0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation |

Prophylaxis Against Deep Vein Thrombosis in Critically Ill Patients With Severe Renal Insufficiency With the Low-Molecular-Weight Heparin Dalteparin:  An Assessment of Safety and Pharmacodynamics: The DIRECT Study FREE

James Douketis, MD, FRCPC; Deborah Cook, MD, MSc, FRCPC; Maureen Meade, MD, FRCPC; Gordon Guyatt, MD, FRCPC; William Geerts, MD, FRCPC; Yoanna Skrobik, MD, FRCPC; Martin Albert, MD, FRCPC; John Granton, MD, FRCPC; Paul Hébert, MD, FRCPC; Guiseppe Pagliarello, MD, FRCSC; John Marshall, MD, FRCSC; Robert Fowler, MD, FRCPC; Andreas Freitag, MD, FRCPC; Christian Rabbat, MD, FRCPC; David Anderson, MD, FRCPC; Nicole Zytaruk, MSc; Diane Heels-Ansdell, MSc; Mark Crowther, MD, MSc, FRCPC ; Canadian Critical Care Trials Group
[+] Author Affiliations

Author Affiliations: Departments of Medicine (Drs Douketis, Cook, Meade, Guyatt, Freitag, Rabbat, and Crowther) and Clinical Epidemiology and Biostatistics (Drs Douketis, Cook, Meade, and Guyatt and Mss Zytaruk and Heels-Ansdell), McMaster University, Hamilton, Ontario, Canada; Department of Medicine (Drs Geerts, Granton, and Fowler), Interdepartmental Divisions of Critical Care (Drs Granton, Marshall, and Fowler) and Surgery (Dr Marshall), University of Toronto, Toronto, Ontario, Canada; Department of Medicine, Université de Montréal, Montréal, Quebec, Canada (Drs Skrobik and Albert); Department of Critical Care, University of Ottawa, Ottawa, Ontario, Canada (Drs Hébert and Pagliarello); and Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada (Dr Anderson).


Arch Intern Med. 2008;168(16):1805-1812. doi:10.1001/archinte.168.16.1805.
Text Size: A A A
Published online

Background  Use of low-molecular-weight heparins is avoided in patients with renal insufficiency because of concerns about an excessive anticoagulant effect and increased bleeding risk. To challenge this premise, we evaluated if deep vein thrombosis (DVT) prophylaxis with dalteparin sodium confers an excessive anticoagulant effect in critically ill patients with severe renal insufficiency.

Methods  We conducted a multicenter, single-arm clinical trial of DVT prophylaxis with dalteparin sodium, 5000 IU once daily in critically ill patients with a creatinine clearance lower than 30 mL/min (to convert to milliliters per second, multiply by 0.0167). Bioaccumulation was defined by a trough anti-Xa level higher than 0.40 IU/mL, measured twice weekly. The pharmacodynamic properties of dalteparin were assessed by serial anti-Xa levels measured on days 3, 10, and 17.

Results  We enrolled 156 patients with a mean (SD) creatinine clearance of 18.9 (6.5) mL/min; 18 were excluded because they died or were discharged before testing (n = 3) or had prevalent DVT (n = 15). Of 138 patients included, the median (interquartile range [IQR]) duration of dalteparin exposure was 7 (4-12) days. In 120 patients who had at least 1 trough anti-Xa level (427 total measurements), no patient had bioaccumulation (0%; 95% confidence interval [CI]: 0%-3.0%); the median (IQR) trough anti-Xa level was undetectable (<0.10 IU/mL [<0.10 to <0.10 IU/mL]). Based on serial measurements, peak anti-Xa levels were 0.29 to 0.34 IU/mL and trough levels were lower than 0.06 IU/mL. Deep vein thrombosis occurred in 7 of 138 patients (5.1%; 95% CI, 2.5%-10.1%); major bleeding occurred in 10 patients (7.2%; 95% CI, 4.0%-12.8%), all with trough anti-Xa levels of 0.18 IU/mL or lower.

Conclusion  In critically ill patients with severe renal insufficiency, DVT prophylaxis with dalteparin sodium, 5000 IU once daily, is not associated with an excessive anticoagulant effect due to drug bioaccumulation and is unlikely to contribute to bleeding.

Trial Registration  clinicaltrials.gov Identifier: NCT00138099

In hospitalized medical and surgical patients at increased risk for developing deep vein thrombosis (DVT), low-molecular-weight heparins (LMWHs) are effective agents to prevent DVT.1 Critically ill patients admitted to an intensive care unit (ICU), like medical patients who have had an ischemic stroke or surgical patients who have had hip or knee arthroplasty, are at high risk for DVT; without anticoagulant prophylaxis, 20% to 40% will develop DVT,24 and 10% will develop proximal DVT despite prophylaxis with unfractionated heparin (UFH).3

Clinicians typically use UFH for DVT prophylaxis in patients with renal insufficiency because its clearance is not affected by impaired renal function.5 Indeed, experts usually advise caution regarding LMWH use in patients with renal insufficiency because its use might result in an excessive anticoagulant effect due to drug bioaccumulation, which predisposes to bleeding.1,57 Patients with renal insufficiency are systematically excludedfrom trials of LMWH assessing DVT prophylaxis,8 limiting the applicability of prior trial results to this population. In patients at risk for DVT, LMWHs are an attractive prophylaxis option because, compared with UFH, they have superior efficacy in other high-risk populations1 and a lower risk of heparin-induced thrombocytopenia (HIT),9 an infrequent but serious adverse event.

Driven by the need to identify alternatives for DVT prophylaxis in critically ill patients with renal insufficiency, we challenged the premise that selected LMWHs bioaccumulate or contribute to bleeding in patients with impaired renal function. This reasoning was based on 3 considerations. First, existing data suggest that bioaccumulation occurs mainly in patients with renal insufficiency who receive therapeutic doses of LMWHs, which are 3- to 4-fold higher than those used for DVT prophylaxis.1 Second, systematic reviews assessing LMWH use in patients with renal insufficiency found that administering prophylactic doses of LMWHs appear to be safe.7,10 Third, preliminary observations suggest that dalteparin sodium, 5000 IU once daily, does not bioaccumulate in ICU patients with renal insufficiency.11,12 The objectives of this study were (1) to determine if DVT prophylaxis with dalteparin in critically ill patients with severe renal insufficiency is associated with an excessive anticoagulant effect due to drug bioaccumulation and (2) to determine the incidence of DVT, bleeding, and HIT in such patients.

