Evaluation of 2 nomogram-based strategies for dosing argatroban in patients with known or suspected heparin-induced thrombocytopenia.

No study has compared 2 different dosing strategies for argatroban titration nor has any published nomogram demonstrated improvement in outcomes. This study was conducted to evaluate the effectiveness of 2 argatroban nomograms on reaching therapeutic anticoagulation. Patients treated with argatroban were separated into 2 sliding scale groups, percentage adjustments (PAs) and predefined dose increments (PDIs). The primary outcome was the time to reach a therapeutic activated partial thromboplastin time (aPTT). The average initial dose and dose to achieve a therapeutic aPTT were similar between the groups. There was also no difference in the number of dose changes. The time to reach a therapeutic aPTT was 2 hours shorter in the PDI compared to the PA group, 8 ± 4 hours versus 10 ± 4 hours, P = .015. This study demonstrates a significant time advantage associated with a PDI nomogram compared to a PA nomogram but no difference with respect to the number of rate changes.

Evaluation of a vancomycin dosing nomogram based on the Modification of Diet in Renal Disease equation in intensive care unit patients.

PURPOSE: The purpose of the study is to evaluate the effectiveness of a vancomycin nomogram using actual body weight and the Modification of Diet in Renal Disease equation to estimate renal function in intensive care unit patients. METHODS: Retrospective evaluation (preimplementation group, n=57) was conducted from March 2011 to April 2011. Prospective evaluation was conducted after nomogram implementation (postimplementation group, n=60) from December 2011 to February 2012. RESULTS: The percentage of patients with an initial vancomycin trough concentration 15 µg/mL or higher increased in the postimplementation group as compared with the preimplementation group (72% vs 39%, P=.0004). The postimplementation group also demonstrated an increase in the percentage of patients with initial trough concentration between 15 and 20 µg/mL (42% vs 19%, P=.0099), and no statistical difference in the percentage of patients with an initial trough greater than 20 µg/mL (30% vs 19%, P=.2041). There was no difference in nephrotoxicity in the postimplementation group compared with the preimplementation group (18% vs 17.5%, P=1.0). CONCLUSION: Use of a vancomycin nomogram increased the percentage of initial vancomycin trough concentrations 15 µg/mL or higher in intensive care unit patients and was not associated with an increased occurrence of nephrotoxicity.

Multicenter trial of desirudin for the prophylaxis of thrombosis: an alternative to heparin-based anticoagulation (DESIR-ABLE).

Desirudin, a subcutaneously (SC) administered direct thrombin inhibitor, is indicated for prevention of venous thromboembolic events (VTEs) after total joint replacement surgery. DESIR-ABLE (multicenter trial of desirudin for the prophylaxis of thrombosis: an alternative to heparin-based anticoagulation) was a multicenter, open-label, single-arm study of hospitalized patients requiring VTE protection designed to extend the safety profile for desirudin to include a broad population of perioperative/critically ill patients. The primary end point was major bleeding. A total of 516 patients undergoing major surgery (378, 73%) or who were medically ill with prolonged immobility (138, 27%) were enrolled at 19 centers and received desirudin 15 mg Q12H. Many patients had high-risk features for bleeding and thrombosis such as thrombocytopenia (<100 x 10(9)/mL, n = 50), severe obesity (body mass index >35, n = 145), and renal impairment (creatinine clearance <60 mL/min, n = 292). There were no major bleeds and no VTE-related deaths in this study. The DESIR-ABLE demonstrated the safety of desirudin in critically ill perioperative and medical patients. Trials in specific surgical or medically ill patients are needed to confirm these findings.

Dabigatran: a review of clinical and pharmacoeconomic evidence.

