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C L I N I C A L C o N s u LtAt I o N
Effect of fondaparinux prophylaxis on anti-factor Xa concentrations in patients with morbid obesity
Larissa Martinez, aLLison Burnett, Matthew Borrego, Jessica c. streeter, KeLLy townsend, and david garcia
enous thromboembolism (VTE) is a common and potentially fatal condition that encompasses two conditions: deep venous thrombosis (DVT) and pulmonary embolism (PE). A recent “call to action” from the U.S. Surgeon General estimated that more than 300,000 Americans develop VTE annually and as many as 100,000 deaths may occur each year as a result.1 Up to 50% of new VTE cases occur during hospitalization.2 Pharmacologic prophylaxis with agents such as unfractionated heparin, low-molecularweight heparins (LMWHs), and the pentasaccharide fondaparinux has been shown to reduce the risk of VTE by as much as 68%.3-15 Morbidly obese patients (those with a body mass index [BMI] of ≥40 kg/m2) were not well represented in the pivotal clinical trials that established the safety and efficacy of pharmacologic VTE prevention strategies. In a meta-analysis of nine randomized controlled trials of VTE prophylaxis involving a total of almost 13,000 medically ill
Purpose. Anti-factor Xa values in morbidly obese patients receiving standard doses of fondaparinux sodium for the prevention of venous thromboembolism (VTE) were analyzed in a retrospective chart evaluation. Summary. The administration of lowmolecular-weight heparins to obese patients (body mass index [BMI] of ≥30 kg/ m2) at the dose recommended for VTE prophylaxis has been reported to result in increased thromboembolic events and decreased anti-factor Xa levels, and some evidence indicates that weight-based dosing adjustments may be appropriate. To study this phenomenon among morbidly obese patients (BMI of ≥40 kg/ m2), a review of the charts of 45 adult patients for whom steady-state anti-factor Xa laboratory values were obtained after at least four fondaparinux injections was conducted; in all instances, fondaparinux sodium was given at the standard dose (2.5 mg once daily). Of the total of 47 anti-factor Xa values analyzed, 22 (47%) were below
the study institution’s target peak range (0.3–0.5 mg/L), 20 values (43%) were within the range, and 5 (11%) were above the range. No documented thromboembolic events occurred during hospitalization in the cases evaluated. A stepwise linear regression analysis of selected demographic and clinical variables indicated that better renal function, male sex, increased BMI, and fewer fondaparinux doses were associated with a greater likelihood of diminished anti-factor Xa activity in the cases evaluated. Conclusion. Anti-factor Xa concentrations in morbidly obese patients receiving fondaparinux sodium 2.5 mg subcutaneously daily for VTE prophylaxis were within or above the target range in 53% of the instances evaluated. Index terms: Anticoagulants; Factor Xa; Fondaparinux sodium; Injections; Obesity; Venous thromboembolism Am J Health-Syst Pharm. 2011; 68:171622
patients, the mean BMI was 25.6 kg/ m2.16 In orthopedic trials comparing fondaparinux with enoxaparin for VTE prophylaxis, the mean ±
S.D. BMI values of patients treated with fondaparinux and enoxaparin were 27.4 ± 5.6 kg/m2 and 27.3 ± 5.7 kg/m2, respectively. 13 In these
Larissa Martinez, PharM.D., is Clinical Pharmacist—Inpatient Pharmacy Department; and aLLison Burnett, PharM.D., is Antithrombosis Pharmacist—Inpatient Pharmacy Department, University of New Mexico (UNM) Hospital, Albuquerque. Matthew Borrego, Ph.D., M.s., is Associate Professor, College of Pharmacy, UNM. Jessica c. streeter, PharM.D., is Clinical Pharmacist— Inpatient Pharmacy Department, Torrance Memorial Medical Center, Tor rance, CA. KeLLy townsenD, Mt(ascP)sh, is Technical Specialist for Coagulation, TriCore Reference Laboratories, Albuquerque. D aviD g arcia , M.D., is Associate Professor—
Internal Medicine Division of Hematology/Oncology, UNM Cancer Center, Albuquerque. Address correspondence to Dr. Burnett at the Inpatient Pharmacy Department, University of New Mexico Hospital, 2211 Lomas Boulevard, N.E., Albuquerque, NM 87106 (firstname.lastname@example.org). The authors have declared no potential conflicts of interest. Copyright © 2011, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/11/0902-1716$06.00. DOI 10.2146/ajhp110010