STUDY DESIGN

The DIRECT (Dalteparin's Influence on the Renally Compromised: Anti-Ten-A) study was a multicenter, prospective, single-arm clinical trial assessing DVT prophylaxis with open-label dalteparin sodium, 5000 IU once daily, in critically ill ICU patients with severe renal insufficiency.

PATIENTS

Patients with the following inclusion criteria were enrolled: adults (age ≥18 years); body weight greater than 45 kg; expected ICU length of stay longer than 72 hours; and severe renal insufficiency, defined by a calculated creatinine clearance lower than 30 mL/min (to convert to milliliters per second, multiply by 0.0167) based on the Cockcroft-Gault formula.13 Exclusion criteria were the following: ICU admission for longer than 2 weeks; orthopedic, cardiac, or neurological surgery within 3 months; active bleeding or high risk for bleeding; platelet count lower than 75 × 103/μL (to convert to ×109/L, multiply by 1.0); international normalized ratio or activated partial thromboplastin time greater than 2 times the upper limit of normal; epidural catheter insertion within 12 hours; receipt of more than 2 doses of LMWH while in the ICU; need for therapeutic dose anticoagulation; prior adverse reaction to heparin; contraindication to blood products; bilateral leg amputation; pregnant or lactating woman; life expectancy less than 14 days or receiving palliative care; and prior enrollment in this study or enrollment in a concurrent study of antithrombotic therapy.

The research ethics boards of all participating sites—Canadian university-affiliated hospitals with closed mixed medical-surgical ICUs—approved the DIRECT study. Surrogate decision makers or patients provided written informed consent.

DALTEPARIN REGIMEN

Enrolled patients received open-label dalteparin sodium, 5000 IU once daily, administered by subcutaneous injection at 10:00 AM. This treatment was continued until ICU discharge or a maximum of 30 days, whichever came first. After ICU discharge or after 30 days, DVT prophylaxis was administered at the attending physician's discretion.

ANTI-Xa OUTCOMES
Trough Anti-Xa Levels

To assess for dalteparin bioaccumulation, we measured trough anti-Xa levels twice weekly (Mondays and Thursdays), 20 hours after the prior dalteparin dose. The first trough anti-Xa level was measured after a patient had received at least 1 dose of dalteparin. A priori, we defined bioaccumulation (excessive anticoagulant effect) of dalteparin prophylaxis in a patient by the presence of at least 1 trough anti-Xa level higher than 0.40 IU/mL.

Several assumptions were made to interpret trough anti-Xa levels. First, we assumed that an anti-Xa level is a reliable measure of the anticoagulant effect of dalteparin. In support of this assumption, the anti-Xa level is approved by consensus groups to measure the anticoagulant effect of LMWHs.14,15 Second, we assumed that an elevated trough anti-Xa level, reflecting an excessive anticoagulant effect, is a surrogate marker of bleeding risk,16 reasoning that elevated levels of other markers of anticoagulant activity (eg, international normalized ratio, activated partial thromboplastin time) reflect an increased risk for bleeding with other anticoagulants (eg, warfarin, UFH).14,15 Third, we assumed that a trough anti-Xa level higher than 0.40 IU/mL would reflect dalteparin bioaccumulation because in patients who receive a prophylactic dose of LMWH, the risk for bleeding increases with a trough anti-Xa level higher than 0.40 IU/mL,16 whereas a trough anti-Xa level between 0.10-0.40 IU/mL is considered a safe level of anticoagulation17 and a trough anti-Xa level of 0.20 IU/mL or lower occurs in patients with normal renal function.18,19

Serial Anti-Xa Levels

To assess dalteparin pharmacodynamics, we measured anti-Xa levels at 0 (baseline), 1, 2, 4, 8, 12, 20, and 24 hours after the prior dalteparin dose, with serial measurements targeted for days 3, 10, and 17 after the start of dalteparin therapy.

CLINICAL OUTCOMES
Deep Vein Thrombosis

Deep vein thrombosis was defined by a noncompressible vein segment on venous ultrasonography.20 All patients underwent bilateral lower limb venous ultrasonography within 48 hours of study enrolment and twice weekly (Mondays and Thursdays) thereafter until ICU discharge or 30 days, whichever came first. A standard technique was used to assess for noncompressible vein segments that has high interrater reliability in ICU patients.21 Screening for pulmonary embolism was not done, and if embolism was diagnosed, it was based on the results from objective diagnostic tests.22,23

Bleeding

Bleeding was defined as major if the patient had 1 or more of the following: (1) decrease in hemoglobin level of 2 g/dL or greater (to convert to grams per liter, multiply by 10.0); transfusion of 2 units of red cells or more and no increase in hemoglobin level; spontaneous decrease in systolic blood pressure of 20 mm Hg or greater or heart rate increase of 20 beats/min or greater or decrease in systolic blood pressure of 10 mm Hg or greater while the patient was upright in the absence of another cause24; (2) bleeding at a critical site (eg, intracranial); or (3) bleeding at a wound site that required an intervention (eg, reoperation). Bleeding that did not satisfy these criteria was defined as minor.

Heparin-Induced Thrombocytopenia and Creatinine Clearance

All cases of suspected HIT were documented, and blood samples were processed at a central laboratory using a single serotonin release assay.25 Creatinine clearance was measured at baseline and at the end of dalteparin administration.

PROCUREMENT AND PROCESSING OF BLOOD SAMPLES

Blood samples (1.0 mL) for anti-Xa measurements were drawn from an arterial catheter into a glass tube (Vacutainer; Becton-Dickinson, Franklin Lakes, New Jersey) containing 3.2% citrate. Blood samples were obtained after a 3- to 5-mL discard to avoid UFH contamination. Blood samples were centrifuged for 15 minutes at 1700g; the plasma was transferred to clean plastic tubes and centrifuged for 5 minutes at 1700g. Blood samples for trough anti-Xa levels were assayed in the laboratory of each clinical site: 10 sites used the Stachrom-Heparin assay (Diagnostica Stago, Asnieres-Sur-Seine, France); 1 site used the Spectrolyse Heparin Xa assay (Trinity Biotech, Wicklow, Ireland); and 1 site used the Electrochrome Beckman Coulter assay (Beckman Coulter Inc, Fullerton, California). Blood samples for serial anti-Xa levels were processed in local laboratories, stored at −70°C, then shipped to a central laboratory (Hemostasis Reference Laboratory, Hamilton, Ontario, Canada) for batch testing using the Stachrom-Heparin assay. To optimize the precision and reliability of serial anti-Xa measurements, a calibration curve for dalteparin was constructed using pooled platelet-poor plasma obtained from healthy volunteers.26 All anti-Xa assays were performed by personnel who were unaware of patient characteristics.

