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Sponsors and Collaborators: |
St. Joseph's Healthcare Heart and Stroke Foundation of Ontario LEO Pharma |
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Information provided by: | St. Joseph's Healthcare |
ClinicalTrials.gov Identifier: | NCT00186745 |
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. We 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. We believe that the levels of tinzaparin will not accumulate to potentially dangerous levels in a significant number of patients with kidney failure.
Condition | Intervention |
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Venous Thrombosis Pulmonary Embolism |
Drug: Tinzaparin |
Study Type: | Interventional |
Study Design: | Open Label, Uncontrolled, Single Group Assignment, Pharmacokinetics Study |
Official Title: | Tinzaparin for Treatment of Venous Thromboembolism in Renal Insufficiency: A Pilot Study |
Estimated Enrollment: | 200 |
Study Start Date: | March 2005 |
Estimated Study Completion Date: | December 2010 |
Estimated Primary Completion Date: | June 2010 (Final data collection date for primary outcome measure) |
Arms | Assigned Interventions |
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1: Experimental
All patients in this cohort receive treatment with tinzaparin and have anti-Xa level measurements on any 2 of days 3, 5 or 7 of treatment.
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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.
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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.
Ages Eligible for Study: | 18 Years and older |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
Contact: Wendy Lim, MD | 905-521-6024 | limwp@mcmaster.ca |
Contact: Mark A Crowther, MD | 905-521-6024 | crowthrm@mcmaster.ca |
Canada, Ontario | |
St Joseph's Hospital | 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 | |
Ottawa Hospital, Parkdale Clinic | Recruiting |
Ottawa, Ontario, Canada, K1Y 4E9 | |
Contact: Marc Rodger, MD 613-798-5555 ext 74641 mrodger@ottawahospital.on.ca | |
Contact: Phil Wells, MD 613-798-5555 ext 18769 pwells@ottawahospital.on.ca | |
Principal Investigator: Marc Rodger, MD |
Principal Investigator: | Wendy Lim, MD | St Joseph's Hospital / McMaster University |
Principal Investigator: | Mark A Crowther, MD | St Joseph's Hospital / McMaster University |
Responsible Party: | McMaster University / St. Joseph's Hospital ( Dr. Wendy Lim ) |
Study ID Numbers: | NA 5723 |
Study First Received: | September 13, 2005 |
Last Updated: | May 30, 2008 |
ClinicalTrials.gov Identifier: | NCT00186745 |
Health Authority: | Canada: Health Canada |
Venous thrombosis Pulmonary embolism Kidney failure Anticoagulants Heparin, Low-Molecular-Weight |
Renal Insufficiency Pulmonary Embolism Heparin, Low-Molecular-Weight Vascular Diseases Venous Thromboembolism Thrombosis Thromboembolism Calcium heparin Body Weight Embolism and Thrombosis |
Urologic Diseases Respiratory Tract Diseases Embolism Lung Diseases Tinzaparin Venous Thrombosis Kidney Diseases Heparin Kidney Failure |
Fibrin Modulating Agents Anticoagulants Molecular Mechanisms of Pharmacological Action Therapeutic Uses Hematologic Agents |
Fibrinolytic Agents Cardiovascular Diseases Cardiovascular Agents Pharmacologic Actions |