Clinical Experience with Argatroban: DISCUSSION
For the prophylaxis or treatment of thrombosis in HIT, the recommended initial dose of argatroban is 2 Fg/kg per minute, unless patients have moderate hepatic impairment (Child-Pugh score > 6 or total serum bilirubin > 25.5 Fmol/L), in which case the recommended initial dose is reduced to 0.5 Fg/kg per minute. The literature suggests that a lower dose may be required for patients who have undergone cardiac surgery and for those with multiple organ system failure, heart failure, severe anasarca, or conditions associated with hepatic congestion. The most common causes of hepatic congestion are volume overload and any cause of right-sided heart failure (constrictive pericarditis, mitral stenosis, tricuspid regurgitation, cor pulmonale, or cardiomyopathy). Recent reports of argatroban use for a variety of clinical indications and in various clinical settings have reported lower doses (0.51.2 Fg/kg per minute) to achieve target aPTT.
The evidence suggests that critically ill patients may require lower doses of argatroban. Small studies and case series of 4 to 65 patients have reported maintenance doses of 0.125 to 0.91 Fg/kg per minute. Conversely, initial infusions of 1.5 to 2 Fg/kg per minute in these patients have resulted in supratherapeutic aPTTs and bleeding. One group of authors suggested that passive hepatic congestion, accumulation of metabolites, and/or interactions with multiple medications used in the ICU may justify lower dose requirements. In a retrospective study of 65 ICU patients, it was noted that significantly lower doses were required to achieve therapeutic aPTT as the number of failed organ systems increased from 1 (n = 26; 1.1 Fg/kg per minute) to 2 (n = 26; 0.87 Fg/kg per minute) to 3 (n = 13; 0.58 Fg/kg per minute) (p = 0.008). Liver failure was present in 3.1% of the patients in that study. In the study reported here, critically ill patients had initial doses of 0.5 to 5 Fg/kg per minute and required the greatest number of dosage reductions, relative to patients with hepatic or renal dysfunction or acute cardiac disease. These results are consistent with reports of lower dosing of argatroban for critically ill patients. suhagra
Because of reduced cardiac output during cardiovascular surgery, cardiac, liver, or kidney function may be transiently impaired for a limited period of time after the procedure.16,30 Decreased hepatic perfusion secondary to hypotension from hypovolemia or lowered systemic vascular resistance after surgery is another proposed mechanism. The potential for reduction in cardiac output and drug elimination is higher after more complex procedures, such as replacement of a cardiac valve. Hoffmann and others reported a median argatroban dose of 0.6 Fg/kg per minute (range 0.05-3 Fg/kg per minute) in 39 patients after coronary artery bypass grafting. The median ALT was 32.3 U/L (range 4-11450 U/L), and median total bilirubin was 18.2 Fmol/L (range 5.1-136.8 Fmol/L). Therapeutic aPTT (45-90 s) generally occurred within 15.6 h in 85% of the patients. Overall, 7 of the patients died, but none had a thromboembolic event within a median follow-up period of 10 days; clinically significant bleeding occurred in 4 patients. In a case series of 4 patients with normal liver function tests, initial infusions of 1 or 2 Fg/kg per minute after cardiac surgery resulted in supratherapeutic aPTT (exceeding 100 s). After cardiopulmonary bypass surgery, initial infusions of 0.8 to 1 Fg/kg per minute provided rapid and effective anticoagulation without overshooting aPTT; however, lower mean doses (0.3-0.4 Fg/kg per minute) were eventually required. In patients requiring renal replacement therapy after cardiac surgery, mean infusion rates of 0.06 to 0.12 Fg/kg per minute have been used to achieve aPTT of 50 to 80 s. In the study reported here, lower doses were not used for any of the patients with acute cardiac disease.
buy female viagra
A pharmacokinetic study of argatroban in 5 patients with hepatic dysfunction (Child-Pugh score > 6) suggested a 3-fold increase in half-life and a 4-fold decrease in clearance, relative to healthy controls. In an analysis of 16 patients with total bilirubin above 25.5 Fmol/L, the mean dose was 0.8 Fg/kg per minute. One centre’s experience with argatroban revealed a lower maintenance dose (0.25 Fg/kg per minute, range 0.05-0.5 Fg/kg per minute) in 4 patients with hepatic dysfunction. Serum bilirubin above 25.5 Fmol/L is suggested to be more predictive of decreased argatroban clearance than elevation of either ALT or AST.22 In the study reported here, 86% (6/7) of the patients with liver dysfunction received a starting dose of 0.5 or 1 Fg/kg per minute, and no patients required a mean dose less than 0.5 Fg/kg per minute. There was no difference between chronic and acute hepatic dysfunction in terms of dose requirements.
