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BRIEF REPORTS/CLINICAL STUDIES |
From The Methodist Hospital, Weill Cornell Medical College, Houston, Texas (Dr Rice), Clinical Science Consulting, Austin, Texas (Dr Hursting), and CTI Clinical Trial and Consulting Services, Cincinnati, Ohio (Dr Baillie and Mr McCollum).
Address for correspondence: Lawrence Rice, MD, 6550 Fannin, Suite 1001, Houston, TX 77030.
Key Words: Heparin-induced thrombocytopenia • obesity • argatroban • body mass index • thrombosis
Heparin-induced thrombocytopenia (HIT) is a severe, antibody-mediated complication of heparin therapy in which 38% to 76% of affected patients, unless appropriately managed, will experience thrombosis within a month.1 Immediate heparin avoidance and early initiation of fast-acting, nonheparin anticoagulation are recommended treatments.2 Argatroban, a parenteral direct thrombin inhibitor, is available in North America and various European countries for use as an anticoagulant in patients with HIT.3,4 Prospective, multicenter, historical controlled trials have demonstrated that argatroban significantly improves HIT-associated outcomes, without increasing bleeding, in patients with clinically diagnosed HIT5-7 and also provides safe, effective anticoagulation in patients with a history of HIT who require acute anticoagulation.8 Argatroban clearance is linearly affected by actual body weight,9 and the Food and Drug Administration-approved dosing of argatroban for thromboprophylaxis or treatment in HIT is body weight-based, that is, 2 µg/kg/min initially (0.5 µg/kg/min if hepatic impairment is present), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5 to 3 times the baseline value.3 Contemporary clinical experiences indicate that many patients achieve therapeutic aPTTs at argatroban doses of approximately 0.5 to 1 µg/kg/min.10-13
Obese patients may present difficulties for drug dosing. Obesity may alter drug distribution and elimination, because of alterations in volume of distribution, body composition, plasma protein binding, and regional blood flow.14 Health care providers may be unsure as to which weight to use to determine the appropriate dose of medication for obese patients—actual body weight, ideal body weight, or a calculated "dosing" weight. It is suggested that drugs with narrow therapeutic windows, such as heparins, be used cautiously in patients with obesity.15 Despite the established effect of body weight on argatroban clearance, the effect of body mass index (BMI), and specifically obesity (BMI >30 kg/m2), on argatroban dosing is unclear.
The primary objective of this retrospective analysis of a multicenter HIT registry was to evaluate the effect of obesity on dose requirements and aPTT responses in patients administered argatroban for prophylaxis or treatment of thrombosis in presumed (clinically diagnosed) HIT or history of HIT. In secondary analyses, we also evaluated these variables plus clinical outcomes in the nonobese versus obese patients with baseline platelet counts <150 x 109/L.
METHODS
Patient Population
Patients for analysis were retrospectively identified from a multicenter, HIT registry database that enrolled 118 patients while open between January 2004 and March 2005. Patients had (presumed) HIT with or without thrombosis that was clinically diagnosed on the basis of unexplained absolute or relative thrombocytopenia in heparin-treated patients (and that may have been confirmed using laboratory assays according to local practice) or had a history of HIT from previous heparin exposure and required acute anticoagulation. The Institutional Review Board at each of the 6 participating centers (see acknowledgments at the end of the text) approved the data collection.
The analysis population for argatroban dosing and aPTT responses included all adults treated with argatroban at doses needed to provide noninterventional levels of anticoagulation (ie, at doses less than required for angioplasty) and who had sufficient data to calculate BMI. BMI was calculated as the patient's actual body weight in kilograms, divided by the square of the patient's height in meters. Patients were stratified according to their BMI: 
30 kg/m2 (nonobese group) or >30 kg/m2 (obese group). We speculated that patients with absolute thrombocytopenia would be more likely to have HIT than patients with normal platelet counts. Hence, in each BMI group, a subgroup of patients with baseline platelet counts <150 x 109/L was identified for additional evaluations.
