PROphylaxis for ThromboEmbolism in Critical Care Trial (PROTECT)
NCT ID: NCT00182143
Last Updated: 2011-01-10
Study Results
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Basic Information
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COMPLETED
PHASE3
3659 participants
INTERVENTIONAL
2006-05-31
2010-06-30
Brief Summary
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Detailed Description
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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.
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 (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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
PREVENTION
QUADRUPLE
Study Groups
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LMWH (Fragmin, dalteparin)
Placebo dose (normal saline) = AM dose LMWH (Fragmin, dalteparin) 5000IU daily = PM dose
LMWH (Fragmin, dalteparin)
Placebo AM dose (normal saline) and LMWH (Fragmin, dalteparin) 5000IU PM dose
2
Unfractionated Heparin 5000IU BID
Unfractionated Heparin
5000 IU BID
Interventions
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LMWH (Fragmin, dalteparin)
Placebo AM dose (normal saline) and LMWH (Fragmin, dalteparin) 5000IU PM dose
Unfractionated Heparin
5000 IU BID
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Actual body weight is \>/= 45 kg
3. Admission to ICU expected to be \>/= 72 hours in duration
Exclusion Criteria
2. Ischemic stroke within last 3 months
3. Intracranial hemorrhage within last 3 months
4. Systolic Blood Pressure \>/= 180mm Hg, Diastolic Blood Pressure \>/= 110mm Hg for \>/= 12 hours requiring vasoactive drug infusion
5. Major hemorrhage within last week unless definitively treated
6. Coagulopathy as defined by INR \>/= 2 times upper limit of normal \[ULN\], or PTT \>/= 2 times ULN, at time of screening
7. Thrombocytopenia defined as platelet count \</= 75 x 109/L, at time of screening
8. Other heparin contraindications (e.g., HIT, pregnancy, lactating)
9. Contraindication to blood products (e.g., Jehovah'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. Lack of informed consent
18 Years
ALL
No
Sponsors
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Canadian Institutes of Health Research (CIHR)
OTHER_GOV
Canadian Critical Care Trials Group
OTHER
Australian and New Zealand Intensive Care Society Clinical Trials Group
NETWORK
McMaster University
OTHER
Responsible Party
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McMaster University
Principal Investigators
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Deborah J Cook, MD
Role: PRINCIPAL_INVESTIGATOR
McMaster University
Locations
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Blacktown Hospital
Blacktown, New South Wales, Australia
St. John's Mercy Medical Center
St Louis, Missouri, United States
Rhode Island Hospital
Providence, Rhode Island, United States
MD Anderson
Houston, Texas, United States
Mayo Clinic
Rochester, Minnesota, United States
Royal Prince Alfred Hospital
Camperdown, New South Wales, Australia
Nepean Hospital
Penrith, New South Wales, Australia
Wollongong Hospital
Wollongong, New South Wales, Australia
Royal Adelaide Hospital
Adelaide, South Australia, Australia
Lyell McEwin Hospital
Elizabeth Vale, South Australia, Australia
Flinders Hospital
Bedford Park, Victoria, Australia
Bendigo Health Care
Bendigo, Victoria, Australia
Box Hill Hospital
Box Hill, Victoria, Australia
Monash Medical Center
Clayton, Victoria, Australia
Dandenong Hospital
Dandenong, Victoria, Australia
Frankston Hospital
Frankston, Victoria, Australia
The Geelong Hospital
Geelong, Victoria, Australia
Austin Hill Hospital
Heidelburg, Victoria, Australia
Royal Melbourne Hospital
Melbourne, Victoria, Australia
The Alfred Hospital
Melbourne, Victoria, Australia
Royal North Shore Hospital
St Leonards, , Australia
UTI da Enfermaria de Clinical Medica do Hospital
São Paulo, Brazil, Brazil
Hospitalar Santa Casa
Porto Alegre, Rio Grande do Sul, Brazil
Hospital Moinhos de Vento
Porto Alegre, Rs Cep, Brazil
Hospital ProCardiaco
Rio de Janeiro, , Brazil
Hospital Coracao
São Paulo, , Brazil
Foothills Hospital
Calgary, Alberta, Canada
The Peter Lougheed Hospital
Calgary, Alberta, Canada
Royal Alexandra Hospital
Edmonton, Alberta, Canada
University of Alberta
Edmonton, Alberta, Canada
