = 0.58) (Swan and Hursting, 2000). Also, argatroban dialytic clearance by high-flux membranes is regarded as being clinically insignificant (Murray et al., 2004; Tang et al., 2005).

After argatroban proved to be a valuable anticoagulant in HD (Matsuo et al., 1986), it was applied successfully to HIT patients undergoing this procedure (Koide et al., 1995; Matsuo et al., 1992). In a retrospective analysis of 47 patients with HIT and renal failure requiring renal replacement therapy (with at least 11 patients receiving continuous venovenous or arteriovenous HD), argatroban provided effective anticoagulation with an acceptable safety profile (Reddy et al., 2005). Initially, argatroban was given according to current dosing recommendations used for the prophylaxis or treatment of thrombosis in HIT, i.e., 2 mg/kg/min (or 0.5 mg/kg/ min if hepatically impaired), adjusted to an aPTT 1.5-3-times baseline (see Chapter 15). For adjustment to reach the target aPTT range, argatroban dosing had to be more frequently adjusted downwards than upwards. A recent prospective crossover study of 12 maintenance HD patients showed three different argatroban dosing regimens (bolus alone, infusion alone, or bolus plus infusion) to be safe and well tolerated (Murray et al., 2004). Recent studies show pharmacokinetics of argatroban not to be significantly influenced by different degrees of renal insufficiency. Argatroban dose adjustments were not found to be necessary in these patients (Tang et al., 2005; Guzzi et al., 2006). In contrast, others show argatroban dosing to clearly depend on renal function (Arpino and Hallisey, 2004).

In ICU patients suffering from renal, but not measurable liver insufficiency, however, dose reductions may be frequently necessary (unpublished observations of the author). Based on this experience, in ICU patients, we start argatroban at a reduced dose, provided there is no acute thrombosis. Careful monitoring and dosing is required. Similar experiences have also been reported by others (de Denus and Spinler, 2003; Guzzi et al., 2006; Reichert et al., 2003). Here, decreased cardiac output or hepatic congestion have been posited to cause reduced argatroban requirements (Guzzi et al., 2006).

Argatroban has also proved effective and safe in HD patients with anti-thrombin deficiency (Ota et al., 2003). Whether anticoagulation with argatroban alone is always sufficient to prevent clotting in the extracorporeal circuit is unclear: in one HD patient treated with argatroban, marked spontaneous platelet aggregation occurred, perhaps due to HIT together with additional platelet activation known to occur in HD (Koide et al., 1995). Because platelet aggregation could not be suppressed by argatroban alone in this patient, aspirin was added to achieve patency of the extracorporeal circuit.

Periodic monitoring of the anticoagulant activity of argatroban is recommended (Matsuo et al., 1992) using for example the aPTT (Koide et al., 1995; Matsuo et al., 1992), the ECT (Berry et al., 1998), or the activated clotting time (ACT) (Murray et al., 2004; Tang et al., 2005).

Argatroban appears to be at least as well suited as r-hirudin for anticoagulation of HIT patients requiring HD. Its predominant hepatic elimination favors argatroban for alternative anticoagulation in chronic renal failure. Its role and dosing in ICU patients suffering from acute renal failure remain to be defined.

Table 2 lists dosing recommendations for use of argatroban for HD. The recommendations should be considered as guidelines and not followed uncritically in any individual patient. In particular, ICU patients often do not require full dose argatroban.

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