Treatment and Assessments
Heparin therapy was discontinued immediately when HIT was suspected. Continuous intravenous argatroban (GlaxoSmithKline, Philadelphia, Pa) was initiated to achieve aPTTs 1.5 to 3 times the baseline value. The treating physicians made all decisions regarding the initial argatroban dose, dosage adjustments, and duration of therapy.
Data collected from the registry included patient demographics and baseline characteristics, argatroban dosing information, aPTTs, and clinical outcomes (death, amputation, new thrombosis, and bleeding). Major bleeding was defined as overt and associated with a hemoglobin decrease of 2 g/dL or more that led to a transfusion of 2 or more units of blood or that was intracranial, retroperitoneal, or into a prosthetic joint. Follow-up was variable in the registry and ranged from initiation of argatroban to hospital discharge, death, or later. Hence, in accordance with previous studies of argatroban in HIT,5,7 outcomes are reported using a 37-day follow-up period from argatroban initiation.
Statistical Analysis
Statistical analysis was performed using SAS statistical software version 8.2 (Cary, NC). For each BMI group, categorical variables were summarized using counts and percents, and continuous variables were summarized using descriptive statistics and are reported as median (range). Between-group comparisons were made using Wilcoxon's or Fisher's exact tests. For each patient, the duration of argatroban therapy was defined as the difference between the dates that the infusion was stopped and started, excluding temporary stoppage times; the maintenance dose of argatroban (ie, mean dose during therapy) was calculated by proportionally weighting each dose during therapy by its duration; and the mean aPTT during therapy was calculated by weighting each aPTT value by the time between consecutive assessments. By-group summary statistics for doses and aPTTs during therapy were computed using the mean values from each individual in the BMI group. Relationships between BMI and initial or maintenance argatroban dose were explored using regression analysis. Time-to-event Kaplan-Meier analysis was used to estimate the median time (and 95% confidence interval, CI) to achieve a therapeutic aPTT (defined as 45-90 seconds). For patients with absolute thrombocytopenia, time-to-event analysis was used to estimate the median (and 95% CI) time to platelet count recovery, defined as a platelet count >100 x 109/L or an increase of at least 1.5-fold above baseline. Times-to-event were compared between groups using the log-rank test. For patients with absolute thrombocytopenia, Cox proportional hazards modeling assessed the impact of obesity, BMI, argatroban dose, gender, and baseline platelet count on the risk of new thrombosis. Tests were 2-sided and conducted at the .05 level of significance.
RESULTS
Patients
Our analysis population comprised 83 argatroban-treated patients, of whom 32 (39%) were obese (Table I). Actual body weights were 40.9 to 130 kg and BMIs were 15.5 to 50.8 kg/m2. Argatroban was administered for treating presumed HIT in 73 (86%) patients (28 obese) and for acute anticoagulation in 10 (12%) patients (4 obese) with a history of HIT. Both overall and by BMI group, the most common indications for previous heparin therapy (or acute anticoagulation) included acute coronary syndromes (30 nonobese and 17 obese patients); surgery, including cardiac surgery (25 nonobese and 16 obese patients); deep vein thrombosis (27 nonobese and 10 obese patients), and percutaneous coronary intervention (19 nonobese and 15 obese patients). At baseline in patients with presumed HIT, median platelet counts were 164 x 109/L and 110 x 109/L, respectively, in the nonobese and obese groups, and 19 patients (5 obese) had HIT-related thrombosis (Table I). Immunoassay confirmed HIT antibodies in 72 of 83 (87%) patients, with the test not performed or results unknown for the remaining patients. Other confirmatory tests included a heparin-induced platelet aggregation assay in 3 patients (1 obese) and a serotonin release assay in an obese patient. Besides patient weight and BMI, each of which was different between groups (P < .001), demographics and baseline features were comparable between groups (P 
.16).