Am J Health-Syst Pharm—Vol 68 Sep 15, 2011
Our reference range for the fondaparinux-associated anti-factor Xa concentration (0. nonadjusted doses of fondaparinux are adequate to achieve target anti-factor Xa levels for VTE prophylaxis in morbidly obese patients.5 mg/L). an estimated creatinine clearance (estimated by the method of Cockcroft and Gault. According to GlaxoSmithKline. 2011 . Parsippany. Diagnostica Stago. which is potentiated by fondaparinux to inhibit factor Xa.5 mg/L) was based on pharmacokinetic information from GlaxoSmithKline (the manufacturer of fondaparinux) and data from clinical trials of fondaparinux. However. BMI was 26. patients’ plasma supplies antithrombin. fewer than 25% of patients had a BMI of ≥30 kg/m2. Methods In a retrospective. it is currently unknown whether this is the optimal target range for the prevention of VTE and the reduction of bleeding events. the medical records of all morbidly obese patients admitted to the University of New Mexico Hospital from May 2009 to March 2010 and receiving fondaparinux for VTE prophylaxis were reviewed. receipt of fondaparinux sodium 2.clinical consultation Fondaparinux trials.19 reported a strong association between increased BMI and a higher rate of thrombosis (p = 0. cross-sectional study.c In a study analyzing two chromogenic substrate methods for monitoring of fondaparinux therapy.0002).3–0. Samama et al. studies suggest that standard prophylactic dosing with unfractionated heparin or a LMWH may not be sufficient to prevent VTE in obese patients.b Fairview Diagnostic Laboratories. anti-factor Xa concentrations were determined by TriCore Reference Laboratories (Albuquerque.5 ± 7.39–0.50 mg/L as its target peak range for anti-factor Xa concentration.2–0. had a higher percentage of obese patients (41.5-fold higher risk of rehospitalization for symptomatic VTE than patients with a lower BMI.15 that compared postoperative fondaparinux with preoperative dalteparin for VTE prophylaxis in patients undergoing high-risk abdominal surgery.7 mg/L three hours after the subcutaneous injection of the drug.18 Furthermore. a BMI of ≥40 kg/m2. In our study.14– 0. 17.3–0. BMI was only 29. a subgroup analysis focusing on obese patients showed that dalteparin conferred no benefit over placebo among patients with a BMI of ≥40 kg/m2. among patients receiving fondaparinux sodium 2.39–0. We conducted a study to determine if standard.5 mg subcutaneously daily for VTE prophylaxis. The kit used by TriCore (Rotachrom Colorimetric assay for heparins and fondaparinux.26 These data suggest that a peak steady-state range of 0. and the minimum steady-state antifactor Xa concentration was 0. The risk of thrombosis was significantly increased in patients with a BMI of >32 kg/m2 (p < 0. a “one-size-fits-all” dosing strategy for VTE prophylaxis with unfractionated heparin or LMWHs may be inappropriate for morbidly obese patients.3 kg/m2. The quantity of released paranitroaniline is inversely proportional to the concentration of fondaparinux in the plas1717 Am J Health-Syst Pharm—Vol 68 Sep 15. A trial by Turpie et al. 23 These findings suggest that the failure to achieve anti-factor Xa activity in obese patients similar to that achieved in nonobese patients leads to increased thromboembolic events.50 mg/L. NJ) does not use exogenous antithrombin.D.14 in which fondaparinux plus mechanical prophylaxis was compared with mechanical prophylaxis alone for VTE prevention in patients having abdominal surgery. In a large case-controlled study among patients undergoing total hip arthroplasty and receiving standard VTE prophylaxis regimens. Residual factor Xa hydrolyzes a synthetic chromogenic substrate that releases paranitroaniline.3 ± 5. which serves the University of Minnesota. uses a slightly broader target peak range (0.5 mg/L may be appropriate for VTE prophylaxis with fondaparinux. 