Clinical trial NCT00138099: Dalteparin's Influence on Renally Compromised: Anti-Ten-A Study (DIRECT)
Official title: Dalteparin's Influence on Renally Compromised: Anti-Ten-A Study (DIRECT)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Renal Insufficiency
Keywords: Critically ill patients (ICU)
Deep Venous Thromboembolism prevention
Renal Failure
Critically ill
Lead sponsor: McMaster University
Sponsor class: OTHER
Collaborators: name: Canadian Critical Care Trials Group
name: Pfizer
First posted: 2005-08-30
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: DEFINED_POPULATION
Time perspective: PROSPECTIVE

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.

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

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Science Centre
state: Nova Scotia
city: Hamilton
country: Canada
facility: Hamilton Health Science Centre - Hamilton General Hospital
state: Ontario
city: Hamilton
country: Canada
facility: Hamilton Health Science Centre - McMaster University
state: Ontario
city: Hamilton
country: Canada
facility: St Joseph's HealthCare
state: Ontario
city: Hamilton
country: Canada
facility: Hamilton Health Science Centre - Henderson Hospital
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa General Hospital
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Civic Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook and Women's College Health Science Centre
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Toronto
country: Canada
facility: University Health Network - Toronto General Hospital
state: Ontario
city: Toronto
country: Canada
facility: University Health Network - Toronto Western Hospital
state: Ontario
city: Greenfield Park
country: Canada
facility: Hopital Charles LeMoyne
state: Quebec
city: Montreal
country: Canada
facility: Hopital Maisonneuve Rosemont
state: Quebec
city: Montreal
country: Canada
facility: Hopital Sacre Couer
state: Quebec
Study officials:
affiliation: McMaster University
name: James Douketis, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: McMaster University
name: Deborah J Cook, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cook D, Sinuff T, Zytaruk N, Rabbat C, Lee A, O'Donnell M, Thabane L, Linkins L, Treleaven D, Patel R, Meade M, Crowther M, Marshall JC, Douketis J; DIRECT Investigators and Canadian Critical Care Trials Group. Event adjudication and data monitoring in an intensive care unit observational study of thromboprophylaxis. J Crit Care. 2009 Jun;24(2):168-75. doi: 10.1016/j.jcrc.2009.01.010. Epub 2009 Mar 27.
citation: Douketis J, Cook D, Meade M, Guyatt G, Geerts W, Skrobik Y, Albert M, Granton J, Hebert P, Pagliarello G, Marshall J, Fowler R, Freitag A, Rabbat C, Anderson D, Zytaruk N, Heels-Ansdell D, Crowther M; Canadian Critical Care Trials Group. 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. Arch Intern Med. 2008 Sep 8;168(16):1805-12. doi: 10.1001/archinte.168.16.1805.
citation: Cook D, Douketis J, Meade M, Guyatt G, Zytaruk N, Granton J, Skrobik Y, Albert M, Fowler R, Hebert P, Pagliarello G, Friedrich J, Freitag A, Karachi T, Rabbat C, Heels-Ansdell D, Geerts W, Crowther M; Canadian Critical Care Trials Group. Venous thromboembolism and bleeding in critically ill patients with severe renal insufficiency receiving dalteparin thromboprophylaxis: prevalence, incidence and risk factors. Crit Care. 2008;12(2):R32. doi: 10.1186/cc6810. Epub 2008 Mar 3.