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Within the analysis population, 41 patients (20 obese) had absolute thrombocytopenia, that is, platelet count <150 x 109/L, at baseline (Table I). Excluding 2 patients with a history of HIT, median baseline platelet counts of 85 and 92 x 109/L, respectively, occurred in these nonobese and obese patients. Their demographic and other baseline features (Table I) and heparin indications (data not shown) were similar to those of the analysis population.
Argatroban Dosing and aPTT Responses
In the analysis population, no differences in argatroban doses were detected between the nonobese and obese patients at initiation of argatroban (median dose of 1.0 µg/kg/min, each group; P = .26) or during therapy (median maintenance doses of 1.2 and 1.1 µg/kg/min, respectively, P = .52) (Table II). By regression analysis of individual patient data, overall or by group, there were no significant associations between BMI and either the initial or maintenance argatroban dose (data not shown).
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No differences were detected in the anticoagulant (aPTT) effects during argatroban therapy between nonobese and obese patients at the first aPTT assessed, which typically occurred 3 to 5 hours after starting therapy (median aPTTs of 53.8 vs 52.1 seconds, P = .71), after 24 hours of therapy (median aPTTs of 55.2 vs 59.9 seconds, P = .52), or overall during therapy (median aPTTs of 58.5 vs 56.7 seconds, P = .91) (Table II). Therapeutic aPTTs were achieved within a median of 8.8 hours in the nonobese group and 11.5 hours in the obese group (P = .43). Patients continued on argatroban therapy typically for 6 to 7 days, without between-group differences in duration (P = .74).
Among patients with absolute thrombocytopenia at baseline, argatroban dosing patterns and aPTT responses generally paralleled those in the larger analysis population, without apparent differences between nonobese and obese patients (Table II). By possible exception, these patients typically achieved therapeutic aPTTs somewhat more rapidly, within 5 to 6 hours of starting argatroban.
Platelet Count Recovery
In patients with a baseline platelet count <150 x 109/L (n = 41), platelet counts recovered within 4.3 (1.4, 5.5; 95% CI) days in the nonobese and 2.4 (1.5, 4.2; 95% CI) days in the obese subjects. Among those with available data, median (range) platelet counts within 24 hours of cessation of argatroban were 116 (11-363) x 109/L (n = 12) in the nonobese and 204 (31-348) x 109/L (n = 12) in the obese.
Clinical Outcomes
Within 37 days of argatroban initiation, 14 (6 obese) of 41 patients with absolute thrombocytopenia experienced death (7 nonobese and 5 obese, P = .73), amputation (0 nonobese and 1 obese, P = .49), or new thrombosis (1 nonobese and 3 obese, P = .34). There was a single major bleeding episode (nonobese patient). Multiple outcomes occurred in 4 patients (3 obese). Two patients (1 in each group) died while receiving argatroban at respective maintenance doses of 0.13 µg/kg/min (10 days of therapy) and 0.15 µg/kg/min (1 day of therapy); their causes of death are unknown, although neither experienced new thrombosis. Among the other 10 fatalities, argatroban, which has an elimination half-life of 39 to 51 minutes,16 had been discontinued for a median 7 (2-17) days. Of these 10 patients, 2 had previous HIT with current thrombocytopenia, 1 of whom also developed thrombosis 2 days after stopping a 24-day course of argatroban therapy and died 5 days later. New thrombosis occurred in 2 patients (each obese) while on argatroban. The first patient, who had HIT-related thrombosis at presentation, suffered new thrombosis on the second day of a 5-day course of argatroban therapy (maintenance dose, 2.6 µg/kg/min) and also underwent amputation 5 days after argatroban was stopped. The second patient was diagnosed with deep vein thrombosis on the fourth day of argatroban therapy (maintenance dose, 0.5 µg/kg/min); argatroban was stopped, and the patient died (cause unknown) 13 days later. The fourth event of new thrombosis (reported as an enlargement of a right femoral pseudoaneurysm) occurred in a nonobese patient 9 days after a 1-day course of argatroban therapy; major hemorrhage occurred on the same day as the thrombotic event. Cox regression analysis failed to identify any significant risk factors for new thrombosis (P .35) among the covariates of BMI, obesity, gender, argatroban dose, baseline platelet count, or aPTT, although the number of events (n = 4) was small.
