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

Sponsor

Hamilton Health Sciences Corporation (Other)

Overall Status

Completed

CT.gov ID

NCT00138099

Collaborator

Canadian Critical Care Trials Group (Other), Pfizer (Industry)

140

Enrollment

Locations

Duration (Months)

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Renal Insufficiency	Drug: Fragmin (dalteparin sodium)

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 Design

Study Type:

Observational

Actual Enrollment :

140 participants

Observational Model:

Defined Population

Time Perspective:

Prospective

Official Title:

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

Study Start Date :

Jul 1, 2004

Actual Study Completion Date :

Jun 1, 2006

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Queen Elizabeth II Health Science Centre	Halifax	Nova Scotia	Canada	B3H 3A7
2	Hamilton Health Science Centre - Hamilton General Hospital	Hamilton	Ontario	Canada	L8L 2X2
3	Hamilton Health Science Centre - McMaster University	Hamilton	Ontario	Canada	L8N 3Z5
4	St Joseph's HealthCare	Hamilton	Ontario	Canada	L8N 4A6
5	Hamilton Health Science Centre - Henderson Hospital	Hamilton	Ontario	Canada	L8V 1C3
6	Ottawa General Hospital	Ottawa	Ontario	Canada	K1H 8L6
7	Ottawa Civic Hospital	Ottawa	Ontario	Canada	K1Y 4E9
8	Sunnybrook and Women's College Health Science Centre	Toronto	Ontario	Canada	M4N 3M5
9	Mount Sinai Hospital	Toronto	Ontario	Canada	M5G 1X5
10	University Health Network - Toronto General Hospital	Toronto	Ontario	Canada	M5G 2C4
11	University Health Network - Toronto Western Hospital	Toronto	Ontario	Canada	M5G 2C4
12	Hopital Charles LeMoyne	Greenfield Park	Quebec	Canada	J4V 2H1
13	Hopital Maisonneuve Rosemont	Montreal	Quebec	Canada	H1T 2M4
14	Hopital Sacre Couer	Montreal	Quebec	Canada	H4J 2C5