PROphylaxis for ThromboEmbolism in Critical Care Trial (PROTECT)

Critical Illness Clinical Trial

Official title:

PROphylaxis for ThromboEmbolism in Critical Care Trial (PROTECT)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00182143
• Other study ID #: ISRCTN54618366
• Status: Completed
• Phase: Phase 3
• First received: September 10, 2005
• Last updated: January 7, 2011
• Start date: May 2006
• Est. completion date: June 2010

Study information

• Verified date: October 2007
• Source: McMaster University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3659
• Est. completion date: June 2010
• Est. primary completion date: June 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Critical Illness
• Deep Venous Thrombosis
• Thromboembolism
• Thrombosis
• Venous Thrombosis

Intervention

Drug:
• LMWH (Fragmin, dalteparin)
Placebo AM dose (normal saline) and LMWH (Fragmin, dalteparin) 5000IU PM dose
• Unfractionated Heparin
5000 IU BID

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Flinders Hospital	Bedford Park	Victoria
Australia	Bendigo Health Care	Bendigo	Victoria
Australia	Blacktown Hospital	Blacktown	New South Wales
Australia	Box Hill Hospital	Box Hill	Victoria
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	Monash Medical Center	Clayton	Victoria
Australia	Dandenong Hospital	Dandenong	Victoria
Australia	Lyell McEwin Hospital	Elizabeth Vale	South Australia
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	Nepean Hospital	Penrith	New South Wales
Australia	Royal North Shore Hospital	St Leonards
Australia	Wollongong Hospital	Wollongong	New South Wales
Brazil	Hospital Moinhos de Vento	Porto Alegre	Rs Cep
Brazil	Hospitalar Santa Casa	Porto Alegre	RS
Brazil	Hospital ProCardiaco	Rio de Janeiro
Brazil	Hospital Coracao	Sao Paulo
Brazil	UTI da Enfermaria de Clinical Medica do Hospital	Sao Paulo
Canada	Foothills Hospital	Calgary	Alberta
Canada	The Peter Lougheed Hospital	Calgary	Alberta
Canada	Royal Alexandra Hospital	Edmonton	Alberta
Canada	University of Alberta	Edmonton	Alberta
Canada	Guelph General Hospital	Guelph	Ontario
Canada	Queen Elizabeth II Health	Halifax	Nova Scotia
Canada	Hamilton Health Science Center - Henderson Hospital	Hamilton	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	Kingston General Hospital	Kingston	Ontario
Canada	Grand River Hospital	Kitchener	Ontario
Canada	London Health Science Center	London	Ontario
Canada	Hopital Charles LeMoyne	Montreal	Quebec
Canada	Hopital Maisonneuve	Montreal	Quebec
Canada	Hopital Sacre Couer	Montreal	Quebec
Canada	Montreal General Hospital, McGill University Health Centre	Montreal	Quebec
Canada	Royal Victoria Hospital, McGill University Health Center	Montreal	Quebec
Canada	Lakeridge Health	Oshawa	Ontario
Canada	Ottawa Hospital - Civic Site	Ottawa	Ontario
Canada	Ottawa Hospital - General Hospital	Ottawa	Ontario
Canada	Hopital Laval	Quebec
Canada	Centre Hospitalier Affilie-Enfant Jesus	Quebec City	Quebec
Canada	Sherbrooke University (CHUS) Hospital	Sherbrooke	Quebec
Canada	Surry Memorial	Surrey	British Columbia
Canada	Mount Sinai Hospital	Toronto	Ontario
Canada	St Michaels Hospital	Toronto	Ontario
Canada	Sunnybrook and Women's College Health Science Centre	Toronto	Ontario
Canada	Toronto General Hospital	Toronto	Ontario
Canada	University Health Network - Toronto Western Hospital	Toronto	Ontario
Canada	Royal Columbian Hospital	Vancouver	British Columbia
Canada	St Paul's Hospital	Vancouver	British Columbia
Canada	Vancouver General Hospital	Vancouver	British Columbia
Canada	Vancouver Island Health Authority	Victoria	British Columbia
Canada	St. Boniface Hospital	Winnipeg	Manitoba
Saudi Arabia	King Abdulaziz University Hospital	Jeddah
Saudi Arabia	King Faisal Specialist & Research Center	Jeddah
Saudi Arabia	King Abdulaziz Medical City Hospital	Riyadh	Riyahd
Saudi Arabia	King Fahad Medical City	Riyadh
Saudi Arabia	Riyadh Military Hospital	Riyadh
United Kingdom	Guys and St Thomas Hospital	London	England
United States	MD Anderson	Houston	Texas
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Mayo Clinic	Rochester	Minnesota
United States	St. John's Mercy Medical Center	St. Louis	Missouri

Sponsors (4)

Lead Sponsor	Collaborator
McMaster University	Australian and New Zealand Intensive Care Society Clinical Trials Group, Canadian Critical Care Trials Group, Canadian Institutes of Health Research (CIHR)

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Canada,  Saudi Arabia,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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