PATIENT AND STUDY MANAGEMENT

Patient management was at the discretion of the ICU team, which was blinded to all anti-Xa levels. Research coordinators who prospectively recorded bleeding and DVT outcomes during the study were unaware of anti-Xa levels. The ICU pharmacists were the only personnel aware of trough anti-Xa level results: in the event of a trough anti-Xa level higher than 0.40 IU, the pharmacist would instruct the ICU team to withhold the next dose of dalteparin.

A steering committee assumed overall responsibility for this study. An independent event adjudication committee reviewed all DVT, bleeding, and HIT outcomes. An independent data monitoring committee reviewed all trough anti-Xa levels and clinical outcomes after approximately 25, 50, 75, and 100 patients were enrolled and determined whether enrollment should continue or be suspended.

STUDY SAMPLE SIZE

Based on our hypothesis that dalteparin does not bioaccumulate and that the proportion of patients with a trough anti-Xa level higher than 0.40 IU/mL would be 10% or lower, we determined that a sample size of between 120 and 140 patients would exclude, based on the upper bound of the 95% confidence interval, more than 17% of patients with an elevated trough anti-Xa level (ie, 12 of 120 patients [10%] with an elevated anti-Xa level [95% confidence interval {CI}, 5.3%-16.8%] or 14 of 140 patients [10%] with an elevated anti-Xa level [95% CI, 5.2%-16.2%]).

STATISTICAL ANALYSIS

For all analyses, we present categorical data as number (percentage) and continuous data as mean (SD) or median (interquartile range [IQR]) if data were skewed. To assess for bioaccumulation of dalteparin, we determined the proportion (95% CI) of patients with at least 1 trough anti-Xa level higher than 0.40 IU/mL and the proportion of patients with at least 1 trough anti-Xa level of 0.10 IU/mL or higher (threshold of detectable anticoagulant effect). To assess for a possible association between bleeding and an excessive anticoagulant effect, we determined the proportion (95% CI) of patients with major bleeding, assessed trough anti-Xa levels in patients with major bleeding, and, using Cox proportional hazards regression analysis, we assessed a possible association between major bleeding and the presence of a detectable trough anti-Xa level (≥0.10 IU/mL), which we used as a surrogate for an excessive anticoagulant effect. The pharmacodynamic profile of dalteparin was assessed based on the median (SD) anti-Xa levels at each time point during serial anti-Xa testing.27 We determined the proportion (95% CI) of patients with DVT, pulmonary embolism, and HIT.

PATIENTS

We enrolled 156 patients with a mean (SD) creatinine clearance of 18.9 (6.5) mL/min. There were 15 patients excluded because DVT (n = 14) or pulmonary embolism (n = 1) was diagnosed within 48 hours of enrollment and 3 patients were excluded because of death (n = 2) or discharge from the ICU (n = 1) before venous ultrasound testing. Thus, the study population consisted of 138 patients who received at least 1 dose of dalteparin. The baseline characteristics are given in Table 1.

Table Graphic Jump LocationTable 1. Clinical Characteristics of Enrolled Patients
DALTEPARIN REGIMEN

The median (IQR) duration of DVT prophylaxis with dalteparin was 7 (4-12) days. Dalteparin was held for at least 1 day in 43 patients for a median (IQR) of 5 (1-10) days. In total, 301 doses of dalteparin were withheld. The reasons (percentage of all doses withheld) for withholding dalteparin included potential bleeding (38%); need for therapeutic anticoagulation (26%); suspected or confirmed HIT (20%); thrombocytopenia (11%); invasive procedure (10%); active bleeding (5%); dosing error (4%); and coagulopathy (1%). In some patients, there were multiple reasons for withholding dalteparin as per clinical practice; however, it was never withheld due to an elevated anti-Xa level.

ANTI-Xa OUTCOMES
Trough Anti-Xa Levels

There were 427 trough anti-Xa levels measured in 120 patients; there were 18 patients in whom a trough anti-Xa level was not measured because it was not feasible. No patient (0%; 95% CI, 0%-3.0%) had bioaccumulation, defined by a trough anti-Xa level higher than 0.40 IU/mL, during the study. The median (IQR) anti-Xa level was undetectable (<0.10 IU/mL [<0.10 to <0.10 IU/mL]). There were 334 trough anti-Xa levels (78%) in 113 patients that were undetectable (<0.10 IU/mL); 79 trough anti-Xa levels (19%) in 47 patients that were between 0.10 and 0.15 IU/mL; 9 trough anti-Xa levels (2%) in 7 patients that were between 0.16 and 0.20 IU/mL; and 5 trough anti-Xa levels (1%) in 4 patients that were higher than 0.20 IU/mL (0.21, 0.23, 0.26, 0.28, and 0.40 IU/mL). The number and timing of the detectable anti-Xa levels according to the duration of dalteparin treatment is given in Table 2.

Table Graphic Jump LocationTable 2. Trough Anti-Xa Levels According to the Duration of Dalteparin Treatment
Serial Anti-Xa Levels

Serial anti-Xa levels were measured in 109 patients after approximately 3 days after the start of dalteparin therapy, in 46 patients after approximately 10 days, and in 15 patients after approximately 17 days; 19 patients did not have serial anti-Xa testing done. Median (IQR) anti-Xa levels at 0, 1, 2, 4, 8, 12, 20, and 24 hours after a targeted 3, 10, and 17 days of dalteparin treatment is presented in Table 3. Peak levels were between 0.29 IU/mL and 0.34 IU/mL, and trough levels were below the lower limit of detection (<0.06 IU/mL) irrespective of the duration of treatment.

