Clinical trial NCT00182143: PROphylaxis for ThromboEmbolism in Critical Care Trial (PROTECT)
Official title: PROphylaxis for ThromboEmbolism in Critical Care Trial (PROTECT)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Critical Illness
Deep Venous Thrombosis
Keywords: Critically Ill
Deep Venous ThromboEmbolism
Randomized Controlled Trial
Lead sponsor: McMaster University
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: Canadian Critical Care Trials Group
name: Australian and New Zealand Intensive Care Society Clinical Trials Group
First posted: 2005-09-16
Enrollment: 3659
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility 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
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

Primary outcomes:
measure: To evaluate the effect of LMWH (Fragmin, dalteparin) versus UFH on the primary outcome of proximal leg DVT diagnosed by compression ultrasound
timeFrame: While in ICU to a maximum of 90 days
Secondary outcomes:
measure: 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
timeFrame: While in ICU to a maximum of 90 days
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: St. Louis
country: United States
facility: St. John's Mercy Medical Center
state: Missouri
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Houston
country: United States
facility: MD Anderson
state: Texas
city: Blacktown
country: Australia
facility: Blacktown Hospital
state: New South Wales
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Penrith
country: Australia
facility: Nepean Hospital
state: New South Wales
city: Wollongong
country: Australia
facility: Wollongong Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Elizabeth Vale
country: Australia
facility: Lyell McEwin Hospital
state: South Australia
city: Bedford Park
country: Australia
facility: Flinders Hospital
state: Victoria
city: Bendigo
country: Australia
facility: Bendigo Health Care
state: Victoria
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Clayton
country: Australia
facility: Monash Medical Center
state: Victoria
city: Dandenong
country: Australia
facility: Dandenong Hospital
state: Victoria
city: Frankston
country: Australia
facility: Frankston Hospital
state: Victoria
city: Geelong
country: Australia
facility: The Geelong Hospital
state: Victoria
city: Heidelburg
country: Australia
facility: Austin Hill Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
city: Porto Alegre
country: Brazil
facility: Hospital Moinhos de Vento
state: Rs Cep
city: Porto Alegre
country: Brazil
facility: Hospitalar Santa Casa
state: RS
city: Rio de Janeiro
country: Brazil
facility: Hospital ProCardiaco
city: Sao Paulo
country: Brazil
facility: Hospital Coracao
city: Sao Paulo
country: Brazil
facility: UTI da Enfermaria de Clinical Medica do Hospital
city: Calgary
country: Canada
facility: Foothills Hospital
state: Alberta
city: Calgary
country: Canada
facility: The Peter Lougheed Hospital
state: Alberta
city: Edmonton
country: Canada
facility: Royal Alexandra Hospital
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Surrey
country: Canada
facility: Surry Memorial
state: British Columbia
city: Vancouver
country: Canada
facility: Royal Columbian Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: St Paul's Hospital
state: British Columbia
city: Victoria
country: Canada
facility: Vancouver Island Health Authority
state: British Columbia
city: Winnipeg
country: Canada
facility: St. Boniface Hospital
state: Manitoba
city: Halifax
country: Canada
facility: Queen Elizabeth II Health
state: Nova Scotia
city: Guelph
country: Canada
facility: Guelph General Hospital
state: Ontario
city: Hamilton
country: Canada
facility: Hamilton Health Science Centre - Hamilton General Hospital
state: Ontario
city: Hamilton
country: Canada
facility: Hamilton Health Science Centre - McMaster University
state: Ontario
city: Hamilton
country: Canada
facility: St Joseph's HealthCare
state: Ontario
city: Hamilton
country: Canada
facility: Hamilton Health Science Center - Henderson Hospital
state: Ontario
city: Kingston
country: Canada
facility: Kingston General Hospital
state: Ontario
city: Kitchener
country: Canada
facility: Grand River Hospital
state: Ontario
city: London
country: Canada
facility: London Health Science Center
state: Ontario
city: Oshawa
country: Canada
facility: Lakeridge Health
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital - General Hospital
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital - Civic Site
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook and Women's College Health Science Centre
state: Ontario
city: Toronto
country: Canada
facility: St Michaels Hospital
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Toronto
country: Canada
facility: University Health Network - Toronto Western Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Montreal
country: Canada
facility: Royal Victoria Hospital, McGill University Health Center
state: Quebec
city: Montreal
country: Canada
facility: Montreal General Hospital, McGill University Health Centre
state: Quebec
city: Montreal
country: Canada
facility: Hopital Sacre Couer
state: Quebec
city: Montreal
country: Canada
facility: Hopital Charles LeMoyne
state: Quebec
city: Montreal
country: Canada
facility: Hopital Maisonneuve
state: Quebec
city: Quebec City
country: Canada
facility: Centre Hospitalier Affilie-Enfant Jesus
state: Quebec
city: Sherbrooke
country: Canada
facility: Sherbrooke University (CHUS) Hospital
state: Quebec
city: Quebec
country: Canada
facility: Hopital Laval
city: Riyadh
country: Saudi Arabia
facility: King Abdulaziz Medical City Hospital
state: Riyahd
city: Jeddah
country: Saudi Arabia
facility: King Abdulaziz University Hospital
city: Jeddah
country: Saudi Arabia
facility: King Faisal Specialist & Research Center
city: Riyadh
country: Saudi Arabia
facility: King Fahad Medical City
city: Riyadh
country: Saudi Arabia
facility: Riyadh Military Hospital
city: London
country: United Kingdom
facility: Guys and St Thomas Hospital
state: England
Study officials:
affiliation: McMaster University
name: Deborah J Cook, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.