PROphylaxis for ThromboEmbolism in Critical Care Trial (PROTECT)

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.

Study Overview

• Status: Completed
• Conditions: Critical Illness; Deep Venous Thrombosis
• Intervention / Treatment: Drug: LMWH (Fragmin, dalteparin); Drug: Unfractionated Heparin

Detailed Description

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.

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.

• Study Type: Interventional
• Enrollment (Actual): 3659
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • St Leonards, Australia, NSW 2065
    • Royal North Shore Hospital
  • New South Wales
    • Blacktown, New South Wales, Australia, 2148
      • Blacktown Hospital
    • Camperdown, New South Wales, Australia
      • Royal Prince Alfred Hospital
    • Penrith, New South Wales, Australia
      • Nepean Hospital
    • Wollongong, New South Wales, Australia
      • Wollongong Hospital
  • South Australia
    • Adelaide, South Australia, Australia
      • Royal Adelaide Hospital
    • Elizabeth Vale, South Australia, Australia, 5112
      • Lyell McEwin Hospital
  • Victoria
    • Bedford Park, Victoria, Australia
      • Flinders Hospital
    • Bendigo, Victoria, Australia
      • Bendigo Health Care
    • Box Hill, Victoria, Australia
      • Box Hill Hospital
    • Clayton, Victoria, Australia
      • Monash Medical Center
    • Dandenong, Victoria, Australia, 3168
      • Dandenong Hospital
    • Frankston, Victoria, Australia
      • Frankston Hospital
    • Geelong, Victoria, Australia, 3220
      • The Geelong Hospital
    • Heidelburg, Victoria, Australia
      • Austin Hill Hospital
    • Melbourne, Victoria, Australia, 3181
      • The Alfred Hospital
    • Melbourne, Victoria, Australia, 3101
      • Royal Melbourne Hospital
• Brazil
  • Rio de Janeiro, Brazil
    • Hospital ProCardiaco
  • Sao Paulo, Brazil
    • Hospital Coracao
  • Sao Paulo, Brazil
    • UTI da Enfermaria de Clinical Medica do Hospital
  • RS
    • Porto Alegre, RS, Brazil, 90020-200
      • Hospitalar Santa Casa
  • Rs Cep
    • Porto Alegre, Rs Cep, Brazil, 90035-001
      • Hospital Moinhos de Vento
• Canada
  • Quebec, Canada, G1V 4G5
    • Hôpital Laval
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Foothills Hospital
    • Calgary, Alberta, Canada, TiY 6J4
      • The Peter Lougheed Hospital
    • Edmonton, Alberta, Canada
      • University of Alberta
    • Edmonton, Alberta, Canada, T5H 3V9
      • Royal Alexandra Hospital
  • British Columbia
    • Surrey, British Columbia, Canada
      • Surry Memorial
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Vancouver General Hospital
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • St Paul's Hospital
    • Vancouver, British Columbia, Canada, V3L 3W4
      • Royal Columbian Hospital
    • Victoria, British Columbia, Canada
      • Vancouver Island Health Authority
  • Manitoba
    • Winnipeg, Manitoba, Canada, R2H 2A6
      • St. Boniface Hospital
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • Queen Elizabeth II Health
  • Ontario
    • Guelph, Ontario, Canada
      • Guelph General Hospital
    • Hamilton, Ontario, Canada, L8N 4A6
      • St Joseph's Healthcare
    • Hamilton, Ontario, Canada, L8N 3Z5
      • Hamilton Health Science Centre - McMaster University
    • Hamilton, Ontario, Canada, L8N 3Z5
      • Hamilton Health Science Centre - Hamilton General Hospital
    • Hamilton, Ontario, Canada
      • Hamilton Health Science Center - Henderson Hospital
    • Kingston, Ontario, Canada, K7L 2V7
      • Kingston General Hospital
    • Kitchener, Ontario, Canada, N2G 1G3
      • Grand River Hospital
    • London, Ontario, Canada
      • London Health Science Center
    • Oshawa, Ontario, Canada
      • Lakeridge Health
    • Ottawa, Ontario, Canada, K1H 8L6
      • Ottawa Hospital - General Hospital
    • Ottawa, Ontario, Canada, K1Y 4E9
      • Ottawa Hospital - Civic Site
    • Toronto, Ontario, Canada, M5G 1X5
      • Mount Sinai Hospital
    • Toronto, Ontario, Canada
      • Toronto General Hospital
    • Toronto, Ontario, Canada, M5T 2S8
      • University Health Network - Toronto Western Hospital
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook and Women's College Health Science Centre
    • Toronto, Ontario, Canada, M5B 1W8
      • St Michaels Hospital
  • Quebec
    • Montreal, Quebec, Canada, H3A 1A1
      • Royal Victoria Hospital, McGill University Health Center
    • Montreal, Quebec, Canada, H4J 2C5
      • Hopital Sacre Couer
    • Montreal, Quebec, Canada, H3G 1A4
      • Montreal General Hospital, McGill University Health Centre
    • Montreal, Quebec, Canada, J4V 2H1
      • Hopital Charles LeMoyne
    • Montreal, Quebec, Canada
      • Hopital Maisonneuve
    • Quebec City, Quebec, Canada, G1J 1Z4
      • Centre Hospitalier Affilie-Enfant Jesus
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Sherbrooke University (CHUS) Hospital
• Saudi Arabia
  • Jeddah, Saudi Arabia, 21418
    • King AbdulAziz University Hospital
  • Jeddah, Saudi Arabia
    • King Faisal Specialist & Research Center
  • Riyadh, Saudi Arabia
    • King Fahad Medical City
  • Riyadh, Saudi Arabia
    • Riyadh Military Hospital
  • Riyahd
    • Riyadh, Riyahd, Saudi Arabia, 11426
      • King Abdulaziz Medical City Hospital
• United Kingdom
  • England
    • London, England, United Kingdom
      • Guys and St Thomas Hospital
• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • St. Louis, Missouri, United States, 63141
      • St. John's Mercy Medical Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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
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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: LMWH (Fragmin, dalteparin); Placebo dose (normal saline) = AM dose LMWH (Fragmin, dalteparin) 5000IU daily = PM dose	Drug: LMWH (Fragmin, dalteparin); Placebo AM dose (normal saline) and LMWH (Fragmin, dalteparin) 5000IU PM dose; Other Names: Fragmin
ACTIVE_COMPARATOR: 2; Unfractionated Heparin 5000IU BID	Drug: Unfractionated Heparin; 5000 IU BID; Other Names: Heparin Sodium

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: McMaster University
• Collaborators: Canadian Institutes of Health Research (CIHR); Australian and New Zealand Intensive Care Society Clinical Trials Group; Canadian Critical Care Trials Group

Publications and helpful links

General Publications

• 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. Erratum In: Respir Res. 2016 Oct 7;17 (1):128.
• 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.

Helpful Links

• PROTECT Collaborator Web Page

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (ACTUAL): June 1, 2010
• Study Completion (ACTUAL): June 1, 2010

Study Registration Dates

• First Submitted: September 10, 2005
• First Submitted That Met QC Criteria: September 10, 2005
• First Posted (ESTIMATE): September 16, 2005

Study Record Updates

• Last Update Posted (ESTIMATE): January 10, 2011
• Last Update Submitted That Met QC Criteria: January 7, 2011
• Last Verified: October 1, 2007

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial; Critically Ill; Deep Venous ThromboEmbolism
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Disease Attributes; Embolism and Thrombosis; Critical Illness; Thrombosis; Venous Thrombosis; Thromboembolism; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin; Calcium heparin; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin
• Other Study ID Numbers: ISRCTN54618366