PROphylaxis for ThromboEmbolism in Critical Care Trial (PROTECT)

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.

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
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
12. Contamination (e.g., >/= 3 doses of LMWH during this ICU admission)

13. Lack of informed consent