24 using adjusted body weight) of >30 mL/ min.9%). patients with a BMI of ≥25 kg/m 2 were found to have a 2. In a study by Agnelli et al. and the mean ± S. instead.5 mg once daily in clinical trials. Obesity is associated with a 2–3fold increase in the occurrence of VTE.D.2 kg/m2.a The Blood Center of Wisconsin uses 0. and the measurement of at least one peak fondaparinux anti-factor Xa concentration after four or more fondaparinux doses. similar findings have been reported in critically ill patients receiving fixed-dose LMWH prophylaxis..3–0. NM) with a chromogenic assay calibrated with the Biophen Arixtra Calibrator (Aniara Corporation.25.19 mg/L. the mean peak steady-state anti-factor Xa concentration was 0.10 compared dalteparin with placebo for VTE prophylaxis in medically ill patients and reported an overall 45% relative reduction in events in the dalteparin recipients.20 Leizorovicz et al. ex vivo samples from 18 orthopedic patients receiving fondaparinux for VTE prophylaxis were found to have peak anti-factor Xa concentrations of 0. only 22% of patients had a BMI of ≥30 kg/m2. Mason. but the mean ± S.001). The inclusion criteria were as follows: age of ≥18 years. In a retrospective study of 817 patients undergoing lower-extremity orthopedic surgery and receiving enoxaparin sodium 40 mg subcutaneously daily for VTE prophylaxis. OH). An inverse relationship between body weight and anti-factor Xa activity in obese patients receiving enoxaparin sodium 40 mg once daily has been demonstrated22.21 The increased rate of VTE events in obese patients receiving standard prophylactic regimens of anticoagulants is supported by pharmacodynamic data. Therefore.
especially BMI. 4–55 days). 47 concentrations from 45 patients met the study inclusion criteria. 0.77 ± 0.3–0.68 ± 0.18 mg/L (range. The correlation between plasma fondaparinux and anti-factor Xa concentrations was high (R = 0. Statistical analyses were performed using SPSS version 16. The patients’ mean ± S. CO.2 ± 11. shared sample testing was conducted semiannually.62 mg/dL). and the assay was linear for anti-factor Xa concentrations of 0.D. A stepwise multiple linear regression analysis was performed to analyze multiple patient variables thought to have an effect on anti-factor Xa levels. serum creatinine concentration (1.D.92 mg/L). Mean anti-factor Xa concentration values were calculated for patients at. and the following variables were significant predictors of the anti-factor Xa concentration: serum Am J Health-Syst Pharm—Vol 68 Sep 15.3–0. below.D. however. 4 (9%) were for altered mental status.D. A total of 20 of 47 values (43%) were within the target anti-factor Xa level range (0. 5 (11%) were for abdominal surgery. or above the target range. below. Results A total of 81 anti-factor Xa concentrations among 79 patients were determined. at. 2011 . 40.5 mL/min (range. Information on bleeding or thrombotic events during hospitalization and for up to 30 days after discharge was also collected. 95. <0. Patients with anti-factor Xa concentrations above the target range had a higher mean ± S.D. At the time of our study. differed significantly among the three groups. n = 10). p = 0. 18 (38%) were for infection. 1718 This study was approved by the human research review committee at the University of New Mexico Health Sciences Center. there were multiple instances of incorrect sample collection (n = 8). and above the target levels. and 19 (42%) were Hispanic. Only the results from the first appropriately collected sample per admission were included.8 years (range. Reasons for exclusion included the following: the sample for anti-factor Xa concentration was not collected at the appropriate time (n = 14).5 mg/L. and summarized via retrospective electronic-chart review.clinical consultation Fondaparinux ma. serum creatinine concentration was 0.9 mL/ min). The model resulted in an adjusted R2 value of 0. and length of hospitalization among the groups of patients whose anti-factor Xa concentrations were within. two patients were admitted twice. and above target). body weight was 142 ± 36 kg (range.. and the TriCore results were within 15% of those of other reference laboratories.8 ± 14. number of fondaparinux doses received before sample collection. Twenty-two anti-factor Xa levels (47%) were below 0. and 11 (23%) were for other reasons. n = 11).34 ± 0.4 kg).38–1. anti-factor Xa peak concentration value (n = 47) was 0.10–0.5 mg/L. Each antifactor Xa concentration result represented a separate hospital admission. patient age was 52. The mean ± S. samples for determining anti-factor Xa concentrations were collected two to four hours after at least four consecutive fondaparinux doses to ensure that patients were at steady state. 