Among the 42 patients without absolute thrombocytopenia, 2 patients (each nonobese) died 6 and 9 days after cessation of a 13- and 6-day course of argatroban, respectively. New thrombosis occurred in 1 obese patient on the day that argatroban was discontinued (3-day course of therapy; mean aPTT, 31.5 seconds) and in 2 nonobese patients 27 and 17 days after cessation of 3- and 4-day courses of argatroban, respectively. No patient had an amputation or major bleeding.
DISCUSSION
With approximately 1 in 3 adults in the United States obese and the prevalence of obesity increasing,17 health care providers should be aware of any necessary alterations to standard approaches to therapy for obese patients. Results of initial clinical trials of new medications may not always provide complete information on the efficacy, safety, and appropriate dosing in obese patients. An emerging body of literature is attempting to describe the impact of obesity on outcomes and drug therapy in critically ill patients. Erstad15 stated that the dosing regimens for medications used in obese patients in the intensive care unit are as much an art as a science, given the lack of published investigations that could be used for evidence-based approaches to therapy.15 Possible discrepancies in pharmacokinetic and pharmacodynamic properties of a drug may be observed in obese patients.18 Until specific data are available, clinicians must often extrapolate dosing regimens for special populations based on known pharmacokinetic and pharmacodynamic data.15
Argatroban, a small, predominantly hepatically metabolized molecule, distributes mainly in the extracellular fluid (apparent steady-state volume of distribution, 174 mL/kg).3 It is bound 54% to human serum proteins, with binding to albumin and 
1-acid glycoprotein being 20% and 34%, respectively.3 Pharmacokinetic studies of drugs highly bound to albumin have shown no significant changes in protein binding in obese patients.14 However, there is conflicting evidence about binding to 1-acid glycoprotein in obese patients.18 The low extent of plasma protein binding of argatroban should not be influenced by obesity. Another consideration could be the impact of steatohepatitis on the metabolic activity of the liver. Obese patients frequently have fatty infiltration of the liver,19 and dosage reduction of argatroban is necessary with liver dysfunction.16,20 Although not clinically significantly affected by patient age, gender, race, or renal function, argatroban clearance is decreased in hepatic dysfunction and increases linearly with body weight.9,16
Our retrospective analysis evaluated the effect of obesity on argatroban dose requirements and aPTT responses in 83 patients with BMIs of 15.5 to 50.8 kg/m2. The nonobese (n = 51) and obese (n = 32) patient groups were well matched. The median BMI in the obese (34.9 kg/m2) was at the upper limit of class I obesity (30.0-34.9 kg/m2), as defined by the National Institutes of Health.21 All patients were from a multicenter HIT registry and received argatroban therapy at noninterventional levels of anticoagulation for presumed HIT or a history of HIT requiring acute anticoagulation. A limitation is that patient selection for argatroban therapy was uncontrolled and based on subjective selection criteria of individual investigators. The elevated median platelet counts at baseline (110-164 x 109/L), compared with values reported in other HIT populations,5,7 suggest that some patients may not have had HIT, despite 87% having heparin-platelet factor 4 antibodies by immunoassay. The decision to use argatroban therapy, however, reflected the clinical judgment of treating physicians, and this population supports evaluation of argatroban dosing in a relatively large number of obese patients, with implications for therapy of presumed HIT.
We also characterized argatroban doses, aPTT responses, platelet count recovery, and clinical outcomes in 41 patients (20 obese) who presented with platelet counts <150 x 109/L. Our rationale for evaluating this more homogeneous subset of patients was that we speculated these patients would be more likely to have "true" HIT than patients with normal platelet counts (recognizing, however, that relative, 50% drops in the count, even with the nadir >150 x 109/L, may also herald HIT2) and because the risk of thrombosis in HIT increases with decreasing platelet count.6,22 The analysis population and the subpopulation with absolute thrombocytopenia were similar in most regards, including baseline features, dosing, and aPTT responses. Ultimately, they also had no substantive difference in their overall frequency of immunoassay-confirmed heparin-platelet factor 4 antibodies (87% and 85%, respectively, Table 1).
