PROphylaxis for ThromboEmbolism in Critical Care Trial (PROTECT)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effect of Low Molecular Weight Heparin (LMWH) (Fragmin, dalteparin) versus Unfractionated Heparin (UFH) on the primary outcome of proximal leg Deep Vein Thrombosis (DVT) diagnosed by compression ultrasound, and the secondary outcomes of Pulmonary Embolism (PE), bleeding, Heparin-Induced Thrombocytopenia (HIT), and objectively confirmed venous thrombosis at any site.

Detailed Description
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PROTECT: The PROphylaxis for ThromboEmbolism in Critical Care Trial. Background: Critically ill patients have an increased risk of deep venous thrombosis (DVT) due to their acute illness, procedures such as central venous catheterization, and immobility. Among patients in the intensive care unit (ICU), DVT is an important problem, since thrombus propagation and embolization can lead to potentially fatal pulmonary embolism (PE). Only 1 randomized trial (n=119) in medical-surgical ICU patients demonstrates that unfractionated heparin (UFH) prevents DVT compared to no prophylaxis; only 1 randomized trial (n=223) in ventilated COPD patients shows that low molecular weight heparin (LMWH) prevents DVT compared to no prophylaxis. In medical-surgical ICUs, the effect of LMWH vs UFH for DVT prevention has not been tested. On one hand, LMWH is likely to be more effective at venous thromboembolism (VTE) prevention and is associated with a lower rate of heparin-induced thrombocytopenia (HIT). On the other hand, UFH is likely associated with less bleeding, and is less expensive. Current guidelines indicate that in the absence of comparative data, both LMWH and UFH are suitable for thromboprophylaxis in this population, but that a randomized trial is needed. PROTECT Pilot: In our Pilot Study, feasibility objectives were to assess: 1) timely enrolment and complete, blinded study drug administration, 2) the bioaccumulation of LMWH in patients with acquired renal insufficiency, 3) twice weekly leg ultrasounds, and 4) recruitment rates. Timely, complete administration occurred for 98% of scheduled doses; every dose was blinded. No LWMH bioaccumulation was observed. Scheduled ultrasounds occurred without exception. Recruitment will be 4 patients/month/centre after modification of 3 exclusion criteria in the PROTECT pilot. Objective: To evaluate the effect of LMWH (dalteparin) vs UFH on the primary outcome of proximal leg DVT diagnosed by compression ultrasound, and the secondary outcomes of PE, bleeding, HIT, and objectively confirmed venous thrombosis at any site. Design: Prospective randomized stratified concealed blinded multicentre trial. Population: Inclusion Criteria: Eligible patients in medical-surgical ICUs will be >18 years old, weigh > 45 kg, and have an expected ICU stay > 72 hours. Exclusion Criteria: Patients admitted to ICU post trauma, orthopedic surgery, or neurosurgery, with severe hypertension, DVT, PE or major hemorrhage within 3 months, International Normalized Ratio (INR) > 2 ULN, Partial Thromboplastin Time (PTT) > 2 ULN, platelets < 75 x 109/L, or those requiring therapeutic anticoagulation will be excluded. Patients with a contraindication to heparin, blood products or pork products, with > 3 days of LMWH or UFH in ICU, patients who are pregnant, undergoing withdrawal of life support, or are enrolled in this or a related trial will also be excluded. Methods: Using centralized telephone randomization, we will allocate 3,650 patients in 40 centres to LMWH (dalteparin) 5,000 IU daily or UFH 5,000 IU twice daily SC for the duration of ICU stay. Patients, families, all clinicians and researcher will be blinded; only the pharmacist will be aware of allocation. Bilateral proximal leg compression ultrasounds will be performed within 48h of ICU admission, twice weekly, and on suspicion of DVT. PE will be diagnosed by a predefined diagnostic algorithm. We will record bleeding, HIT, other venous thrombosis and complications. Protocol adherence will be maximized using training, manuals, study aids, site visits, audit and feedback. Blinded Adjudication Committees will adjudicate endpoints. PROTECT will be conducted by the Canadian Critical Care Trials Group and overseen by an independent DSMB. Relevance: The results of PROTECT will be used to develop evidence based practice guidelines regarding the safety and efficacy of LMWH (dalteparin) vs UFH for thromboprophylaxis in medical-surgical ICU patients around the world.

Official Title
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PROphylaxis for ThromboEmbolism in Critical Care Trial (PROTECT)

Conditions
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Critical Illness, Deep Venous Thrombosis

Intervention / Treatment
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* Drug: LMWH (Fragmin, dalteparin)
* Drug: Unfractionated Heparin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient is >/= 18 years of age Actual body weight is >/= 45 kg Admission to ICU expected to be >/= 72 hours in duration Exclusion Criteria: Neurosurgery within last 3 months Ischemic stroke within last 3 months Intracranial hemorrhage within last 3 months Systolic Blood Pressure >/= 180mm Hg, Diastolic Blood Pressure >/= 110mm Hg for >/= 12 hours requiring vasoactive drug infusion Major hemorrhage within last week unless definitively treated Coagulopathy as defined by INR >/= 2 times upper limit of normal [ULN], or PTT >/= 2 times ULN, at time of screening Thrombocytopenia defined as platelet count </= 75 x 109/L, at time of screening Other heparin contraindications (e.g., HIT, pregnancy, lactating) Contraindication to blood products (e.g., Jehovah's Witness) Unable to perform lower limb ultrasound (e.g., bilateral above the knee amputation, or severe distal extremity burns) Limitation of life support, Life expectancy </= 14 days, or palliative care Contamination (e.g., >/= 3 doses of LMWH during this ICU admission) Lack of informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: LMWH (Fragmin, dalteparin)<br>Placebo dose (normal saline) = AM dose LMWH (Fragmin, dalteparin) 5000IU daily = PM dose | Drug: LMWH (Fragmin, dalteparin)<br>* Placebo AM dose (normal saline) and LMWH (Fragmin, dalteparin) 5000IU PM dose<br>* Other names: Fragmin;|
| Active Comparator: 2<br>Unfractionated Heparin 5000IU BID | Drug: Unfractionated Heparin<br>* 5000 IU BID<br>* Other names: Heparin Sodium;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the effect of LMWH (Fragmin, dalteparin) versus UFH on the primary outcome of proximal leg DVT diagnosed by compression ultrasound |  | While in ICU to a maximum of 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the effect of LMWH (Fragmin, dalteparin) versus UFH on the secondary outcomes of PE, bleeding, HIT, and objectively confirmed venous thrombosis at any site |  | While in ICU to a maximum of 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Critically Ill, Deep Venous ThromboEmbolism, Randomized Controlled Trial