15 (36%) were white. 6 (13%) were for knee or hip surgery.2 ± 12.9861).2–99.7–299. IL). 42. We also evaluated patient factors that may have influenced anti-factor Xa levels. serum creatinine. Measures of renal function. below. and 5 (11%) were above 0.e.2 ± 67.425. BMI. BMI was 51.D. Among the 47 hospital admissions.5 mg/L.3–348. with a sample collected during each hospitalization. and none was found. 22– 77 years). 3 (6%) were for polytrauma or trauma related to a motor vehicle accident. There were no significant differences in age. including age. weight. Chicago. estimated creatinine clearance was 150. TX.0% for results in the target prophylactic range of 0.45 mg/dL) than those within the target range (0.20 mg/dL). and fondaparinux doses received before sample collection.19 mg/dL) or below it (0.D. The anti-factor Xa data that resulted from inappropriately timed sample collection were excluded from analysis. the University of Illinois— Chicago (n = 5). length of hospitalization was 17.8 kg/m2 (range. and Methodist Hospital (Houston. and the mean ± S.. The mean ± S. abstracted.D. We examined the recorded times at which samples for obtaining anti-factor Xa concentrations were collected and reconciled them with recorded medication administration times and with the pharmacy dispensing log. The primary outcome of this study was the percentage of morbidly obese patients receiving standard prophylactic doses of fondaparinux who achieved an anti-factor Xa concentration of 0. Our methodology was validated by comparing ex vivo samples from patients receiving fondaparinux and plasma samples spiked with fondaparinux with results from Esoterix Laboratory (Denver. All variables included in the stepwise multiple-regression analysis model were checked for colinearity. Of the 45 patients. The a priori level of significance was 0.10–2.30 mg/dL (range.3 mg/L.3–0.00 mg/L. the sample was collected before the fourth fondaparinux dose (n = 11).0 days (range. In our study.12 ± 0. sex.5 mg/L). with a coefficient of variation of 9. Descriptive statistics were used to describe patient demographics and primary outcome data. The study population comprised 18 men (40% of the population) and 27 women.4 kg/m2). The Kruskal-Wallis one-way analysis of variance test was used to compare differences among the anti-factor Xa level categories (i.05. and the mean ± S.77 ± 0.0 (SPSS Inc.021 (Table 1). and two doses of fondaparinux were administered in the 24 hours before sample collection (n = 1). The mean ± S. The mean ± S. BMI.
7 ± 1.36. sex.7 ± 14.1 6.6 ± 49. without an increased frequency of bleeding events.3–0.19 1.27 compared enoxaparin sodium dosages of 30 and 40 mg twice daily in patients undergoing bariatric surgery whose median BMI was approximately 50 kg/m2. LMWHs have been used since the early 1990s. –0. BMI (p = 0. Valueb Below target (<0. No thromboembolic events were documented in the study population during hospitalization.68 ± 0. Am J Health-Syst Pharm—Vol 68 Sep 15. They further stated that while dalteparin 7500 units subcutaneously daily may be appropriate for the majority of morbidly obese patients. its use has not been nearly as extensive as the use of LMWHs.45 179.6 ± 12. One patient developed minor bleeding after a muscle biopsy.004). cross-sectional study to describe the fondaparinux anti-factor Xa levels achieved using standard prophylactic doses of fondaparinux in morbidly obese patients. To our knowledge. During the postoperative period.022).2 ± 11.4 ± 2.5 ± 73. The analysis was also conducted using estimated creatinine clearance instead of serum creatinine concentration. higher doses may be needed for very-high-weight patients. the patient’s anti-factor Xa concentration was within the target range at the time of the event (0.5 mg/L) Above target (>0. sex (p = 0. that patient’s antifactor Xa concentration (0. Thus.7 ± 13.7 ± 13.41 mg/L).2 135. as compared with the standard regimen of 30 mg twice daily (p < 0.32.3 mg/L) At target (0. differences among groups were not significant (Kruskal-Wallis one-way analysis of variance test). none of the 45 patients had a thrombotic event within 30 days after hospital discharge documented in the electronic medical record.001 for differences among groups.6%.005). Simoneau et al. and number of fondaparinux doses before sample collection (p = 0. p = 0. While fondaparinux has been avail- Table 1. d p = 0. and it has been postulated that standard prophylactic LMWH doses may be insufficient to prevent VTE or achieve suggested anti-factor Xa target levels in obese patients. Documentation of clinical follow-up 30 days after discharge was available for 28 (59. Serum creatinine concentration.009). 