Reduced argatroban doses after coronary artery bypass graft surgery.

BACKGROUND: The Food and Drug Administration-approved argatroban dose for heparin-induced thrombocytopenia (HIT) is 2 microg/kg/min (0.5 microg/kg/min in hepatic impairment), adjusted to achieve activated partial thromboplastin time (aPTT) 1.5-3 times baseline. Recent data suggest that reduced doses are required after cardiovascular surgery. OBJECTIVE: To characterize dosing requirements, aPTTs, factors affecting dosage, and clinical outcomes in patients administered argatroban after coronary artery bypass graft (CABG) surgery. METHODS: Charts of 39 patients who underwent CABG surgery and were administered argatroban postoperatively for laboratory-confirmed HIT (n = 25), antibody-negative suspected HIT (n = 10), or previous HIT requiring anticoagulation (n = 4) were retrospectively reviewed. Patient characteristics, argatroban dosing information, aPTTs (target range 45-90 sec), and outcomes were summarized. Regression analyses explored potential effectors of dosage. RESULTS: Patient features, argatroban dosing patterns, and aPTTs were similar among groups. Many patients had laboratory evidence of some hepatic and/or renal dysfunction (median [range] bilirubin 1.0 [0.3-8.0] mg/dL, creatinine clearance 47 [18-287] mL/min). Overall, median argatroban doses were 0.5 microg/kg/min initially and 0.6 microg/kg/min during therapy (median duration 5.3 days). After argatroban initiation, aPTTs were greater than 90 seconds at first assessment in 4 patients (3 with abnormal hepatic function test results) initially administered 0.5, 1, 2, and 2 microg/kg/min, respectively. Within approximately 16 hours of therapy, 33 (85%) patients achieved consecutive therapeutic aPTTs. No association was detected between mean dose during therapy and preoperative ejection fraction, routine hepatic or renal function test results (other than blood urea nitrogen [BUN]), or surgery type. A clinically insignificant association existed between dose and BUN: there was an approximately 0.15 microg/kg/min dose decrease for each 10 mg/dL BUN increase. One patient developed thrombosis, 1 underwent finger amputation, 7 died (5 after argatroban cessation), and 4 had significant bleeding. CONCLUSIONS: These findings suggest that reduced initial argatroban doses (eg, 0.5 microg/kg/min), adjusted to achieve therapeutic aPTTs, provide rapid, adequate anticoagulation in postoperative CABG patients with presumed or previous HIT. Prospective study of reduced initial dosing in this setting is warranted.

Effect of renal function on argatroban therapy in heparin-induced thrombocytopenia.

BACKGROUND: Argatroban is considered to be an alternative anticoagulant of choice in patients with heparin-induced thrombocytopenia (HIT) and renal impairment. The recommended initial dose in HIT is 2 microg/kg/min (0.5 microg/kg/min in hepatic impairment), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline. Although argatroban is predominantly hepatically metabolized with minimal renal clearance, recent limited data have suggested that a patient's renal function should also be considered when initiating argatroban therapy for HIT. We retrospectively evaluated the effect of renal function on argatroban therapy in HIT patients with normal hepatic function, with the goal of refining dosing guidance, if needed. METHODS: From case records of previous prospective studies of argatroban in clinically diagnosed HIT, we identified patients who had baseline laboratory data on liver and renal function. Individuals with abnormal hepatic function (serum total bilirubin > 1.5 mg/dl or ALT or AST > 100 U/l) were excluded. Patients were stratified according to their estimated creatinine clearance (CL(cr)): normal or mild impairment (CL(cr) > 60 ml/min), moderate impairment (CL(cr) 30-60 ml/min), or severe impairment (CL(cr) < 30 ml/min). Argatroban doses, aPTTs, and clinical outcomes were summarized overall and by group. By-patient relationships between CL(cr) and dose or aPTT during therapy were explored using regression analyses. RESULTS: The analysis population included 260 patients with normal to mild (n = 144), moderate (n = 80), or severe (n = 36) renal impairment. Argatroban was initiated at a mean infusion dose of 1.8 +/- 0.7 microg/kg/min (overall), titrated to achieve aPTTs 1.5-3 times baseline. Among renal function groups, no significant differences occurred in argatroban dose during therapy (overall value, 1.9 +/- 1.1 microg/kg/min), duration of therapy (7 +/- 6 days), or aPTTs (63 +/- 17 s). Regression analyses showed a 0.1 microg/kg/min increase in dose (r2 = 0.02) for each 30 ml/min increase in CL(cr). Within a 37 day follow-up, 46 (17.7%) patients died, most often when severe renal impairment was present. New thrombosis (11.5% overall) and major bleeding (5.0%) did not differ among groups. CONCLUSIONS: In this large cohort of HIT patients with normal hepatic function and varying levels of renal function, argatroban administered in accordance with current recommendations provided adequate levels of anticoagulation and was well tolerated. Altered renal function did not clinically significantly affect argatroban doses, aPTT responses, or rates of thrombosis or bleeding. These findings further support argatroban as an alternative anticoagulant of choice, without need for initial dose adjustment, in most patients with HIT and renal impairment. CONDENSED ABSTRACT: We retrospectively evaluated the effect of renal function on argatroban therapy in HIT patients with normal hepatic function, with the goal of refining current dosing guidance, if needed. From previous prospective studies of argatroban in HIT, we identified 260 patients with clinically diagnosed HIT, normal hepatic function, and varying degrees of renal function. Among patients whose renal function was normal or mildly impaired (estimated creatinine clearance, CL(cr) > 60 ml/min); moderately impaired (CL(cr) 30-60 ml/min), or severely impaired (CL(cr) < 30 ml/min), no significant differences occurred in the argatroban dose, aPTT response, duration of therapy, or rates of thrombosis or major bleeding. By regression analysis, there was a clinically insignificant 0.1 microg/kg/min increase in dose for each 30 ml/min increase in CL(cr). Overall, argatroban administered in accordance with current recommendations provided adequate levels of anticoagulation and was well tolerated, supporting its use as an alternative anticoagulant of choice, without need for initial dose adjustment, in most patients with HIT and renal impairment.

