Clinical Studies

Argatroban has been evaluated in three multicenter, open-label prospective studies in patients with or at risk of HIT undergoing PCI, including percutaneous

Hit Risk Label

FIGURE 6 Guidelines for conversion from argatroban to oral anticoagulant therapy with warfarin. Warfarin should be initiated only once there has been substantial resolution of the thrombocytope-nia, and beginning only with anticipated maintenance doses (<5 mg/day). Argatroban and warfarin should be overlapped for at least 5 days before discontinuing argatroban. Ideally, the INR should be within the target therapeutic range (i.e., >4.0 during cotherapy for argatroban doses up to 2 mg/kg/ min) for at least the last 2 days of overlap. *For argatroban infusion at <2mg/kg/min, the INR on monotherapy may be estimated from the INR on cotherapy. +If the dose of argatroban is >2mg/kg/min, temporarily reduce to a dose of 2 mg/kg/min 4-6 h prior to measuring the INR. Abbreviation: INR, international normalized ratio.

FIGURE 6 Guidelines for conversion from argatroban to oral anticoagulant therapy with warfarin. Warfarin should be initiated only once there has been substantial resolution of the thrombocytope-nia, and beginning only with anticipated maintenance doses (<5 mg/day). Argatroban and warfarin should be overlapped for at least 5 days before discontinuing argatroban. Ideally, the INR should be within the target therapeutic range (i.e., >4.0 during cotherapy for argatroban doses up to 2 mg/kg/ min) for at least the last 2 days of overlap. *For argatroban infusion at <2mg/kg/min, the INR on monotherapy may be estimated from the INR on cotherapy. +If the dose of argatroban is >2mg/kg/min, temporarily reduce to a dose of 2 mg/kg/min 4-6 h prior to measuring the INR. Abbreviation: INR, international normalized ratio.

transluminal coronary angioplasty, stent implantation, or rotational atherectomy. The studies (ARG-216, ARG-310, and ARG-311) were similar in design with respect to eligibility criteria, argatroban dosing regimen, and main outcome assessments, and their pooled analysis has been reported (Lewis et al., 2002). Overall, 91 patients with or at risk of HIT underwent 112 PCIs on argatroban anticoagulation. Patients received 325 mg oral aspirin 2-24 h before PCI. In the catheterization laboratory, patients received iv argatroban at 25 mg/kg/min (initial bolus dose of 350 mg/kg) titrated to achieve an ACT of 300-450 s during PCI (mean infusion dose, 23 mg/kg/min). Additional bolus doses of 150 mg/kg to achieve or maintain the target ACT were allowed, though usually not needed. Target ACT values were achieved typically within 10 min of initiating argatroban and were maintained throughout the infusion. When argatroban was discontinued after the procedure, ACTs rapidly returned to baseline.

Primary efficacy endpoints were subjective assessment of the satisfactory outcome of the procedure and adequate anticoagulation, which occurred in 94.5% and 97.8%, respectively, of patients undergoing their initial PCI with argatroban (n = 91) (Table 5). Death (no patients), myocardial infarction (four patients), and revascularization at 24h after PCI (four patients) occurred in seven (7.7%) patients. Other efficacy endpoints were also consistent with argatroban enabling a satisfactory outcome (Table 5). One patient (1%) experienced major periprocedural bleeding (nonfatal retroperitoneal hemorrhage). No unsatisfactory outcomes occurred during repeat PCIs with argatroban (n = 21; mean separation of 150 days from the initial PCI). Overall, the clinical outcomes compared favorably with those reported historically for heparin anticoagulation during PCI.

TABLE 5 Efficacy Assessments in Patients with or at Risk of HIT Undergoing PCI Using Argatroban Anticoagulation

Number of patients with outcome/total n (%)

Outcome Initial group Repeat group

Satisfactory outcome of procedurea

86/91

(94.5%)

21/21

(100%)

Adequate anticoagulation61

89/91

(97.8%)

21/21

(100%)

Lack of major acute complicationsb

89/91

(97.8%)

21/21

(100%)

Angiographic successc

86/88

(97.7%)

20/20

(100%)

Clinical successd

86/88

(97.7%)

20/20

(100%)

aPrimary, subjective outcomes.

bNo death, emergent coronary artery bypass graft surgery, or Q-wave myocardial infarction during argatroban infusion or 24 h of its cessation (or discharge, whichever came first). cFinal stenosis of <50% in at least one lesion attempted, for patients with angiographic data available. dAngiographic success plus the lack of major acute complications.

Abbreviations: HIT, heparin-induced thrombocytopenia; PCI, percutaneous coronary intervention.

aPrimary, subjective outcomes.

bNo death, emergent coronary artery bypass graft surgery, or Q-wave myocardial infarction during argatroban infusion or 24 h of its cessation (or discharge, whichever came first). cFinal stenosis of <50% in at least one lesion attempted, for patients with angiographic data available. dAngiographic success plus the lack of major acute complications.

Abbreviations: HIT, heparin-induced thrombocytopenia; PCI, percutaneous coronary intervention.

In a separate multicenter prospective study of 152 patients (including one patient with previous HIT) undergoing PCI, reduced doses of argatroban were evaluated in combination with the glycoprotein (GP) IIb/IIIa antagonists abcix-imab (n = 150) or eptifibatide (n = 2) (Jang et al., 2004). Patients received argatroban as an initial bolus of 250 or 300 mg/kg followed by an infusion of 15 mg/kg/ min during PCI. An additional bolus of 150 mg/kg was administered if ACTs 5-15 min after initiating argatroban were <275 s. Median ACTs achieved were approximately 300 s. The primary efficacy composite endpoint of death (no patients), myocardial infarction (four patients), and urgent revascularization (two patients) at 30 days occurred in four (2.6%) patients overall. Two (1.3%) patients had major bleeding (one retroperitoneal, one groin hematoma). Although not specifically conducted in patients with or at risk of HIT, the results suggest that a reduced dose of argatroban may be appropriate if used in combination with GPIIb/IIIa inhibition during PCI.

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