Use of Low Molecular Weight Heparin (Tinzaparin) to Treat Blood Clots in Patients With Kidney Failure

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2013 by St. Joseph's Healthcare Hamilton
Sponsor:
Collaborators:
Heart and Stroke Foundation of Ontario
LEO Pharma
Information provided by (Responsible Party):
Wendy Lim, St. Joseph's Healthcare Hamilton
ClinicalTrials.gov Identifier:
NCT00186745
First received: September 13, 2005
Last updated: February 12, 2013
Last verified: February 2013
  Purpose

Blood clots in the leg veins, known as deep vein thrombosis, are important because they may travel to the lung (known as pulmonary embolism) and cause death. Blood clots are treated with blood thinners, or anticoagulants. The preferred treatment is an anticoagulant known as low molecular weight heparin (LMWH). LMWH is given by an injection under the skin, which is convenient for patients because they can self-administer this medication at home, and no blood testing is required. However, LMWH is cleared from the body through the kidneys, so patients who have kidney failure are generally not treated with LMWH because they may be at a higher risk of bleeding.

One type of LMWH, known as tinzaparin, may be less dependent on the kidneys for clearance and may not increase in patients with kidney failure. The investigators would like to use tinzaparin to treat patients who have deep vein thrombosis or pulmonary embolism, and who also have kidney failure.

The purpose of this study is to determine whether the blood thinning effects of tinzaparin build up, or accumulate, in patients with varying degrees of kidney failure compared to patients without kidney failure. The blood thinning effects will be measured using a blood test known as an anti-Xa level. Patients will be followed over the time they receive tinzaparin and those patients who are found to have potentially high levels of tinzaparin (based on the anti-Xa level) will have their tinzaparin dose adjusted. The investigators believe that the levels of tinzaparin will not accumulate to potentially dangerous levels in a significant number of patients with kidney failure.


Condition Intervention
Venous Thrombosis
Pulmonary Embolism
Drug: Tinzaparin

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Tinzaparin for Treatment of Venous Thromboembolism in Renal Insufficiency: A Pilot Study

Resource links provided by NLM:


Further study details as provided by St. Joseph's Healthcare Hamilton:

Primary Outcome Measures:
  • Anti-Xa level measured on any two of Days 3, 5 or 7 of treatment [ Time Frame: Up to 7 days of treatment ] [ Designated as safety issue: No ]

Estimated Enrollment: 200
Study Start Date: March 2005
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
All patients in this cohort receive treatment with weight-adjusted, standard-dose tinzaparin for treatment of venous thromboembolism. Trough anti-Xa level measurements done on any 2 of days 3, 5 or 7 of treatment. Patients with a trough anti-Xa level > 0.5 IU/mL receive dose adjustment of the tinzaparin.
Drug: Tinzaparin
Dose: 175 IU/kg subcutaneously once daily, up to 7 days. Dose reduction as per protocol if anti-Xa levels exceed pre-defined limits.
Other Name: Brand name: Innohep

  Hide Detailed Description

Detailed Description:

Background and rationale. Venous thromboembolism (VTE) is an important clinical problem because it is common, preventable, contributes to morbidity and mortality, and is costly. Low molecular weight heparin (LMWH) is the preferred anticoagulant for VTE treatment, but is renally excreted. Consequently, LMWH use in patients with renal insufficiency may result in accumulation of the anticoagulant effects and the potential for avoidable bleeding complications. As a result, most patients with renal insufficiency who also have VTE are unable to benefit from LMWH treatment. These patients are therefore generally treated in hospital using unfractionated heparin (UFH), since it is eliminated by extra-renal mechanisms. In addition to those patients with known renal insufficiency, many elderly patients have previously unrecognized renal insufficiency and treatment of these patients with LMWH can be associated with accumulation of the anticoagulant effect and avoidable bleeding.

Tinzaparin, relative to other LMWHs, has a higher molecular weight and greater negative charge: both biochemical features that favour non-renal clearance. There is limited evidence to support the hypothesis that tinzaparin, unlike other LMWHs, does not accumulate in patients with renal insufficiency. 1) Observational studies demonstrated no increase in anti-Xa levels (i.e., no accumulation) when tinzaparin was used for VTE treatment in elderly patients with renal insufficiency. 2) One study showed undetectable LMWH anticoagulant activity by 24 hours after dosing in hemodialysis patients. 3) A systematic review and meta-analysis of the literature in this area performed by our research group found no difference in bleeding and thrombosis complication rates when LMWH (compared to UFH) was used to maintain dialysis circuit patency in patients on hemodialysis.

The current factors which limit the use of tinzaparin in the treatment of patients with VTE and renal insufficiency are: 1) the true risk of accumulation is unknown in a spectrum of patients with varying renal function, and 2) the bleeding risk associated with tinzaparin use is unknown.

Hypothesis. We hypothesize that accumulation during a 5-day course of tinzaparin will not be related to the degree of renal insufficiency.