Nomogram for predicting the likelihood of delayed graft function in adult cadaveric renal transplant recipients.

Delayed graft function (DGF) is the need for dialysis in the first week after transplantation. Studied were risk factors for DGF in adult (age >/=16 yr) cadaveric renal transplant recipients by means of a multivariable modeling procedure. Only donor and recipient factors known before transplantation were chosen so that the probabilities of DGF could be calculated before transplantation and appropriate preventative measures taken. Data on 19,706 recipients of cadaveric allografts were obtained from the United States Renal Data System registry (1995 to 1998). Graft losses within the first 24 h after surgery were excluded from the analysis (n = 89). Patients whose DGF information was missing or unknown (n = 2820) and patients missing one or more candidate predictors (n = 2951) were also excluded. By means of a multivariable logistic regression analysis, factors contributing to DGF in the remaining 13,846 patients were identified. After validating the logistic regression model, a nomogram was developed as a tool for identifying patients at risk for DGF. The incidence of DGF was 23.7%. Sixteen independent donor or recipient risk factors were found to predict DGF. A nomogram quantifying the relative contribution of each risk factor was created. This index can be used to calculate the risk of DGF for an individual by adding the points associated with each risk factor. The nomogram provides a useful tool for developing a pretransplantation index of the likelihood of DGF occurrence. With this index in hand, better informed treatment and allocation decisions can be made.

Improved freedom from rejection after a loading dose of sirolimus.

BACKGROUND: Sirolimus (SIR) in combination with cyclosporine reduces the incidence of acute rejection in renal transplant recipients. Limited data are available regarding SIR in combination with tacrolimus (TAC). METHODS: A single-center, retrospective review of renal transplant recipients receiving SIR, TAC, and corticosteroids postoperatively was conducted. A total of 118 consecutive renal transplant recipients were included on the basis of availability of day 1 SIR dose information. Seventy-seven patients received an SIR loading dose (SIR-LD) immediately posttransplantation, and 41 patients did not (SIR no loading dose [SIR-NLD]). RESULTS: The two groups showed similar demographic and transplant characteristics. SIR doses and trough levels were significantly higher in the SIR-LD patients at 1 and 7 days posttransplantation; however, no differences occurred beyond day 7. Patients receiving an SIR-LD experienced significantly better freedom from rejection at 1, 3, and 6 months posttransplantation (P<0.05). This rejection benefit in the SIR-LD group was independent of donor source and use of antibody induction. SIR-LD patients experienced fewer serious infections (12% SIR-LD vs. 27% SIR-NLD, P=0.04) and a lower incidence of delayed graft function (21% SIR-LD vs. 39% SIR-NLD, P<0.05). No significant differences in serum creatinine, hemoglobin, and platelet counts occurred in the first 180 days posttransplantation, but the patients in the SIR-NLD group experienced lower hemoglobin levels at day 30 than those in the SIR-LD group (10.8 g/dL SIR-LD vs. 9.7 g/dL SIR-NLD, P=0.03). CONCLUSION: SIR-LD significantly improves early posttransplantation freedom from rejection in renal transplant recipients without increasing other complications.