Surry Memorial
Surrey, British Columbia, Canada
Royal Columbian Hospital
Vancouver, British Columbia, Canada
Vancouver General Hospital
Vancouver, British Columbia, Canada
St Paul's Hospital
Vancouver, British Columbia, Canada
Vancouver Island Health Authority
Victoria, British Columbia, Canada
St. Boniface Hospital
Winnipeg, Manitoba, Canada
Queen Elizabeth II Health
Halifax, Nova Scotia, Canada
Guelph General Hospital
Guelph, Ontario, Canada
Hamilton Health Science Centre - Hamilton General Hospital
Hamilton, Ontario, Canada
Hamilton Health Science Centre - McMaster University
Hamilton, Ontario, Canada
St Joseph's HealthCare
Hamilton, Ontario, Canada
Hamilton Health Science Center - Henderson Hospital
Hamilton, Ontario, Canada
Kingston General Hospital
Kingston, Ontario, Canada
Grand River Hospital
Kitchener, Ontario, Canada
London Health Science Center
London, Ontario, Canada
Lakeridge Health
Oshawa, Ontario, Canada
Ottawa Hospital - General Hospital
Ottawa, Ontario, Canada
Ottawa Hospital - Civic Site
Ottawa, Ontario, Canada
Sunnybrook and Women's College Health Science Centre
Toronto, Ontario, Canada
St Michaels Hospital
Toronto, Ontario, Canada
Mount Sinai Hospital
Toronto, Ontario, Canada
University Health Network - Toronto Western Hospital
Toronto, Ontario, Canada
Toronto General Hospital
Toronto, Ontario, Canada
Royal Victoria Hospital, McGill University Health Center
Montreal, Quebec, Canada
Montreal General Hospital, McGill University Health Centre
Montreal, Quebec, Canada
Hopital Sacre Couer
Montreal, Quebec, Canada
Hopital Charles LeMoyne
Montreal, Quebec, Canada
Hopital Maisonneuve
Montreal, Quebec, Canada
Centre Hospitalier Affilie-Enfant Jesus
Québec, Quebec, Canada
Hopital Laval
Québec, Quebec, Canada
Sherbrooke University (CHUS) Hospital
Sherbrooke, Quebec, Canada
King Abdulaziz Medical City Hospital
Riyadh, Riyahd, Saudi Arabia
King Abdulaziz University Hospital
Jeddah, , Saudi Arabia
King Faisal Specialist & Research Center
Jeddah, , Saudi Arabia
King Fahad Medical City
Riyadh, , Saudi Arabia
Riyadh Military Hospital
Riyadh, , Saudi Arabia
Guys and St Thomas Hospital
London, England, United Kingdom
Countries
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References
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Li G, Cook DJ, Thabane L, Friedrich JO, Crozier TM, Muscedere J, Granton J, Mehta S, Reynolds SC, Lopes RD, Lauzier F, Freitag AP, Levine MA; PROTECT Investigators for the Canadian Critical Care Trials Group, and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Risk factors for mortality in patients admitted to intensive care units with pneumonia. Respir Res. 2016 Jul 11;17(1):80. doi: 10.1186/s12931-016-0397-5.
Li G, Thabane L, Cook DJ, Lopes RD, Marshall JC, Guyatt G, Holbrook A, Akhtar-Danesh N, Fowler RA, Adhikari NKJ, Taylor R, Arabi YM, Chittock D, Dodek P, Freitag AP, Walter SD, Heels-Ansdell D, Levine MAH. Risk factors for and prediction of mortality in critically ill medical-surgical patients receiving heparin thromboprophylaxis. Ann Intensive Care. 2016 Dec;6(1):18. doi: 10.1186/s13613-016-0116-x. Epub 2016 Feb 27.
Li G, Cook DJ, Levine MAH, Guyatt G, Crowther M, Heels-Ansdell D, Holbrook A, Lamontagne F, Walter SD, Ferguson ND, Finfer S, Arabi YM, Bellomo R, Cooper DJ, Thabane L; PROTECT Investigators for the Canadian Critical Care Trials Group, and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Competing Risk Analysis for Evaluation of Dalteparin Versus Unfractionated Heparin for Venous Thromboembolism in Medical-Surgical Critically Ill Patients. Medicine (Baltimore). 2015 Sep;94(36):e1479. doi: 10.1097/MD.0000000000001479.
Fowler RA, Mittmann N, Geerts WH, Heels-Ansdell D, Gould MK, Guyatt G, Krahn M, Finfer S, Pinto R, Chan B, Ormanidhi O, Arabi Y, Qushmaq I, Rocha MG, Dodek P, McIntyre L, Hall R, Ferguson ND, Mehta S, Marshall JC, Doig CJ, Muscedere J, Jacka MJ, Klinger JR, Vlahakis N, Orford N, Seppelt I, Skrobik YK, Sud S, Cade JF, Cooper J, Cook D; Canadian Critical Care Trials Group; Australia and New Zealand Intensive Care Society Clinical Trials Group. Economic evaluation of the prophylaxis for thromboembolism in critical care trial (E-PROTECT): study protocol for a randomized controlled trial. Trials. 2014 Dec 20;15:502. doi: 10.1186/1745-6215-15-502.