Table Graphic Jump LocationTable 3. Serial Anti-Xa Levels at 0, 1, 2, 4, 8, 12, 20, and 24 Hours After a Targeted 3, 10, and 17 Days of Dalteparin Treatmenta
Association Between Bleeding and Trough Anti-Xa Levels

Of 10 patients with major bleeding, 4 had detectable trough anti-Xa levels during dalteparin prophylaxis: 1 patient had 3 detectable trough anti-Xa levels (0.10, 0.11, and 0.12 IU/mL); the second patient had 3 detectable trough anti-Xa levels (0.10, 0.10, and 0.13 IU/mL); the third patient had 2 detectable trough anti-Xa levels (0.10 and 0.18 IU/mL); the fourth patient had 1 detectable trough anti-Xa level (0.10 IU/mL). Using univariate regression analysis, we found no association between major bleeding and a detectable trough anti-Xa level in the preceding 3 days (hazard ratio, 0.76; 95% CI, 0.15-3.81).

CLINICAL OUTCOMES

Seven patients (5.1%; 95% CI, 2.5%-10.2%) developed DVT, which was asymptomatic and involved the proximal leg veins in all patients. In 6 patients, DVT occurred in association with a femoral vein catheter. No patient developed pulmonary embolism. Ten patients (7.2%; 95% CI, 4.0%-12.8%) developed major bleeding, 2 of whom died with bleeding. Two patients (1.4%; 95% CI, 0.4%-5.1%) with prior exposure to UFH had serologically confirmed HIT. Mean (SD) creatinine clearance at baseline and at the end of dalteparin prophylaxis was 18.9 (6.4) and 28.4 (17.3), respectively.

In critically ill patients with severe renal insufficiency who receive, on average, 7 days of DVT prophylaxis with dalteparin sodium, 5000 IU once daily, we found that this treatment does not result in an excessive anticoagulant effect from drug bioaccumulation. In support of this conclusion, no patient had bioaccumulation (trough anti-Xa level >0.40 IU/mL) and trough anti-Xa levels were undetectable (<0.10 IU/mL) or minimal (0.10-0.20 IU/mL) in 99% of measurements. Furthermore, dalteparin had a “rapid rise and gradual fall to baseline” pharmacodynamic profile, typical of drugs that do not bioaccumulate. Finally, dalteparin prophylaxis was unlikely to contribute to major bleeding, since all patients with such bleeding had undetectable (<0.10 IU/mL) or minimal (0.10-0.18 IU/mL) trough anti-Xa levels, and an association between detectable trough anticoagulant levels and major bleeding was lacking (hazard ratio, 0.76; 95% CI, 0.15-3.81). Taken together, these findings challenge the premise that DVT prophylaxis with LMWHs should be avoided in patients with renal insufficiency, including patients with severe renal insufficiency.

We also evaluated clinical outcomes relevant to patients who are receiving DVT prophylaxis, since patients with renal insufficiency are at high risk for both DVT and bleeding.28,29 The incidence of proximal leg DVT (approximately 5%) is consistent with findings from previous studies in critically ill patients who received DVT prophylaxis.3 However, 6 of 7 cases of DVT occurred in association with a central vein catheter, which suggests the need for careful clinical monitoring and, possibly, screening for DVT in such patients. The incidence of major bleeding (approximately 7%) is considerably higher than that reported in other DVT prophylaxis trials1 but likely reflects the disease burden in critically ill patients and is consistent with findings from other studies assessing bleeding rates in such patients who receive anticoagulants.3

Our study is novel in that it assessed bioaccumulation and the pharmacodynamics of LMWH exclusively in patients with severe renal insufficiency. Our findings are consistent with a pilot study involving 19 critically ill patients with moderate to severe renal insufficiency (creatinine clearance <50 mL/min), in which we found no detectable trough anticoagulant effect (anti-Xa level <0.10 IU/mL) 23 hours after administration of dalteparin sodium, 5000 IU once daily.12 Although LMWHs have been widely studied for the prevention and treatment of DVT and in patients with an acute coronary syndrome, these trials excluded patients with severe renal insufficiency.1,30,31

Others have investigated the potential for dalteparin bioaccumulation in patients with renal insufficiency. Kani and associates32 studied 10 critically ill patients with moderate to severe renal insufficiency (mean creatinine clearance, 29.5 mL/min) who received dalteparin sodium, 5000 IU once daily, and had undergone serial anti-Xa testing. Although there was no dalteparin bioaccumulation, the clinical applicability of this study is limited because patients received only one dose of dalteparin. Tincani and associates33 assessed DVT prophylaxis with dalteparin in 109 elderly patients (mean age, 83 years) with renal insufficiency. Although there was no evidence of dalteparin bioaccumulation after 6 days of treatment, only 24 patients had severe renal insufficiency, and selected patients received a lower dose of dalteparin sodium (2500 IU once daily) instead of the 5000-IU once-daily dose that is recommended for DVT prophylaxis.

There are 2 considerations relating to the study population that may affect the generalizability of our findings. First, 62% of patients had acute renal failure, in whom renal function may improve as interventions to restore renal function are initiated. In our study population, renal function improved overall during the study period (mean creatinine clearance, 18.9-28.4 mL/min), and this may have contributed to the lack of dalteparin bioaccumulation. However, renal function remained severely impaired (creatinine clearance <30 mL/min) in 64% and moderately impaired (creatinine clearance 30-50 mL/min) in 26% of patients at the end of the study, as given in Table 1. From a practical perspective, decisions about DVT prophylaxis in patients with impaired renal function take place at presentation. Our aim was to include a spectrum of patients representing a typical clinical population with impaired renal function, which, we believe, has greater generalizability than if we had limited our study to patients with less dynamic, end-stage renal disease. Nonetheless, caution should be used in applying our findings to patient subgroups, especially dialysis-dependent patients. Second, the bioavailability of LMWHs in critically ill patients may be theoretically less than in noncritically ill patients because of inotrope administration and subcutaneous edema, which may affect pharmacokinetic properties.3436 However, peak anti-Xa levels in this study were 0.20 to 0.40 IU/mL, which is consistent with prophylactic levels of anticoagulation observed in hospitalized medical and surgical patients and suggests adequate bioavailability of dalteparin.17,37