Overall, patients received a wide range of argatroban infusion doses that were based on body weight (ie, 0.03-7.8 µg/kg/min initially) and then aPTT-adjusted during therapy. The median initial argatroban dose in both the nonobese and obese patients was 1.0 µg/kg/min, suggesting that the treating physicians made no initial dose adjustment for obesity. This starting dose is less than the 2.0 µg/kg/min initial dose approved by the Food and Drug Administration for patients without hepatic impairment.2,5,7 The dose is consistent, however, with the reduced doses more recently reported to support therapeutic aPTTs in many patients.10-13 The median maintenance doses of 1.1 to 1.2 µg/kg/min suggest that only minimal, if any, dose adjustment was required after initiating therapy to achieve and maintain target aPTTs, irrespective of BMI group. Therapeutic aPTTs were achieved within a few hours of initiating argatroban in both the nonobese and obese patients. We used categorical (by-group) and regression (by-patient) analyses to differentiate the effects of BMI or obesity on dosing. Given our sample size, regression analysis had 50% power to detect a significant effect (categorical analysis had less power). No effect of obesity or BMI on argatroban dosing was detected by either approach.
Clinical follow-up was variable, and so we analyzed outcome data using a 37-day period, as previously used in prospective clinical trials of argatroban.5,7 The frequencies of outcomes in the argatroban-treated nonobese or obese patients with absolute thrombocytopenia were generally similar, by indirect comparison, to those of argatroban-treated patients in previously published studies in HIT.5,7 In the previous studies, an all-cause composite of death, amputation, or new thrombosis occurred in 26% of patients with HIT (or history of HIT) and 44% of patients with HIT with thrombosis. In the present analysis, this composite endpoint occurred in 34% (14/41) of patients with baseline thrombocytopenia and 23% (19/83) overall. No patient experienced major bleeding while on argatroban. Of 14 deaths overall, only 1 in each BMI group occurred while the patient was on argatroban, with neither event associated with hemorrhage or thrombosis. By Cox regression analyses, no relationship was detected between BMI (or obesity) and thrombotic risk, although events were few.
CONCLUSIONS
Results from this retrospective analysis suggest that (1) argatroban dosing requirements, aPTT responses, and clinical outcomes are similar between nonobese and obese patients; (2) therapeutic levels of anticoagulation are achieved rapidly and maintained in many patients, including individuals who are obese, administered argatroban at doses of approximately 1 µg/kg/min; and (3) thrombotic risk in HIT is not predicted by obesity or BMI. Together, these findings support the use of actual body weight-adjusted (and aPTT-adjusted) argatroban dosing for safe, effective anticoagulation in presumed HIT, or history of HIT if acute anticoagulation is required, and suggest that adjustment of the initial dose is unnecessary in obesity (BMI up to 51 kg/m2). Prospective study to validate these findings is warranted.
ACKNOWLEDGEMENTS
The investigative sites (and lead investigator at each site) for the HIT registry database were Baylor College of Medicine, Houston, Texas (Lawrence Rice, MD); Massachusetts General Hospital, Boston, Massachusetts (Ik-Kyung Jang, MD, PhD); Oregon Health Sciences University, Portland, Oregon (Lynn Boshkov, MD); The Cleveland Clinic, Cleveland, Ohio (John R. Bartholomew, MD); University of Chicago, Illinois (Madelyn Kahana, MD); and University of Pennsylvania, Philadelphia, Pennsylvania (William H. Matthai, Jr, MD).
Financial disclosure: This study was supported by GlaxoSmithKline. Dr Rice is on the speaker's bureau and has been on advisory boards for GlaxoSmithKline. Dr Hursting is a consultant with GlaxoSmithKline. Dr Baillie and Mr McCollum report no conflict of interest.
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