2011 BMI = body mass index.5 mg/L) 22 20 5 50. Doses Before Sample Collection Estimated CLcrd (mL/min) SCr (mg/dL)c Body Weight (kg) Age (yr) n Anti-Factor Xa Concentration BMI (kg/m2) Mean ± S.6 ± 25.0%.0 16. 4. with beta coefficients of 0. –0. able for nearly a decade.6 ± 11. One patient was discharged to a nursing home and rehospitalized 29 days later for gastrointestinal bleeding of unknown origin. respectively. It is possible that with more time and the increased use of fondaparinux.9 126. The authors reported a statistically significant reduction in VTE events among the patients receiving 40 mg twice daily.5 46. an increased risk of VTE among morbidly obese persons receiving standard doses of the drug might become apparent.01). 28 conducted a retrospective study in 135 morbidly obese patients undergoing bariatric surgery. CLcr = creatinine clearance. 9.0 4.34.3 1719 c . the study described here is the first retrospective. The authors reported that over 30% of patients had a level below target despite receiving a higher-thanstandard dose.8 ± 35.4 79.7%. b a creatinine concentration (p = 0.5 138. patients were given dalteparin 7500 units subcutaneously daily for VTE prophylaxis.8 52. and 0.30.35 mg/L) was within the target range during the index admission.D. Length of Hospitalization (days) No. and 6.4 ± 5. that dosage was higher than the standard recommended dosage of 5000 units daily. Scholten et al.9 ± 21.4 ± 20.12 ± 0.4 4. SCr = serum creatinine concentration.6%) of the 47 anti-factor Xa levels included in the study. The efficacy of dalteparin therapy was determined using anti-factor Xa levels. clinical experience with this agent and outcomes data are far more limited.021 for differences among groups.1 26.4 52. with no difference in the results.8 ± 1.7 148. Several investigators have analyzed adjusted-dose VTE prophylaxis with LMWHs in obese patients by evaluating rates of thromboembolic events and pharmacodynamic parameters.9 ± 13. but the bleeding resolved without intervention.3 16.2 ± 38. Unless otherwise noted.77 ± 0.clinical consultation Fondaparinux Patient Characteristics Stratified by Anti-Factor Xa Concentrationa Discussion Obesity is associated with an increased risk of VTE.2% of the overall variance in the anti-factor Xa concentration.1 0. and number of fondaparinux doses before sample collection accounted for 22.2 50. and only in the last few years have adjusted doses for obese populations been suggested. BMI.2 58.20 0. respectively.
15. VTE occurred in 4 (2.3 mg/L).9%).35 indicating that those results might not be applicable to very-highweight patients. and anti-factor Xa levels were determined after the first or second dose. There is very little published evidence to facilitate the analysis of the hypothesis that fondaparinux therapy is associated with lower antifactor Xa activity in obese patients compared with nonobese patients. The fondaparinux arm of the trial by Agnelli et al. 51.4% (28 of 805 patients) in the nonobese group and 8. Rondina et al.25 Information regarding the dosing of fondaparinux in morbidly obese patients is more limited than that for LMWHs or unfractionated heparin.1–76. The rate of VTE among the 501 nonobese patients was significantly lower at 10 days in those receiving fondaparinux (3 events in 246 patients [1. The results of the stepwise linear regression analysis showed that renal function. 