There are other potential study limitations. First, the study design precludes inferences about the efficacy and safety of dalteparin for DVT prophylaxis compared with other prophylaxis strategies, although this is being addressed in a randomized trial (the PROTECT [Prophylaxis of Thromboembolism in Critical Care] Trial11) comparing UFH and dalteparin in critically ill patients. Second, we studied dalteparin and cannot comment on the applicability of our findings to other LMWHs. Smaller LMWH fractions (enoxaparin) are cleared primarily by the kidney, whereas larger LMWHs (dalteparin and tinzaparin) have greater clearance by nonrenal mechanisms.14,15 Previous studies have suggested that enoxaparin, especially when given in therapeutic doses, may bioaccumulate in patients with severe renal insufficiency.7,38 Third, dalteparin administration was interrupted in 43 patients because of central venous catheter insertion and other reasons, which reflects how LMWH is used in the critical care setting. Finally, 3 assays were used to measure trough anti-Xa levels (same assay in 10 of 12 centers), with the potential for interassay variability in anti-Xa levels.39 However, in a preplanned analysis in 10 patients who had 80 anti-Xa levels measured by 3 different assays, there was high interassay correlation (r = 0.98) in anti-Xa levels (Rita Selby, MD, oral communication, August 2007).

Strengths of this study include the comprehensive assessments of bioaccumulation and pharmacodynamics of dalteparin prophylaxis, clinical outcomes (bleeding, DVT, and HIT), and renal function in a well-defined patient population with severe renal insufficiency. Through daily screening in the ICU, consecutive eligible patients were enrolled, thereby minimizing the potential for selection bias that might occur in an observational study. To avoid biased interpretation of bleeding and thrombotic events, the critical care team and research coordinators were blinded to trough and serial anti-Xa levels. Furthermore, laboratory personnel measuring anti-Xa levels were unaware of patient characteristics and renal function.

Our study has implications for clinical practice. Our findings challenge the premise that selected LMWHs should be avoided in patients with severe renal insufficiency when administered for DVT prophylaxis. Furthermore, although we studied critically ill patients, we believe our findings may be generalizable to noncritically ill patients with severe renal insufficiency and to patients with mild to moderate renal insufficiency, in whom there may have been concerns about administering LMWHs because of potential bioaccumulation.

In conclusion, in critically ill patients with severe renal insufficiency, DVT prophylaxis with dalteparin is not associated with an excessive anticoagulant effect due to drug bioaccumulation and is unlikely to contribute to bleeding. Dalteparin sodium, 5000 IU once daily, appears to be a reasonable option for DVT prophylaxis in patients with severe renal insufficiency.

Correspondence: James Douketis, MD, FRCPC, St Joseph's Hospital, Room F-544, 50 Charlton Ave E, Hamilton, ON L8N 4A6, Canada (jdouket@mcmaster.ca).

Accepted for Publication: January 13, 2008.

Author Contributions:Study concept and design: Douketis, Cook, Meade, Guyatt, Geerts, Skrobik, Fowler, Rabbat, Anderson, and Crowther. Acquisition of data: Skrobik, Granton, Pagliarello, Marshall, Freitag, Anderson, and Zytaruk. Analysis and interpretation of data: Douketis, Cook, Geerts, Albert, Hébert, Rabbat, and Heels-Ansdell. Drafting of the manuscript: Douketis, Zytaruk, and Crowther. Critical revision of the manuscript for important intellectual content: Douketis, Cook, Meade, Guyatt, Geerts, Skrobik, Granton, Albert, Hébert, Pagliarello, Marshall, Fowler, Freitag, Rabbat, Anderson, and Heels-Ansdell. Statistical analysis: Heels-Ansdell. Obtained funding: Douketis, Cook, Geerts, and Rabbat. Administrative, technical, and material support: Douketis, Geerts, Skrobik, Granton, Albert, Pagliarello, Freitag, Anderson, Zytaruk, and Crowther. Study supervision: Douketis, Meade, Guyatt, Albert, Freitag, and Zytaruk.

Financial Disclosure: Dr Geerts has received research grants/support from Sanofi-Aventis and Bayer Healthcare; has served as a consultant for Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Leo Pharma, Pfizer, and Sanofi-Aventis; and has received honoraria for presentation(s) from Pfizer and Sanofi-Aventis.

Funding/Support: The DIRECT study was an investigator-initiated study of the Canadian Critical Care Trials Group that was supported by funds from the Canadian Institutes of Health Research (CIHR) and an unrestricted arms-length grant-in-aid from Pfizer (New York, New York), which also supplied the dalteparin.

Role of the Sponsors: The CIHR and Pfizer had no role in the design, execution, analysis, interpretation, or publication of this study.

Additional Contributions: We express our deep gratitude to the Research Coordinators of the Canadian Critical Care Trials Group. Marilyn Johnson, ART of the Hemostasis Reference Laboratory, Hamilton, Ontario, Canada, provided laboratory and technical expertise, and Stephen Walter, PhD, provided statistical advice.

Additional Information: Dr Cook is a research chair and mentor of the CIHR. Dr Meade is a mentor of the CIHR. Dr Crowther is an investigator of the Heart and Stroke Foundation of Canada.

Box Section Ref ID

Canadian Critical Care Trials Group

Steering Committee

James Douketis (coprincipal investigator), Deborah Cook (coprincipal investigator), Mark Crowther, Maureen Meade, Gordon Guyatt, David Anderson, William Geerts, Nicole Zytaruk (project coordinator), and Diane Heels-Ansdell (biostatistician).

Participating Centers (All in Canada)

St Joseph's Healthcare, Hamilton, Ontario: Ellen McDonald, France Clarke, Andrea Tkaczyk, and Deborah Cook; Hamilton Health Science Center, Hamilton General Hospital, Hamilton: Karen Woods and Maureen Meade; Hamilton Health Science Center–McMaster University Medical Center, Hamilton: Christine Wynne, Mark Duffett, and Andreas Freitag; University Health Network, Toronto General and Toronto Western Hospitals, Toronto, Ontario: Marilyn Steinberg, Andrea Matte, and John Granton; Hamilton Health Science Center, Henderson Hospital, Hamilton: France Clarke, Andrea Tkaczyk, and Tim Karachi; Ottawa Hospital, Civic Site, Ottawa, Ontario: Mary-Jo Lewis, Julia Foxall, and Guiseppe Pagliarello; Ottawa Hospital, General Site, Ottawa: Irene Watpool, Tracy McArdle, and Paul Hébert; Maissoneuve Rosemont Hospital, Montreal, Quebec: Johanne Harvey and Yoanna Skrobik; Hopital Sacre-Coeur, Montreal, Quebec: Carole Sirois, Carole Nadon, and Martin Albert; Sunnybrook Hospital, Toronto: Mel Keogh, Craig Dale, and Rob Fowler; and St Michael's Hospital, Toronto: Orla Smith, Andrea Richards, Ines DeCampos, Jan Friedrich, and John Marshall.