Study design and methods. We will perform a prospective cohort study of 200 patients with acute VTE, stratified into 4 equal-sized groups by renal function, who will receive initial anticoagulation with tinzaparin for 5 days concurrent with oral anticoagulants. The LMWH anticoagulant effect will be assessed at days 3 and 5 (+/- 1) using trough anti-Xa heparin levels. If accumulation occurs, defined as a trough anti-Xa level > 0.5 IU/mL, the tinzaparin dose will be adjusted according to a nomogram. Patients with an anti-Xa level ≤ 0.5 IU/mL will have no dose adjustment; patients with levels > 0.5 IU/mL will have their tinzaparin dose reduced.

The primary outcome of this study is the proportion of patients in each renal function group with accumulation on or before day 5. We will follow the patients for 48 hours after their final tinzaparin injection. Secondary outcomes are bleeding, recurrent thrombosis, accumulation by day 3, and trough anti-Xa levels > 1.0 IU/mL at any point in the study.

Significance. We hypothesize that tinzaparin does not accumulate in patients with renal insufficiency. However, if accumulation occurs, we hypothesize that dose adjustment according to our novel nomogram will prevent potentially-dangerous levels occurring by day 5. In either case, we will be able to proceed to the next stage in our research plan: an application for funding for a large simple randomized controlled trial examining the safety and efficacy of tinzaparin compared with UFH in patients with renal insufficiency. If accumulation occurs despite the use of the nomogram, then this surrogate outcome suggests that the use of therapeutic-dose tinzaparin is unlikely to be safe in patients with renal insufficiency, a finding which will limit the need to expend further resources on this line of research.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult patients 18 years of age or older
  • Objectively confirmed VTE requiring anticoagulant therapy, including lower extremity and upper extremity deep vein thrombosis (catheter and non-catheter related, including dialysis access thrombosis [i.e., graft, fistula]); peripheral vein thrombosis (e.g., portal vein, mesenteric vein, cerebral vein thrombosis), and pulmonary embolism

Exclusion Criteria:

  • Weight exceeding 105 kg
  • Unstable declining renal function, defined as documented change in creatinine > 20% in the past 3 months or clinical circumstances likely to be associated with change in renal function, such as dehydration or severe intercurrent illness. Where no previous creatinine values exist and the patient is otherwise stable, patients will not be excluded on the basis of unknown previous renal function.
  • Known allergy to heparin/LMWHs or history of heparin induced thrombocytopenia
  • Treatment with UFH, LMWH, danaparoid, oral direct thrombin inhibitors for >48 h
  • Bleeding requiring hospitalization or blood transfusion within 6 months(exception is blood transfusion given in relation to surgical procedures within 6 months)
  • History of intracerebral hemorrhage
  • Known active liver disease (AST or ALT > 3 times the upper limit of normal, or bilirubin > 50 umol/L)
  • Known active peptic ulcer disease, with ongoing symptoms or need for anti-ulcer medical therapy
  • Thrombocytopenia (platelet count of < 100 x 109/L)
  • Ongoing need for antiplatelet agents (clopidogrel, ticlopidine, aspirin > 325 mg daily)
  • Pregnancy or lactation
  • Geographic inaccessibility
  • Unable, or unwilling, to provide written informed consent
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00186745

Contacts
Contact: Wendy Lim, MD 905-521-6024 limwp@mcmaster.ca
Contact: Mark A Crowther, MD 905-521-6024 crowthrm@mcmaster.ca

Locations
Canada, Ontario
St Joseph's Healthcare Hamilton Recruiting
Hamilton, Ontario, Canada, L8N 4A6
Contact: Wendy Lim, MD    905-521-6024    limwp@mcmaster.ca   
Contact: Mark Crowther, MD    905-521-6024    crowthrm@mcmaster.ca   
Principal Investigator: Wendy Lim, MD         
Sponsors and Collaborators
St. Joseph's Healthcare Hamilton
Heart and Stroke Foundation of Ontario
LEO Pharma
Investigators
Principal Investigator: Wendy Lim, MD St Joseph's Healthcare Hamilton / McMaster University
Principal Investigator: Mark A Crowther, MD St Joseph's Healthcare Hamilton / McMaster University
  More Information

No publications provided

Responsible Party: Wendy Lim, Associate Professor, Department of Medicine, St. Joseph's Healthcare Hamilton
ClinicalTrials.gov Identifier: NCT00186745     History of Changes
Other Study ID Numbers: NA 5723
Study First Received: September 13, 2005
Last Updated: February 12, 2013
Health Authority: Canada: Health Canada

Keywords provided by St. Joseph's Healthcare Hamilton:
Venous thrombosis
Pulmonary embolism
Kidney failure
Anticoagulants
Heparin, Low-Molecular-Weight

Additional relevant MeSH terms:
Thrombosis
Embolism
Pulmonary Embolism
Venous Thrombosis
Venous Thromboembolism
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Thromboembolism
Heparin, Low-Molecular-Weight
Dalteparin
Tinzaparin
Anticoagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Cardiovascular Agents

ClinicalTrials.gov processed this record on October 19, 2014