Cpb

Cardiac catheterization

PCI or intra-aortic balloon pump

Catheter patency Pediatric dosage considerations

750 U sc b.i.d. or t.i.d. for patients with history of HIT or who have low suspicion for HIT. For patients with (confirmed or strongly suspected) acute HIT with or without thrombosis, use treatment doses (see below) 2250 U iv bolusa followed by 400 U/h for 4 h, 300 U/h for 4 h, then 150-200 U/h for > 5 days, aiming for a plasma anti-Xa level of 0.50.8 U/mL Subcutaneous administration": 1500-2250 U sc b.i.d. Preoperative: 2250 U iv bolusa; intraoperative flushes: 750 U in 250 mL saline, using up to 50 mL; postoperative: 750 U sc t.i.d. (low-risk patients) or 150-200 U/h (high-risk patients) beginning at least 6 h after surgery 3750 U iv before first and second dialyses; 3000 U for third dialysis; then 2250 U for subsequent dialyses, aiming for plasma anti-Xa level of < 0.3 U/mL predialysis, and 0.5-0.8 U/mL during dialysis. 2250 U iv bolus, followed by 400 U/h for 4 h, then 300 U/h for 4 h, then 150-400c U/h aiming for a plasma anti-Xa level of 0.5-0.8 U/mL

125 U/kg iv bolus after thoracotomy; 3 U/mL in priming fluid of apparatus; 7 U/kg/h iv infusion commencing after CPB hookup, and continued until 45 min before expectation of stopping CPB Preprocedure: 2250 U iv bolus (3000 U if 75-90 kg and

3750 U if > 90 kg) Preprocedure: bolus as per foregoing

Postprocedure: 150-200 U/h for 1-2 days post-PCI (or until removal of balloon pump) 750 U in 50 mL saline, then 5-10 mL per port, or as required Refer to Bidlingmaier et al., 2006; see also Chapter 20

Note: Compatibility with intravenous solutions: Danaparoid is compatible for dilution with the following solutions: saline, dextrose, dextrose—saline, Ringer's, lactated Ringer's, 10% mannitol. Preparation of solution for infusion: One option is to add four ampules containing 3000 U (i.e., 750 anti-Xa U/0.6 mL ampule) of danaparoid to 300 mL of intravenous solution, i.e., a solution that comprises 10 U danaparoid per milliliter of intravenous solution: thus, an infusion rate of 40 mL/h corresponds to a dose of 400 U/h: 20 mL/h to a dose of 200 U/h, and so on. aAdjust iv danaparoid bolus for body weight: <60 kg, 1500 U; 60-75 kg, 2250 U; 75-90 kg, 3000 U; >90 kg, 3750 U.

bDanaparoid should be given iv during the acute (thrombocytopenic) phase of HIT (see above). "Initially up to 600 U/h may be required if the filter has recently shown excessive clotting. Once filter life is restored to normal, the rate can be lowered.

Abbreviations: b.i.d., twice daily; b.w., body weight; CPB, cardiopulmonary bypass surgery; CRRT, continuous renal replacement therapy; HIT, heparin-induced thrombocytopenia; iv, intravenous; PCI, Percutaneous coronary intervention; t.i.d., three times daily; VTE, venous thromboembolism.

agent that has been used to prevent DVT in postoperative patients (Aberg and Rausing, 1978; Bergqvist, 1980). Known to block HIT antibody-induced platelet aggregation in vitro (Sobel et al., 1986), it was regarded as a potentially useful drug for the treatment of HIT. Dextran 70 was also the only other rapid-acting non-heparin antithrombotic drug available in Australia at study commencement in 1988.

The danaparoid treatment regimen for this early study differed slightly from that of the compassionate-use program because ampules at that time contained 800 U. Thus, danaparoid was given as a bolus of 2400 U, followed by an infusion of 400 U/h for 2 h, 300 U/h for 2 h, and then 200 U/h for 5 days. In the dextran 70 arm, patients received dextran, 1 L on day 1, and then 500 mL/day from days 2 to 5. In both treatment arms, the patients also received warfarin, with doses adjusted to an international normalized ratio (INR) of 2-4; the warfarin was continued for 3 mo. Patients were also stratified at randomization, depending on the severity of their thrombosis, using predefined criteria.

Resolution of thrombocytopenia showed a non-significant trend in favor of danaparoid over dextran 70. Among the patients stratified as having "mild" thrombosis, a slightly higher percentage of patients treated with danaparoid (83%) improved compared with those who received dextran 70 (73%). In contrast, a substantial and significant difference in treatment outcome occurred in patients with "serious" thrombosis: 88% of danaparoid-treated thromboembolic events recovered, compared with only 44% of those treated with dextran 70. No serious bleeding events were observed. These data suggest that the use of an effective anticoagulant to treat HIT-associated thromboembolism is particularly important in those with more severe disease.

In another study, patients treated prospectively with lepirudin were compared with patients treated with danaparoid (Farner et al., 2001). Although not a randomized trial, this study had important strengths. First, all patients had serologically confirmed HIT (about 70% had thrombosis at study entry). Second, all patients met identical inclusion and exclusion criteria, had similar baseline characteristics, and were treated during the same time period (25 mo ending April 1996). Third, many patients were studied (danaparoid, n = 126; lepirudin, n = 175). Furthermore, patients were subdivided into those treated with prophylactic or therapeutic doses. The results of this study suggest that both danaparoid and lepirudin have similar efficacy for treatment of HIT-associated thrombosis when given in therapeutic doses: the day 42 success rate was about 80% for either agent, when failure was defined as having a composite endpoint of new thrombosis, death, and/or limb loss (Fig. 2a). When evaluating the single endpoint of new thrombosis in patients who received therapeutic doses of study drug, danaparoid and lepirudin also showed similar efficacy (90.6% vs. 92.1%; p = 0.74). Moreover, safety analysis of all patients (regardless of dose received) showed significantly fewer major bleeds with danaparoid (2.5% vs. 10.4%; p = 0.009) (Fig. 2b). These data suggest that the favorable therapeutic index of danaparoid extends also to HIT complicated by thrombosis.

More recently, a retrospective evaluation of treatment outcomes was made between a period when HIT patients were often treated with the defibrinogen-ating snake venom, ancrod (usually with coumarin) or coumarin alone, and a later period when treatment of new HIT patients was mainly performed using danaparoid (usually with overlapping coumarin) (Lubenow et al., 2006). This historical "switch" in choice of HIT treatment (which occurred in Canada) was associated with a highly significant reduction in the composite endpoint of new/progressive/recurrent thrombosis, thrombotic death, and limb amputation among patients treated with danaparoid (day 7 outcomes: 12.9% vs. 39.3%; p = 0.0014) (Fig. 3). In addition, significantly less major bleeding was observed with danaparoid (11.3% vs. 28.6%; p = 0.0211). These investigators further compared the efficacy and safety outcomes observed using danaparoid treatment against those of published trials of lepirudin and argatroban (Table 2). The results suggest that the efficacy : safety relationship of danaparoid is especially favorable, although the lack of head-to-head randomized comparisons between danaparoid and either direct thrombin inhibitors (DTIs) prevents any definitive conclusions.

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