Dalteparin's Influence on Renally Compromised: Anti-Ten-A Study (DIRECT)

NCT00138099

Last updated date
Study Location
Queen Elizabeth II Health Science Centre
Halifax, Nova Scotia, B3H 3A7, Canada
Contact
1-800-718-1021

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Renal Insufficiency
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

- Adult patient aged > 18 years

- Admitted to an ICU with an expected ICU length of stay > 72 hours

- Severe renal insufficiency, defined by a calculated CrCl < 30 mL/min/1.73m2

Exclusion Criteria
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


- ICU admission for > 2 weeks at time of screening


- ICU admission within 3 months of cardiac surgery or neurosurgery


- Active bleeding or at high risk for bleeding complications


- Thrombocytopenia (platelet count < 75 x 10^9/L) at time of screening


- Coagulopathy (International Normalized Ratio [INR] or activated partial thromboplastin
time [aPTT] > 2 times upper limit of normal) at time of screening


- Patient had an indwelling epidural catheter for epidural analgesia within the last 12
hours


- Receipt of > 2 doses of LMWH (prophylactic- or therapeutic-dose) in the ICU


- Receiving or requiring therapeutic-dose anticoagulation (eg., deep vein thrombosis
[DVT]) at time of screening


- Receiving dialysis that requires anticoagulation (eg., PRISMA, slow continuous
ultrafiltration [SCUF]) at time of screening


- Weight < 45 kg


- Woman who is pregnant or lactating


- Bilateral lower limb amputation


- Previous adverse reaction to heparin or LMWH (eg., allergy, heparin-induced
thrombocytopenia [HIT])


- Contraindication to receiving blood products


- Life expectancy < 14 days or receiving palliative care


- Prior enrolment in this study or enrolment in a concurrent related clinical trial


- Patient or surrogate decision-maker does not provide consent to participate in study

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Advanced Information
Descriptive Information
Brief Title Dalteparin's Influence on Renally Compromised: Anti-Ten-A Study (DIRECT)
Official Title Dalteparin's Influence on Renally Compromised: Anti-Ten-A Study (DIRECT)
Brief Summary

The investigators' primary research objective is:

  • To determine the safety of dalteparin prophylaxis, 5,000 IU once-daily, in Intensive Care Unit (ICU) patients based on:

    • the proportion of patients with trough anti-Xa > 0.40 IU/mL during dalteparin prophylaxis after 3 + 1 days, 10 + 1 days, and 17 + 1 days of dalteparin prophylaxis;
    • the risk of major bleeding during the treatment period.

The investigators' secondary research objectives are:

  • To determine the pharmacokinetic properties of dalteparin prophylaxis in ICU patients with severe renal insufficiency;
  • To identify clinical and laboratory factors that predict an excessive anticoagulant effect (anti-Xa > 0.10 IU/mL);
  • To estimate the relationship between trough anti-Xa levels and bleeding.

The DIRECT Pilot Study:

Before embarking on a large trial of low molecular weight heparin (LMWH) versus standard unfractionated heparin (UFH), the DIRECT Study is needed to observe whether bioaccumulation of LMWH occurs in ICU patients with moderate to severe renal insufficiency, and to address potential problems with protocol implementation.

Detailed Description

Critically ill patients who are admitted to an intensive care unit (ICU) are at high risk for deep vein thrombosis (DVT), with an estimated 20-40% of patients developing DVT without prophylaxis. Preventing DVT is important because DVT is usually clinically silent in such patients, and its first manifestation may be life-threatening pulmonary embolism.

About 30% of ICU patients have renal insufficiency, based on a calculated creatinine clearance (CrCl), and such patients have 4-fold higher risk of DVT than those with normal renal function.

The current anticoagulant regimen that is used to prevent DVT in such patients, consisting of unfractionated heparin (UFH), 5000 IU twice-daily, may be inadequate.

A recent prospective cohort study by our research group that investigated the risk of DVT in 261 ICU patients found that 10% of patients developed proximal vein DVT after admission to the ICU despite receiving UFH, 5000 IU twice-daily.

In other patient groups at high risk for DVT, low-molecular-weight heparins (LMWHs) have replaced UFH for DVT prophylaxis because of superior efficacy.

Despite superior efficacy and safety in many patients, there is concern about using LMWHs in patients with renal insufficiency because LMWHs are cleared by the kidney. LMWH use in such patients might result in an excessive anticoagulant effect, with the potential to increase bleeding.

Much of the concern about the safety of LMWH in patients with renal insufficiency pertains to therapeutic-dose LMWH used to treat DVT. Prophylactic-(or low) dose LMWH that is used to prevent DVT in ICU patients is about 25-33% of a therapeutic-dose.