2011 . Turpie et al.205 mg/L) than men (0.5 mg subcutaneously once daily.d The frequency of VTE was 3. It is predominantly excreted unchanged in the urine and has a half-life of 17–21 hours.395 ± 0.257 ± 0.35 which may predispose heavier patients to lower antifactor Xa levels.30 examined medically ill patients who received weightadjusted enoxaparin dosing for VTE prophylaxis. Raftopoulus et al.3%].2%]) than in those receiving placebo (16 events in 255 patients [6. sex. 95% confidence interval [CI] –94.7% to –35.14 included 340 obese patients among 841 patients in their efficacy analysis. In our study. The investigators found that this weight-based dosing strategy resulted in “peak anti-factor Xa levels within or near the recommended range for prophylaxis without any evidence of excessive anti-factor Xa activity.4%). a subgroup analysis was performed to compare the frequency of VTE and major bleeding among nonobese and obese patients. the plasma clearance of fondaparinux increased by 9% for every 10-kg increase in weight. –81. so the association between serum creatinine concentration and anti-factor Xa levels was expected. The authors suggested that the 5-mg dose would achieve target anti-factor Xa concentrations in morbidly obese patients more consistently than the 2.6% (19 of 222 patients) in the obese group. range. the heaviest patient was 169 kg.6 kg/m2 in women).29 compared enoxaparin sodium 40. compared with nonobese patients.and 5-mg doses of fondaparinux sodium in morbidly obese volunteers (mean BMI. compared with no patients in the group receiving the 60-mg dose. anti-factor Xa levels were collected to determine efficacy.and 60-mg twicedaily dosing in patients with a median BMI of 47 kg/m2.5. Nearly 44% of patients receiving the 40-mg dose had anti-factor Xa concentrations below the target range by the third dose. The association between the number of fondaparinux doses before sample Am J Health-Syst Pharm—Vol 68 Sep 15. only 53% of antifactor Xa concentration values in morbidly obese patients (those with a BMI of ≥40 kg/m2) were at or higher than the suggested minimum target for VTE prophylaxis (0.5%.5 mg/kg of enoxaparin sodium. they do provide some insight as to potential differences. the number of fondaparinux doses before sample collection.2% to 118. As previously stated. These two studies suggest that obese patients may be at an increased risk of developing VTE when receiving standard doses of fondaparinux.14. The standard prophylactic dose is 2. odds ratio [OR]. the results of the four clinical trials described above suggest that weight-based dosing adjustments result in a greater percentage of patients achieving target anti-factor Xa levels.clinical consultation Fondaparinux Simone et al.31-34 In Phase III clinical trials of fondaparinux for VTE prevention 1720 after major orthopedic surgery. Twenty-eight obese patients were given once-daily doses of 0. Fondaparinux is renally eliminated.6%. the inclusion of zero within the CI indicated that obese patients may derive no benefit from standard prophylactic doses of fondaparinux.5 kg/m2.6 kg/m2).D. The reduction in VTE was less dramatic among obese patients.” Collectively. and BMI were significantly correlated with the anti-factor Xa level.7%) of 163 patients in the placebo group (OR. While a subgroup analysis of obese patients in these trials showed no difference in VTE rates between obese and nonobese patients.5-mg dose and might be a more favorable alternative for thromboprophylaxis in this population.3%) of 177 patients in the fondaparinux group and 6 (3. anti-factor Xa concentration (0. Although some patients in the higher-dose group had anti-factor Xa concentrations above the target range by the third enoxaparin dose. with no increased risk of bleeding events and a potential decrease in thromboembolic events. In this population. 35.40 described a doseproportional increase in the maximum concentration of anti-factor Xa and in the area under the anti-factor Xa concentration–time curve over 24 hours for 2. Women had a higher mean ± S.36-39 While these trials were not specifically designed to examine differences in VTE rates between obese and nonobese patients. 95% CI.15 included 222 obese patients in the study population of 1027. the bleeding risk was similar in the two groups. this may be due to sex-related differences in body composition having a pharmacodynamic effect on fondaparinux. –39. –83. allowing for once-daily dosing. early clinical trials of fondaparinux did not entirely exclude patients with obesity (generally defined as a BMI of ≥30 kg/m2 in men and a BMI of ≥28. Fondaparinux sodium is a newer synthetic anticoagulant that is used for both VTE treatment and prophylaxis.091 mg/L).
