To evaluate the effect of LMWH 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.

Condition	Intervention	Phase
Critically Ill Deep Venous Thromboembolism	Drug: Fragmin (Dalteparin) versus Unfractionated Heparin (UFH)	Phase III

Further Study Details: 

Primary Outcomes: To evaluate the effect of LMWH vs UFH on the primary outcome of proximal leg DVT diagnosed by compression ultrasound.
Secondary Outcomes: To evaluate the effect of LMWH vs UFH on the secondary outcomes of PE, bleeding, HIT, and objectively confirmed venous thrombosis at any site.
Expected Total Enrollment:  3600

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 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 LWMH 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. 1) Timely, complete administration occurred for 98% of scheduled doses; every dose was blinded. 2) No LWMH bioaccumulation was observed. 3) Scheduled ultrasounds occurred without exception. 4) Recruitment will be 4 patients/month/centre after modification of 3 exclusion criteria in the PROTECT pilot.

Objective: To evaluate the effect of LMWH 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 >18years old, weigh > 45 kg, and have an expected ICU stay >72h.

Exclusion Criteria: Patients admitted to ICU post trauma, orthopedic surgery, or neurosurgery, with severe hypertension, DVT, PE or major hemorrhage within 3 months, INR >2ULN, PTT >2ULN, platelets <75 x109/L, or those requiring therapeutic anticoagulation will be excluded. Patients with a contraindication to heparin, blood products or pork products, with >2 doses 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 3,600 patients in 28 centres to 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 vs UFH for thromboprophylaxis in medical-surgical ICU patients around the world.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

1. Patient is >/= 18 years of age
2. Actual body weight is >/= 45 kg
3. Admission to ICU expected to be >/= 72 hours in duration

Exclusion Criteria:

1. Neurosurgery within last 3 months
2. Ischemic stroke within last 3 months
3. Intracranial hemorrhage within last 3 months

3. SBP >/= 180mmHg, DBP >/= 110 mmHg for >/= 12 hours requiring vasoactive drug infusion 4. Major hemorrhage within last week unless definitively treated 5. Coagulopathy as defined by INR >/= 2 times upper limit of normal [ULN], or PTT >/= 2 times ULN, at time of screening 6. Thrombocytopenia defined as platelet count </= 75 x 109/L, at time of screening 7. Other heparin contraindications (e.g., HIT, pregnancy, lactating) 8. Contraindication to blood products (e.g., Jahovah''''s Witness) 10. Unable to perform lower limb ultrasound (e.g., bilateral above the knee amputation, or severe distal extremity burns) 11. Limitation of life support, Life expectancy </= 14 days, or palliative care 12. Contamination (e.g., >/= 3 doses of LMWH during this ICU admission) 13. Estimated creatinine clearance </= 30ml/min within last 24 hours 14. Lack of informed consent

Please refer to this study by ClinicalTrials.gov identifier  NCT00182143

Deborah J Cook, MD      905-525-9140  Ext. 22900    debcook@McMaster.ca

California
      Stanford University Medical Centre, Stanford,  California,  94305-5236,  United States
      Stanford School of Medicine VA Hospital, Palo Alto,  California,  94304,  United States
Australia
      Royal North Shore Hospital, St. Leonards,  NSW 2065,  Australia
      University of South Wales, South Wales,  2217,  Australia
Australia, Victoria
      The Alfred Hospital, Melbourne,  Victoria,  3181,  Australia
      Royal Melbourne Hospital, Melbourne,  Victoria,  3101,  Australia
Canada, Alberta
      Foothills Hospital, Calgary,  Alberta,  T2N 2T9,  Canada
      Royal Alexandra Hospital, Edmonton,  Alberta,  T5H 3V9,  Canada
Canada, British Columbia
      Westminster Hospital, Vancouver,  British Columbia,  V3Z 5E7,  Canada
      Vancouver General Hospital, Vancouver,  British Columbia,  V5Z 1M9,  Canada
      St Paul''''s Hospital, Vancouver,  British Columbia,  V6Z 1Y6,  Canada
Canada, Nova Scotia
      Queen Elizabeth II Health, Halifax,  Nova Scotia,  B3H 3A7,  Canada
Canada, Ontario
      St Joseph''''s HealthCare, Hamilton,  Ontario,  L8N 4A6,  Canada
      Hamilton Health Science Centre - Hamilton General Hospital, Hamilton,  Ontario,  L8N 3Z5,  Canada
      Hamilton Health Science Centre - McMaster University, Hamilton,  Ontario,  L8N 3Z5,  Canada
      University Health Network - Toronto General Hospital, Toronto,  Ontario,  M5G 2C4,  Canada
      Ottawa Hospital - Civic Site, Ottawa,  Ontario,  K1Y 4E9,  Canada
      Ottawa Hospital - General Hospital, Ottawa,  Ontario,  K1H 8L6,  Canada
      Mount Sinai Hospital, Toronto,  Ontario,  M5G 1X5,  Canada
      Sunnybrook and Women''''s College Health Science Centre, Toronto,  Ontario,  M4N 3M5,  Canada
      St Michaels Hospital, Toronto,  Ontario,  M5B 1W8,  Canada
      Kingston General Hospital, Kingston,  Ontario,  K7L 2V7,  Canada
      London Health Science Centre - University Campus, London,  Ontario,  N6A 5A5,  Canada
      London Health Science Centre - Victoria, London,  Ontario,  N6Z 4G5,  Canada
      University Health Network - Toronto Western Hospital, Toronto,  Ontario,  M5T 2S8,  Canada
Canada, Quebec
      Centre Hospitalier Affilie-Enfant Jesus, Quebec City,  Quebec,  G1J 1Z4,  Canada
      Hopital Charles LeMoyne, Montreal,  Quebec,  J4V 2H1,  Canada
      Hopital Maisonneuve Rosemont, Montreal,  Quebec,  H1T 2M4,  Canada
      Hopital Sacre Couer, Montreal,  Quebec,  H4J 2C5,  Canada
      Jewish General Hospital, Montreal,  Quebec,  H2X 2P4,  Canada
Singapore
      National University Hospital, MICU, Singapore,  119074,  Singapore
      National University Hospital, Singapore,  119074,  Singapore

Study chairs or principal investigators

Deborah J Cook, MD,  Principal Investigator,  Hamilton Health Sciences - McMaster University Medical Centre   

Study ID Numbers:  ISRCTN54618366
Last Updated:  September 15, 2005
Record first received:  September 10, 2005
ClinicalTrials.gov Identifier:  NCT00182143
Health Authority: Canada: Health Canada
ClinicalTrials.gov processed this record on 2005-09-20