Dabigatran etexilate is the first commercially available oral direct thrombin inhibitor. A single trial has studied patients at risk for stroke associated with nonvalvular atrial fibrillation; in this trial, dabigatran 150 mg twice a day met the criteria for superiority over warfarin in preventing stroke and systemic embolism while reducing the rate of hemorrhagic stroke with a similar risk of major bleeding. For the treatment of venous thromboembolism, dabigatran 150 mg twice a day had comparable efficacy and safety versus warfarin. In contrast, dabigatran was less effective than enoxaparin 30 mg twice a day in venous thromboembolism prevention in orthopedic surgery. Advantages of dabigatran over warfarin include its lack of need for routine laboratory monitoring, a fixed-dose regimen, and potentially fewer clinically important drug interactions. Concerns include higher incidences of dyspepsia and gastrointestinal bleeding, twice-daily dosing, and lack of effective antidote. Additional drawbacks include higher drug cost versus warfarin, accumulation in case of renal impairment, higher discontinuation rates due to adverse events, and limited long-term safety and trial data. From a payer perspective, overall costs will be higher with dabigatran compared with warfarin, but dabigatran does meet the threshold to be considered a cost-effective therapy. In addition, the lack of need for regular laboratory monitoring is a quality of life advantage for patients on dabigatran. These observations suggest that dabigatran is a valuable addition to the therapeutic armamentarium for stroke prevention in selected patients with atrial fibrillation although caution should be exercised given the limited data on this agent and higher cost.

Incidence of propofol-related infusion syndrome in critically ill adults: a prospective, multicenter study.

INTRODUCTION: While propofol is associated with an infusion syndrome (PRIS) that may cause death, the incidence of PRIS is unknown. Determining the incidence of PRIS and the frequency of PRIS-related clinical manifestations are key steps prior to the completion of any controlled studies investigating PRIS. This prospective, multicenter study sought to determine the incidence of PRIS and PRIS-related clinical manifestations in a large cohort of critically ill adults prescribed propofol. METHODS: Critically ill adults from 11 academic medical centers administered an infusion of propofol for [>or=] 24 hours were monitored at baseline and then on a daily basis until propofol was discontinued for the presence of 11 different PRIS-associated clinical manifestations and risk factors derived from 83 published case reports of PRIS. RESULTS: Among 1017 patients [medical (35%), neurosurgical (25%)], PRIS (defined as metabolic acidosis plus cardiac dysfunction and [>or=] 1 of: rhabdomyolysis, hypertriglyceridemia or renal failure occurring after the start of propofol therapy) developed in 11 (1.1%) patients an average of 3 (1-6) [median (range)] days after the start of propofol. While most (91%) of the patients who developed PRIS were receiving a vasopressor (80% initiated after the start of propofol therapy), few received a propofol dose >83 mcg/kg/min (18%) or died (18%). Compared to the 1006 patients who did not develop PRIS, the APACHE II score (25 +/- 6 vs 20 +/- 7, P = 0.01) was greater in patients with PRIS but both the duration of propofol use (P = 0.43) and ICU length of stay (P = 0.82) were similar. CONCLUSIONS: Despite using a conservative definition for PRIS, and only considering new-onset PRIS clinical manifestations, the incidence of PRIS slightly exceeds 1%. Future controlled studies focusing on evaluating whether propofol manifests the derangements of critical illness more frequently than other sedatives will need to be large. These studies should also investigate the mechanism(s) and risk factors for PRIS.

Practical pharmacologic aspects of therapeutic hypothermia after cardiac arrest.

Abstract Therapeutic hypothermia has emerged as an effective means of improving neurologic outcomes among cardiac arrest survivors. To achieve optimal results, clinicians must understand and anticipate potential adverse effects of cooling and provide rigorous monitoring and/or pharmacologic interventions as appropriate. Using pharmacotherapy to counter adverse effects of cooling or to treat an intrinsic process under hypothermic conditions requires understanding how hypothermia will influence the clinical effects of the drug, including the drug's pharmacokinetics and pharmacodynamics. The pharmacologic aspects of therapeutic hypothermia in relation to physiology and adverse effects are reviewed.

Use of the chromogenic factor X assay to predict the international normalized ratio in patients transitioning from argatroban to warfarin.