Kleber FX. Samama MM. BMJ. Bauer KA. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. c Fairview Diagnostic Laboratories. 23.bcw. 2006. Fraisse F. A multicenter randomized double-blind study of enoxaparin compared with unfractionated heparin in the prevention of venous thromboembolic disease in elderly inpatients bedridden for an acute medical illness. Holzapfel L. Arixtra (fondaparinux) level. Bergmann JF. 10. Davidson BL. WI. Subcutaneous low-molecular-weight heparin versus standard heparin and the prevention of thromboembolism in medical inpatients. Schramm W. the clinical implications of low anti-factor Xa levels in morbidly obese patients are unknown. 1996. including the retrospective design and the small sample size. Harenberg J. There is no evidence at this time to support increasing fondaparinux dosing for VTE prophylaxis in morbidly obese patients. Turpie AG et al. 14.7. References 1. 332:325-9. Paul. Cardiology patient pages. Tapson VF. evidence-based clinical practice guidelines (8th edition). We attempted to include only patients whose anti-factor Xa concentrations were obtained from samples collected at steady state and at the appropriate time after a fondaparinux dose. Our study had several limitations. 1999. 2008. 119:e480-2.5 mg subcutaneously daily for VTE prophylaxis were within or above the target range in 53% of the instances evaluated. Am J Cardiol. Human Pharmacokinetics and Bioequivalence Summary. Prophylaxis in Medical Patients with Enoxaparin Study Group. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a metaanalysis of 4 randomized double-blind studies. Previous studies of adjusteddose LMWH therapy in obese patients and studies involving greater attainment of anti-factor Xa levels have not evaluated the clinical outcomes of thrombosis and bleeding rates. Goldhaber SZ. 162:183340. Turpie AG. Geerts WH. MN. 4. Lechler E. 1996. This finding substantiates pharmacokinetic evidence that plasma clearance of fondaparinux increases as the patient’s weight increases35. www. 3. 5. Br J Surg.7 Arixtra Clinical Summary EN-E01. Cohen AT. Fondaparinux combined with intermit- Am J Health-Syst Pharm—Vol 68 Sep 15. the relationship between anti-factor Xa levels and clinical outcomes has not been established. Randomized. Section2. Madison. Meta-analysis of low molecular weight heparin in the prevention of venous thromboembolism in general surgery. 2011 1721 . 341:793-800.g. Cohen AT. 110:874-9. GlaxoSmithKline (GSK). we did not have long-term clinical outcome data to assess thrombotic and bleeding events in all patients. and Arixtra NDA Submission. 2009. 1996. standard prophylactic doses of fondaparinux may be insufficient. 2. Chest.4 Pharmacokinetics-Pharmacodynamics. A prospective registry of 5. The Surgeon General’s call to action to prevent deep vein thrombosis and pulmonary embolism.. d Data on file for Study EFC3557. placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. 133(suppl 6):381S-453S. Arixtra (fondaparinux) assay. b Blood Center of Wisconsin. http:// l a b g u i d e . Arch Intern Med. Thromb Haemost. Am Heart J. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. The Enoxaparin in Medicine Study Group. 9. Couland JM et al. 145:61421. 6. The Association of Non-University Affiliated Intensive Care Specialist Physicians of France. Conclusion Anti-factor Xa concentrations in morbidly obese patients receiving fondaparinux sodium 2. Mismetti P. 12. 2004. pt. Another limitation was the lack of a nonobese comparator group. Haemostasis. a Data on file Module 2. Gallus AS et al. Heene DL. Bauer KA. 26(suppl 2):49-56. Vogel G et al. June 2003. N Engl J Med. We did not account for differences in the composition of body weight (e. 1):1109-14.3. Caprini JA et al. 93:259-62. 2001. 26:127-39. Most important. Flosbach CW.41 These findings suggest that in morbidly obese patients. 2000. Randomized comparison of enoxaparin with unfractionated heparin for the prevention of venous thromboembolism in medical patients with heart failure or severe respiratory disease. The Prime Study Group. o r g / s h o w t e s t .htm (accessed 2011 Jun 9). BMI had a significant effect on anti-factor Xa levels in the stepwise regression analysis. Am J Respir Crit Care Med. Roebruck P. Witt C. 2001.clinical consultation Fondaparinux collection and anti-factor Xa concentrations suggests that the accumulation of fondaparinux may occur with prolonged administration. dry weight. Prevention of venous thromboembolism: American College of Chest Physicians 13. it also corresponds with evidence from previous studies of LMWH therapy in morbidly obese patients indicating lower anti-factor Xa levels with increasing BMI or body weight. 8. St. Our investigation should be considered a hypothesis-generating study for future analysis of the clinical significance of low anti-factor Xa levels in patients receiving standard prophylactic doses of fondaparinux. 2004. f a i r v i e w. whose inclusion would have allowed a determination as to whether similar variability in anti-factor Xa concentrations might exist in nonobese patients. suggesting that a higher BMI will result in a lower antifactor Xa level. Circulation. Our observational study included a wider variety of patient types and heavier patients than were included in some previous studies of VTE prophylaxis.edu/ bcw/lab/catalog/index. Neuhart E. 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