Three sources of evidence suggest that prophylactic-dose LMWH may be safe in patients with renal insufficiency. First, current evidence does not support the fact that prophylactic-dose LMWH accumulates and should be avoided in such patients. Second, prophylactic-dose LMWH appears to be safe in hemodialysis patients. Third, preliminary work by our research group suggests that dalteparin, 5000 IU once-daily, does not accumulate in ICU patients with renal insufficiency. Thus, 0 of 10 ICU patients with a CrCl <50 mL/min/1.73m2 who received dalteparin had a detectable trough anticoagulant effect (anti-Xa >0.10 IU/mL). Further, when the relationship between CrCl and peak anti-Xa levels was assessed, there was no correlation (r<0.2). Finally, in 2 patients with severe renal insufficiency (CrCl<30 mL/min/1.73m2) who received dalteparin, 5000 IU once-daily, all 9 trough anti-Xa values were <0.10 IU/mL.

No study has investigated the safety of low-dose LMWH in ICU patients with impaired renal function; until such a study is completed, randomized trials assessing the efficacy of low-dose LMWH for DVT prophylaxis among ICU patients will not be feasible.

As a first step in addressing this problem, we propose an open-label pilot study to assess the safety of dalteparin prophylaxis, 5000 IU once-daily, in ICU patients with severe renal insufficiency.

The safety of the proposed dalteparin prophylaxis regimen will be assessed by determining the risk of an excessive anticoagulant effect and the risk of major bleeding. Dalteparin prophylaxis will be considered safe if 2 criteria are satisfied by the end of the treatment period:

  • proportion of patients with trough anti-Xa level >0.40 IU/mL is ~10% or less (exclude 17% with 95% confidence);
  • risk of major bleeding is ~4% or less (exclude 10% with 95% confidence).

If we show that dalteparin prophylaxis is safe in ICU patients with severe renal insufficiency, this will improve patient care in 2 ways:

  • dalteparin may reduce the risk of DVT (although this should be tested in future trials); and
  • dalteparin would reduce heparin induced thrombocytopenia (HIT), an infrequent but serious complication of UFH.
Study Type Observational
Study Design Observational Model: Defined Population
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Not Provided
Sampling Method Not Provided
Study Population Not Provided
Condition Renal Insufficiency
Intervention Drug: Fragmin (dalteparin sodium)
Study Groups/Cohorts Not Provided
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Completed
Actual Enrollment
 (submitted: August 29, 2005)
140
Original Enrollment Same as current
Actual Study Completion Date June 2006
Primary Completion Date Not Provided
Eligibility Criteria

Inclusion Criteria:

  • Adult patient aged > 18 years
  • Admitted to an ICU with an expected ICU length of stay > 72 hours
  • Severe renal insufficiency, defined by a calculated CrCl < 30 mL/min/1.73m2

Exclusion Criteria:

  • ICU admission for > 2 weeks at time of screening
  • ICU admission within 3 months of cardiac surgery or neurosurgery
  • Active bleeding or at high risk for bleeding complications
  • Thrombocytopenia (platelet count < 75 x 10^9/L) at time of screening
  • Coagulopathy (International Normalized Ratio [INR] or activated partial thromboplastin time [aPTT] > 2 times upper limit of normal) at time of screening
  • Patient had an indwelling epidural catheter for epidural analgesia within the last 12 hours
  • Receipt of > 2 doses of LMWH (prophylactic- or therapeutic-dose) in the ICU
  • Receiving or requiring therapeutic-dose anticoagulation (eg., deep vein thrombosis [DVT]) at time of screening
  • Receiving dialysis that requires anticoagulation (eg., PRISMA, slow continuous ultrafiltration [SCUF]) at time of screening
  • Weight < 45 kg
  • Woman who is pregnant or lactating
  • Bilateral lower limb amputation
  • Previous adverse reaction to heparin or LMWH (eg., allergy, heparin-induced thrombocytopenia [HIT])
  • Contraindication to receiving blood products
  • Life expectancy < 14 days or receiving palliative care
  • Prior enrolment in this study or enrolment in a concurrent related clinical trial
  • Patient or surrogate decision-maker does not provide consent to participate in study
Sex/Gender
Sexes Eligible for Study:All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries Canada
Removed Location Countries  
 
Administrative Information
NCT Number NCT00138099
Other Study ID Numbers 092103
File No: 9427-M1133-21C
Control No: 092103
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party Not Provided
Study Sponsor Hamilton Health Sciences Corporation
Collaborators
  • Canadian Critical Care Trials Group
  • Pfizer
Investigators
Principal Investigator:James Douketis, MDMcMaster University
Principal Investigator:Deborah J Cook, MDMcMaster University
PRS Account McMaster University
Verification Date November 2006