Data and Monitoring Committee

Lehana Thabane (chair), Lori Linkins, Darin Treleaven, Tasnim Sinuff, and Rakesh Patel.

Events Adjudication Committee

Christian Rabbatt (chair), Agnes Lee, and Martin O’Donnell.

Geerts  WHPineo  GFHeit  JA  et al.  Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126 (3) ((suppl)) 338S- 400S
PubMed Link to Article
Attia  JRay  JCook  DJ  et al.  Deep venous thrombosis and its prevention in critically ill adults. Arch Intern Med 2001;161 (10) 1268- 1279
PubMed Link to Article
Cook  DJCrowther  MMeade  M  et al.  Deep venous thrombosis in medical-surgical critically ill patients: prevalence, incidence, and risk factors. Crit Care Med 2005;33 (7) 1565- 1571
PubMed Link to Article
Cook  DJMcMullin  JHodder  R  et al. Canadian ICU Directors Group, Prevention and diagnosis of venous thromboembolism in critically ill patients: a Canadian survey. Crit Care 2001;5 (6) 336- 342
PubMed Link to Article
Duplaga  BARivers  CWNutescu  E Dosing and monitoring of low-molecular-weight heparins in special populations. Pharmacotherapy 2001;21 (2) 218- 234
PubMed Link to Article
Weitz  JI Low molecular weight heparins. N Engl J Med 1997;337 (10) 688- 698
PubMed Link to Article
Lim  WDentali  FEikelboom  JWCrowther  MA Meta-analysis: low-molecular-weight heparin and bleeding in patients with severe renal insufficiency. Ann Intern Med 2006;144 (9) 673- 684
PubMed Link to Article
Van Spall  HGToren  AKiss  AFowler  RA Eligibility criteria of randomized controlled trials published in high-impact general medical journals: a systematic sampling review. JAMA 2007;297 (11) 1233- 1240
PubMed Link to Article
Martel  NLee  JWells  PS Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005;106 (8) 2710- 2715
PubMed Link to Article
Nagge  JCrowther  MHirsh  J Is impaired renal function a contraindication to the use of low molecular weight heparin? Arch Intern Med 2002;162 (22) 2605- 2609
PubMed Link to Article
Cook  DJRocker  GMeade  M  et al. PROTECT Investigators; Canadian Critical Care Trials Group, Prophylaxis of Thromboembolism in Critical Care (PROTECT) Trial: a pilot study. J Crit Care 2005;20 (4) 364- 372
PubMed Link to Article
Rabbat  CGCook  DJCrowther  MA  et al.  Dalteparin thromboprophylaxis for critically ill medical-surgical patients with renal insufficiency. J Crit Care 2005;20 (4) 357- 363
PubMed Link to Article
Cockcroft  DWGault  MH Prediction of creatinine clearance from serum creatinine. Nephron 1976;16 (1) 31- 41
PubMed Link to Article
Laposata  MGreen  DVan Cott  EMBarrowcliffe  TWGoodnight  SHSosolik  RC College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: the clinical use and laboratory monitoring of low-molecular-weight heparin, danaparoid, hirudin and related compounds, and argatroban. Arch Pathol Lab Med 1998;122 (9) 799- 807
PubMed
Hirsh  JWarkentin  TEShaughnessy  SG  et al.  Heparin and low-molecular weight heparin: Mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy and safety: Sixth ACCP Consensus Conference on Antithrombotic Therapy. Chest 2001;119 (1) ((suppl)) 64S- 94S
PubMed Link to Article
Sanderink  G-JCMGuimart  CGOzoux  MLJariwala  NUShukla  UABoutouyrie  BX Pharmacokinetics and pharmacodynamics of the prophylactic dose of enoxaparin once daily over 4 days in patients with renal impairment. Thromb Res 2002;105 (3) 225- 231
PubMed Link to Article
Levine  MNPlanes  AHirsh  JGoodyear  MVochelle  NGent  M The relationship between anti-factor Xa level and clinical outcome in patients receiving enoxaparine low molecular weight heparin to prevent deep vein thrombosis after hip replacement. Thromb Haemost 1989;62 (3) 940- 944
PubMed
Samama  MBernard  PBonnardot  VPTissot  ELanson  YCombe-Tamzali  S Low molecular weight heparin compared with unfractionated heparin in prevention of postoperative thrombosis. Br J Surg 1988;75 (2) 128- 131
PubMed Link to Article
Hunt  BJDoughty  HAMajumdar  G  et al.  Thromboprophylaxis with low molecular weight heparin (Fragmin) in high risk pregnancies. Thromb Haemost 1997;77 (1) 39- 43
PubMed
Kearon  CJulian  JANewman  TE  et al.  Noninvasive diagnosis of deep venous thrombosis: McMaster Diagnostic Imaging Practice Guidelines Initiative. Ann Intern Med 1998;128 (8) 663- 677
PubMed Link to Article
Cook  DJMedic  AAndrews  J  et al.  Doppler compression ultrasound of the lower extremities in ICU patients: an inter-rater reliability study [abstract 346]. Crit Care Med 2002;30 (12) ((suppl)) A77
PubMed Link to Article
The PIOPED Investigators, Value of ventilation/perfusion scan in acute pulmonary embolism: results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA 1990;263 (20) 2753- 2759
PubMed Link to Article
Remy-Jardin  MRemy  JDeschildre  F  et al.  Diagnosis of pulmonary embolism with spiral CT: comparison with pulmonary angiography and scintigraphy. Radiology 1996;200 (3) 699- 700
PubMed Link to Article
Arnold  DMDonahoe  LClarke  FJ  et al.  Bleeding during critical illness: a prospective cohort study using a new measurement tool. Clin Invest Med 2007;30 (2) E93- E102
PubMed
Warkentin  TESheppard  JAMoore  JCMoore  KMSigouin  CSKelton  JG Laboratory testing for the antibodies that cause heparin-induced thrombocytopenia: how much class do we need? J Lab Clin Med 2005;146 (6) 341- 346
PubMed Link to Article
 Expert Committee on Biological Standardization, 37th Report.  Geneva, Switzerland World Health Organization1987;22WHO Technical Report Series 760
Powers  JD Statistical considerations in pharmacokinetic study design. Clin Pharmacokinet 1993;24 (5) 380- 387
PubMed Link to Article
Elliott  MJZimmerman  DHolden  RM Warfarin anticoagulation in hemodialysis patients: a systematic review of bleeding rates. Am J Kidney Dis 2007;50 (3) 433- 440
PubMed Link to Article
Gangireddy  CRectenwald  JRUpchurch  GR  et al.  Risk factors and clinical impact of postoperative symptomatic venous thromboembolism. J Vasc Surg 2007;45 (2) 335- 341
PubMed Link to Article
Büller  HRAgnelli  GHull  RDHyers  TMPrins  MHRaskob  GE Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126 (3) ((suppl)) 401S- 428S
PubMed Link to Article
Cairns  JATheroux  PLewis  DH  JrEzekowitz  MMeade  TW Antithrombotic agents in coronary artery disease. Chest 2001;119 (1) ((suppl)) 228S- 252S
PubMed Link to Article
Kani  CMarkantonis  SLNicolaou  CMaggina  N Monitoring of subcutaneous dalteparin in patients with renal insufficiency under intensive care: an observational study. J Crit Care 2006;21 (1) 79- 84
PubMed Link to Article
Tincani  EMannucci  CCasolari  B  et al.  Safety of dalteparin for the prophylaxis of venous thromboembolism in elderly medical patients with renal insufficiency: a pilot study. Haematologica 2006;91 (7) 976- 979.
PubMed
Dörffler-Melly  Jde Jonge  Ede Pont  AC  et al.  Bioavailability of subcutaneous low-molecular-weight heparin to patients on vasopressors. Lancet 2002;359 (9309) 849- 850
PubMed Link to Article
Rommers  MKVan Der Lely  NEgberts  TCGvan den Bent  PMLA Anti-Xa activity after subcutaneous administration of dalteparin in ICU patients with and without subcutaneous oedema: a pilot study. Crit Care 2006;10 (3) R93
PubMed Link to Article
Haas  CENelsen  JLRghavendran  K  et al.  Pharmacokinetics and pharmacodynamics of enoxaparin in multiple trauma patients. J Trauma 2005;59 (6) 1336- 1343
PubMed Link to Article
Mahé  IAghassarian  MDrouet  L  et al.  Tinzaparin and enoxaparin given at prophylactic dose for eight days in medical elderly patients with impaired renal function: a comparative pharmacokinetic study. Thromb Haemost 2007;97 (4) 581- 586
PubMed
Cadroy  YPourrat  YBaladre  MF  et al.  Delayed elimination of enoxaparin in patients with chronic renal insufficiency. Thromb Res 1991;63 (3) 385- 390
PubMed Link to Article
Kitchen  SIampietro  RWoolley  AMPreston  FE Anti Xa monitoring during treatment with low molecular weight heparin or danaparoid: inter-assay variability. Thromb Haemost 1999;82 (4) 1289- 1293
PubMed