Crowther M, Cook D, Guyatt G, Zytaruk N, McDonald E, Williamson D, Albert M, Dodek P, Finfer S, Vallance S, Heels-Ansdell D, McIntyre L, Mehta S, Lamontagne F, Muscedere J, Jacka M, Lesur O, Kutsiogiannis J, Friedrich J, Klinger JR, Qushmaq I, Burry L, Khwaja K, Sheppard JA, Warkentin TE; PROTECT collaborators; Canadian Critical Care Trials Group; Australian and New Zealand Intensive Care Society Clinical Trials Group. Heparin-induced thrombocytopenia in the critically ill: interpreting the 4Ts test in a randomized trial. J Crit Care. 2014 Jun;29(3):470.e7-15. doi: 10.1016/j.jcrc.2014.02.004. Epub 2014 Feb 14.
Lamontagne F, McIntyre L, Dodek P, Heels-Ansdell D, Meade M, Pemberton J, Skrobik Y, Seppelt I, Vlahakis NE, Muscedere J, Reece G, Ostermann M, Padayachee S, Alhashemi J, Walsh M, Lewis B, Schiff D, Moody A, Zytaruk N, Leblanc M, Cook DJ; Prophylaxis for Thromboembolism in Critical Care Trial Investigators; Canadian Critical Care Trials Group; Australian and New Zealand Intensive Care Society Clinical Trials Group. Nonleg venous thrombosis in critically ill adults: a nested prospective cohort study. JAMA Intern Med. 2014 May;174(5):689-96. doi: 10.1001/jamainternmed.2014.169.
Lauzier F, Arnold DM, Rabbat C, Heels-Ansdell D, Zarychanski R, Dodek P, Ashley BJ, Albert M, Khwaja K, Ostermann M, Skrobik Y, Fowler R, McIntyre L, Nates JL, Karachi T, Lopes RD, Zytaruk N, Finfer S, Crowther M, Cook D. Risk factors and impact of major bleeding in critically ill patients receiving heparin thromboprophylaxis. Intensive Care Med. 2013 Dec;39(12):2135-43. doi: 10.1007/s00134-013-3044-3. Epub 2013 Aug 14.
Smith OM, McDonald E, Zytaruk N, Foster D, Matte A, Clarke F, Fleury S, Krause K, McArdle T, Skrobik Y, Cook DJ. Enhancing the informed consent process for critical care research: strategies from a thromboprophylaxis trial. Intensive Crit Care Nurs. 2013 Dec;29(6):300-9. doi: 10.1016/j.iccn.2013.04.006. Epub 2013 Jul 18.
Williamson DR, Albert M, Heels-Ansdell D, Arnold DM, Lauzier F, Zarychanski R, Crowther M, Warkentin TE, Dodek P, Cade J, Lesur O, Lim W, Fowler R, Lamontagne F, Langevin S, Freitag A, Muscedere J, Friedrich JO, Geerts W, Burry L, Alhashemi J, Cook D; PROTECT collaborators, the Canadian Critical Care Trials Group, and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Thrombocytopenia in critically ill patients receiving thromboprophylaxis: frequency, risk factors, and outcomes. Chest. 2013 Oct;144(4):1207-1215. doi: 10.1378/chest.13-0121.
Smith OM, McDonald E, Zytaruk N, Foster D, Matte A, Clarke F, Meade L, O'Callaghan N, Vallance S, Galt P, Rajbhandari D, Rocha M, Mehta S, Ferguson ND, Hall R, Fowler R, Burns K, Qushmaq I, Ostermann M, Heels-Ansdell D, Cook D; PROTECT Research Coordinators; PROTECT Investigators; Canadian Critical Care Trials Group; Australian, New Zealand Intensive Care Society Clinical Trials Group. Rates and determinants of informed consent: a case study of an international thromboprophylaxis trial. J Crit Care. 2013 Feb;28(1):28-39. doi: 10.1016/j.jcrc.2012.08.005. Epub 2012 Oct 22.
Cook D, Meade M, Guyatt G, Walter SD, Heels-Ansdell D, Geerts W, Warkentin TE, Cooper DJ, Zytaruk N, Vallance S, Berwanger O, Rocha M, Qushmaq I, Crowther M. PROphylaxis for ThromboEmbolism in Critical Care Trial protocol and analysis plan. J Crit Care. 2011 Apr;26(2):223.e1-9. doi: 10.1016/j.jcrc.2011.02.010.
PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group; Cook D, Meade M, Guyatt G, Walter S, Heels-Ansdell D, Warkentin TE, Zytaruk N, Crowther M, Geerts W, Cooper DJ, Vallance S, Qushmaq I, Rocha M, Berwanger O, Vlahakis NE. Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med. 2011 Apr 7;364(14):1305-14. doi: 10.1056/NEJMoa1014475. Epub 2011 Mar 22.
Related Links
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PROTECT Collaborator Web Page
Other Identifiers
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ISRCTN54618366
Identifier Type: -
Identifier Source: org_study_id
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