STUDY OBJECTIVE: To determine the clinical utility of the chromogenic factor X level for conversion from argatroban to warfarin in hospitalized patients. DESIGN: Prospective observational study. PATIENTS: Sixty-two hospitalized patients with indications for anticoagulation in whom the chromogenic factor X assay was used for conversion from argatroban to warfarin. SETTING: University-affiliated hospital. INTERVENTION: From December 2003-May 2004, data for all patients in whom the chromogenic factor X assay was used for conversion from argatroban to warfarin were screened for inclusion. When the chromogenic factor X level was satisfactory, the clinician discontinued the argatroban and a confirmatory international normalized ratio (INR) was obtained. MEASUREMENTS AND MAIN RESULTS: To determine the ability of the chromogenic factor X level to predict the INR free of argatroban influence, we calculated the sensitivity and specificity by using a cutoff chromogenic factor X level of 45% or less, or greater than 45%, which corresponded to an INR of 2 or greater, or less than 2, respectively. We constructed a receiver operating characteristic curve to illustrate various cutoff levels of chromogenic factor X. Of 146 patients screened, 62 had data that met criteria for analysis. An average of 6 +/- 3 doses of warfarin were administered before the confirmatory coagulation studies were obtained. The average time from the chromogenic factor X measurement to obtainment of confirmatory coagulation studies was 9 +/- 4 hours. Use of a chromogenic factor X level of 45% or less to predict an INR of 2 or greater absent of argatroban influence had a sensitivity of 93%, a specificity of 78%, and an accuracy of 89%. The area under the receiver operating characteristic curve was 0.91 (95% confidence interval 0.81-0.99, p<0.0001). CONCLUSION: The chromogenic factor X level is an accurate alternative when converting hospitalized patients from argatroban to warfarin. A chromogenic factor X level of 45% or less is a reliable predictor that the INR will be therapeutic when argatroban therapy is discontinued.

Effect of renal function on the pharmacodynamics of argatroban.

BACKGROUND: Argatroban is a direct thrombin inhibitor used to treat heparin-induced thrombocytopenia (HIT). Argatroban is primarily cleared by hepatic mechanisms, with only small amounts of unchanged drug cleared by the kidneys. OBJECTIVE: To assess the effects of renal function on argatroban dose and activated partial thromboplastin time (aPTT). METHODS: Patients treated with argatroban were identified and prospectively screened. Patients with liver dysfunction were excluded from the analysis. Charts and laboratory data were reviewed daily until a therapeutic aPTT was reached or argatroban was discontinued. Data points collected included age, weight, gender, admitting diagnosis, past medical history, indication for anticoagulation, indication for argatroban, initial dose, goal aPTT, titration instructions, liver function tests, serum creatinine (S(cr)), blood urea nitrogen, and estimated creatinine clearance (Cl(cr)). RESULTS: A total of 66 patients were evaluated and 44 met criteria for inclusion. Baseline S(cr) was elevated at 1.5 mg/dL (0.9, 2.3; median 25th, 75th percentile), with an estimated Cl(cr) 40 mL/min/1.73 m(2) (26, 74). The median dose of argatroban to reach the predefined therapeutic range was 1 microg/kg/min (0.68, 2), with a corresponding aPTT of 60 seconds (54, 66). After univariate analysis, Cl(cr) significantly predicted the therapeutic dose (coefficient b +/- SE 0.019 +/- 0.004; r(2) 0.35; p < 0.001). Covariates that predicted dose were the presence of HIT (coefficient b +/- SE -0.61 +/- 0.3; p = 0.045), history of myocardial infarction (coefficient b +/- SE -0.74 +/- 0.3; p = 0.02), and an indication for anticoagulation of deep-vein thrombosis/pulmonary embolism (coefficient b +/- SE 0.69 +/- 0.3; p = 0.03). CONCLUSIONS: Estimated Cl(cr) significantly predicted the dose of argatroban needed to reach a therapeutic aPTT.