Figures

Tables

Table Graphic Jump LocationTable 1. Clinical Characteristics of Enrolled Patients
Table Graphic Jump LocationTable 2. Trough Anti-Xa Levels According to the Duration of Dalteparin Treatment
Table Graphic Jump LocationTable 3. Serial Anti-Xa Levels at 0, 1, 2, 4, 8, 12, 20, and 24 Hours After a Targeted 3, 10, and 17 Days of Dalteparin Treatmenta

References

Geerts  WHPineo  GFHeit  JA  et al.  Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126 (3) ((suppl)) 338S- 400S
PubMed Link to Article
Attia  JRay  JCook  DJ  et al.  Deep venous thrombosis and its prevention in critically ill adults. Arch Intern Med 2001;161 (10) 1268- 1279
PubMed Link to Article
Cook  DJCrowther  MMeade  M  et al.  Deep venous thrombosis in medical-surgical critically ill patients: prevalence, incidence, and risk factors. Crit Care Med 2005;33 (7) 1565- 1571
PubMed Link to Article
Cook  DJMcMullin  JHodder  R  et al. Canadian ICU Directors Group, Prevention and diagnosis of venous thromboembolism in critically ill patients: a Canadian survey. Crit Care 2001;5 (6) 336- 342
PubMed Link to Article
Duplaga  BARivers  CWNutescu  E Dosing and monitoring of low-molecular-weight heparins in special populations. Pharmacotherapy 2001;21 (2) 218- 234
PubMed Link to Article
Weitz  JI Low molecular weight heparins. N Engl J Med 1997;337 (10) 688- 698
PubMed Link to Article
Lim  WDentali  FEikelboom  JWCrowther  MA Meta-analysis: low-molecular-weight heparin and bleeding in patients with severe renal insufficiency. Ann Intern Med 2006;144 (9) 673- 684
PubMed Link to Article
Van Spall  HGToren  AKiss  AFowler  RA Eligibility criteria of randomized controlled trials published in high-impact general medical journals: a systematic sampling review. JAMA 2007;297 (11) 1233- 1240
PubMed Link to Article
Martel  NLee  JWells  PS Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005;106 (8) 2710- 2715
PubMed Link to Article
Nagge  JCrowther  MHirsh  J Is impaired renal function a contraindication to the use of low molecular weight heparin? Arch Intern Med 2002;162 (22) 2605- 2609
PubMed Link to Article
Cook  DJRocker  GMeade  M  et al. PROTECT Investigators; Canadian Critical Care Trials Group, Prophylaxis of Thromboembolism in Critical Care (PROTECT) Trial: a pilot study. J Crit Care 2005;20 (4) 364- 372
PubMed Link to Article
Rabbat  CGCook  DJCrowther  MA  et al.  Dalteparin thromboprophylaxis for critically ill medical-surgical patients with renal insufficiency. J Crit Care 2005;20 (4) 357- 363
PubMed Link to Article
Cockcroft  DWGault  MH Prediction of creatinine clearance from serum creatinine. Nephron 1976;16 (1) 31- 41
PubMed Link to Article
Laposata  MGreen  DVan Cott  EMBarrowcliffe  TWGoodnight  SHSosolik  RC College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: the clinical use and laboratory monitoring of low-molecular-weight heparin, danaparoid, hirudin and related compounds, and argatroban. Arch Pathol Lab Med 1998;122 (9) 799- 807
PubMed
Hirsh  JWarkentin  TEShaughnessy  SG  et al.  Heparin and low-molecular weight heparin: Mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy and safety: Sixth ACCP Consensus Conference on Antithrombotic Therapy. Chest 2001;119 (1) ((suppl)) 64S- 94S
PubMed Link to Article
Sanderink  G-JCMGuimart  CGOzoux  MLJariwala  NUShukla  UABoutouyrie  BX Pharmacokinetics and pharmacodynamics of the prophylactic dose of enoxaparin once daily over 4 days in patients with renal impairment. Thromb Res 2002;105 (3) 225- 231
PubMed Link to Article
Levine  MNPlanes  AHirsh  JGoodyear  MVochelle  NGent  M The relationship between anti-factor Xa level and clinical outcome in patients receiving enoxaparine low molecular weight heparin to prevent deep vein thrombosis after hip replacement. Thromb Haemost 1989;62 (3) 940- 944
PubMed
Samama  MBernard  PBonnardot  VPTissot  ELanson  YCombe-Tamzali  S Low molecular weight heparin compared with unfractionated heparin in prevention of postoperative thrombosis. Br J Surg 1988;75 (2) 128- 131
PubMed Link to Article
Hunt  BJDoughty  HAMajumdar  G  et al.  Thromboprophylaxis with low molecular weight heparin (Fragmin) in high risk pregnancies. Thromb Haemost 1997;77 (1) 39- 43
PubMed
Kearon  CJulian  JANewman  TE  et al.  Noninvasive diagnosis of deep venous thrombosis: McMaster Diagnostic Imaging Practice Guidelines Initiative. Ann Intern Med 1998;128 (8) 663- 677
PubMed Link to Article
Cook  DJMedic  AAndrews  J  et al.  Doppler compression ultrasound of the lower extremities in ICU patients: an inter-rater reliability study [abstract 346]. Crit Care Med 2002;30 (12) ((suppl)) A77
PubMed Link to Article
The PIOPED Investigators, Value of ventilation/perfusion scan in acute pulmonary embolism: results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA 1990;263 (20) 2753- 2759
PubMed Link to Article
Remy-Jardin  MRemy  JDeschildre  F  et al.  Diagnosis of pulmonary embolism with spiral CT: comparison with pulmonary angiography and scintigraphy. Radiology 1996;200 (3) 699- 700
PubMed Link to Article
Arnold  DMDonahoe  LClarke  FJ  et al.  Bleeding during critical illness: a prospective cohort study using a new measurement tool. Clin Invest Med 2007;30 (2) E93- E102
PubMed
Warkentin  TESheppard  JAMoore  JCMoore  KMSigouin  CSKelton  JG Laboratory testing for the antibodies that cause heparin-induced thrombocytopenia: how much class do we need? J Lab Clin Med 2005;146 (6) 341- 346
PubMed Link to Article
 Expert Committee on Biological Standardization, 37th Report.  Geneva, Switzerland World Health Organization1987;22WHO Technical Report Series 760
Powers  JD Statistical considerations in pharmacokinetic study design. Clin Pharmacokinet 1993;24 (5) 380- 387
PubMed Link to Article
Elliott  MJZimmerman  DHolden  RM Warfarin anticoagulation in hemodialysis patients: a systematic review of bleeding rates. Am J Kidney Dis 2007;50 (3) 433- 440
PubMed Link to Article
Gangireddy  CRectenwald  JRUpchurch  GR  et al.  Risk factors and clinical impact of postoperative symptomatic venous thromboembolism. J Vasc Surg 2007;45 (2) 335- 341
PubMed Link to Article
Büller  HRAgnelli  GHull  RDHyers  TMPrins  MHRaskob  GE Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126 (3) ((suppl)) 401S- 428S
PubMed Link to Article
Cairns  JATheroux  PLewis  DH  JrEzekowitz  MMeade  TW Antithrombotic agents in coronary artery disease. Chest 2001;119 (1) ((suppl)) 228S- 252S
PubMed Link to Article
Kani  CMarkantonis  SLNicolaou  CMaggina  N Monitoring of subcutaneous dalteparin in patients with renal insufficiency under intensive care: an observational study. J Crit Care 2006;21 (1) 79- 84
PubMed Link to Article
Tincani  EMannucci  CCasolari  B  et al.  Safety of dalteparin for the prophylaxis of venous thromboembolism in elderly medical patients with renal insufficiency: a pilot study. Haematologica 2006;91 (7) 976- 979.
PubMed
Dörffler-Melly  Jde Jonge  Ede Pont  AC  et al.  Bioavailability of subcutaneous low-molecular-weight heparin to patients on vasopressors. Lancet 2002;359 (9309) 849- 850
PubMed Link to Article
Rommers  MKVan Der Lely  NEgberts  TCGvan den Bent  PMLA Anti-Xa activity after subcutaneous administration of dalteparin in ICU patients with and without subcutaneous oedema: a pilot study. Crit Care 2006;10 (3) R93
PubMed Link to Article
Haas  CENelsen  JLRghavendran  K  et al.  Pharmacokinetics and pharmacodynamics of enoxaparin in multiple trauma patients. J Trauma 2005;59 (6) 1336- 1343
PubMed Link to Article
Mahé  IAghassarian  MDrouet  L  et al.  Tinzaparin and enoxaparin given at prophylactic dose for eight days in medical elderly patients with impaired renal function: a comparative pharmacokinetic study. Thromb Haemost 2007;97 (4) 581- 586
PubMed
Cadroy  YPourrat  YBaladre  MF  et al.  Delayed elimination of enoxaparin in patients with chronic renal insufficiency. Thromb Res 1991;63 (3) 385- 390
PubMed Link to Article
Kitchen  SIampietro  RWoolley  AMPreston  FE Anti Xa monitoring during treatment with low molecular weight heparin or danaparoid: inter-assay variability. Thromb Haemost 1999;82 (4) 1289- 1293
PubMed

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 56

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles