Prophylaxis of Thromboembolism in Critical Care (PROTECT)Trial:

a pilot study Deborah J. Cook MDa,b,*, Graeme Rocker MDc,

Maureen Meade MDa,b, Gordon Guyatt MDa,b, William Geerts
MDd, David Anderson MDc, Yoanna Skrobik MDe, Paul Hebert MDf,
Martin Albert MDe, Jamie Cooper MDg, Shannon Bates MDa,
Christopher Caco MDa, Simon Finfer MDh, Robert Fowler MDd,
Andreas Freitag MDa, John Granton MDd, Graham Jones MDa,
Stephan Langevin MDi, Sangeeta Mehta MDd, Giuseppe
Pagliarello MDf, Germain Poirier MDj, Christian Rabbat MDa, David
Schiff MDk, Lauren Griffith MDb, Mark Crowther MDa, for the
PROTECT Investigators and the Canadian Critical Care Trials Group
A Department of Medicine, McMaster University, Hamilton,
Ontario, Canada L8N 3Z5b Department of Clinical Epidemiology &
Biostatistics, McMaster University, Hamilton, Ontario, Canada L8N
3Z5c Department of Medicine, Dalhousie University, Halifax, Nova
Scotia, Canada B3H 3A7 d Department of Medicine, University of
Toronto, Toronto, Ontario, Canada M4N 3M5 eDepartment of
Medicine, Universite de Montreal, Montreal, Quebec, Canada H3C
3J7 fDepartment of Critical Care, University of Ottawa, Ottawa,
Ontario, Canada K1Y 4E9 gDepartment of Medicine and Surgery,
Monash University, Melbourne, Victoria, 3800 Australia hIntensive
Therapy Unit, University of Sydney, Sydney, NSW 2006 Australia
iDepartment of Medicine, University of Sheerbrooke, Quebec City,
Quebec, Canada J1K 2R1 jCharles LeMoyne Hospital, Greenfield
Park, Quebec, Canada J4V 2H1 kDepartment of Radiology,
McMaster University, Hamilton, Ontario, Canada L8N 3Z5
Received 1 August 2005; revised 31 August 2005; accepted 8
September 2005
Abstract
Purpose: There is no randomized trial comparing lowmolecular
weight heparin (LMWH) and unfractionated heparin (UFH) for
thromboprophylaxis in medical-surgical ICU patients. The primary
objective of this randomized pilot study on LMWH vs UFH was to
assess the feasibility of conducting a large randomized trial with
respect to timely enrollment and blinded study drug
administration,
practicality of twice-weekly lower limb ultrasounds to screen for
deep venous thrombosis, LMWH bioaccumulation and dose
adjustment in renal insufficiency, and recruitment rates for a
future trial in medical-surgical intensive care unit (ICU) patients.
Its additional goals were to evaluate the suitability of 0883-9441/$
see front matter D 2005 Elsevier Inc. All rights
reserved.doi:10.1016/j.jcrc.2005.09.010
4 Corresponding author. Departments of Medicine and
Epidemiology and Biostatistics, McMaster University Health
Sciences Center, Hamilton, Ontario,
Canada L8N 3Z5. Tel.: +1 905 525 9140x22900; fax: +1 905 524
3841.
E-mail address: debcook@mcmaster.ca (D.J. Cook).
Keywords:
Low molecular weight heparin; Unfractionated heparin;
Thrombopro phylaxis;
Deep venous thrombosis Journal of Critical Care (2005) 20, 364
372
the exclusion criteria and to document the range of research
activities that precede accrual of patients into a trial to plan
multisite management.
Materials and Methods: By computerized telephone
randomization, we allocated 129 medical-surgical ICU patients to
treatment with dalteparin 5000 IU QD SC or that with UFH 5000 IU
BID SC. Within each clinical center, only the study pharmacist was
not blinded. We performed bilateral lower limb compression
ultrasounds within 48 hours of ICU admission, twice weekly, on
suspicion of deep venous thrombosis, and 7 days after ICU
discharge. Research coordinators and investigators at 7 centers
reported the time they engaged in all research activities before
the first patient was randomized.
Results: Timely complete study drug administration occurred after
enrollment. More than 99% of scheduled doses were administered
in a blinded fashion. Scheduled ultrasounds were performed
without exception. No bioaccumulation of dalteparin was
observed when creatinine clearance decreased to lower than 30
mL/min. Average recruitment was 2 patients/center per month
before the study exclusion criteria were modified. Study startup
activities required, on average, 65.5 hours of combined
investigator and research coordinator time at each center. Careful
examination of the accrual in the pilot study led to a
reexamination of the Prophylaxis of Thromboembolism in Critical
Care Trial (PROTECT) study exclusion criteria.
Conclusions: This pilot study suggests that a multicenter
randomized clinical trial comparing LMWH with UFH in critically ill
medical-surgical patients is feasible. Pilot studies can improve the
design of larger trials and may enhance successful timely
completion. D 2005 Elsevier Inc. All rights reserved.
1. Introduction
In this article, we describe the Prophylaxis of Thromboembolism in
Critical Care Trial (PROTECT) Pilot Study. The PROTECT was
designed as part of a multifaceted research program on venous
thromboembolism (VTE) in medical-surgical critically ill patients
(Fig. 1). To date, only 2 randomized trials on thromboprophylaxis
in critically ill medical-surgical patients have been published
[1,2]. One blinded trial allocated 199 medical-surgical ICU
patients to subcutaneous unfractionated heparin (UFH) 5000 IU
BID or to placebo injections [1]. Using serial fibrinogen lower limb
scanning for 5 days, the researchers
found the rates of deep venous thrombosis (DVT) to be 13% in the
UFH group and 29% in the placebo group (relative risk reduction, .
65; P b .05). Rates of bleeding,
pulmonary embolus (PE), and mortality were not reported. The
second study was a multicenter trial in which 223 patients with an
acute exacerbation of chronic
obstructive pulmonary disease requiring mechanical ventilation
for at least 2 days were randomized to the low molecular weight
heparin (LMWH) nadroparin (3800 anti- Xa U for 45-70 kg or 5700
anti-Xa U for 71-110 kg) once daily or to placebo [2]. Patients
were screened with weekly duplex ultrasounds. Venography was
attempted in all patients at 21 days or earlier if ultrasound results
were Fig. 1 The VTE in Medical-Surgical ICU Patients Research
Program. VETEC indicates Venous Thromboembolism in Critical
Care; CRIPTEC, Coagulation Risk Profiling for Thromboembolism in
Critical Care; BEHAVE, Behavioral Reinforcement of Heparin to
Avert Venous Emboli; BITEC, Burden of Illness: Thromboembolism
in Critical Care.
The Prophylaxis of Thromboembolism in Critical Care Trial 365
positive. The rate of DVT was 16% in the nadroparin group and
28% in the placebo group (relative risk reduction, .45; P b .05).
The investigators observed trends toward increased bleeding (25
vs 18 patients; P = .18) and major hemorrhage (6 vs 3 patients; P
= .28) in the patients receiving nadroparin. The frequency of PE
was not systematically evaluated; 8 patients in each group died
(P = .72). An extensive body of literature outside the ICU setting
and in critically ill subgroups such as trauma patients [3]
suggested that critically ill patients receiving LMWH will have a
lower risk of venous thrombosis than similar patients
receiving UFH prophylaxis. These 2 types of heparin have not
been directly compared in critically ill medical-surgical ICU
patients. Extrapolating from randomized trials in other high-risk
groups, LMWH may be more effective than UFH.However, because
it is more potent, LMWH may bioaccumulate at high doses and
cause more bleeding thanUFH. Furthermore, it is more expensive
than UFH. As a result, uncertainty [4], equipoise [5], and
international practice variation [6] exist regarding which heparin
to use for thromboprophylaxis in medical-surgical ICU patients.
Only a rigorous and adequately powered randomized trial will
resolve this issue.The PROTECT will be a large randomized,
stratified, blinded, multicenter trial in medical-surgical ICU
patients comparing UFH with LMWH for the prevention of DVT. The
scientific objectives of the PROTECT will be to evaluate the effect
of LMWH as compared with that of UFH on the primary outcome of
lower limb DVT and the secondary outcomes of PE, bleeding, and
heparininduced thrombocytopenia (HIT). To optimally preparefor
PROTECT, we conducted the PROTECT Pilot Study to test several
implementation strategies. In this article, we address 3 overall
goals of this pilot study and report the lessons learned from each
preparatory component of the study.
2. Objectives
2.1. Measurement of protocol adherence and recruitment
The 5 feasibility objectives of the PROTECT Pilot Study were to
assess the following: (1) timely enrollment; (2) complete, blinded
study drug administration; (3) compliance with twice-weekly
lower limb ultrasounds; (4) LMWH bioaccumulation and possible
dose adjustment in renal insufficiency; and (5) recruitment rates
for a future trial.
2.2. Evaluation of eligibility
After completion of the PROTECT Pilot, a secondary objective was
to reexamine the need for, and consequences of, conservative
exclusion criteria on recruitment.
2.3. Assessment of workload before protocol implementation
Beyond the immediate feasibility objectives of the PROTECT Pilot
Study, a tertiary objective was to document the range of research
activities that precede accrual of patients into a multicenter trial.
3. Methods
3.1. Description of pilot study
In this concealed and blinded multicenter randomized pilot trial in
16 closed university-affiliated ICUs (14 in Canada and 2 in
Australia), we included patients aged 18 years or older with an
expected ICU stay of 72 hours or longer. We excluded patients
admitted to the ICU following trauma, orthopedic, cardiac, or
neurosurgery; those with severe hypertension, DVT, PE, or
hemorrhage within 3 months; those with an international
normalized ratio greater than 2 times the upper limit of normal
(2_ ULN), partial thromboplastin time greater than 2_ ULN, or a
platelet count of less than 100 _ 109/L; those with an estimated
creatinine clearance of lower than 30 mL/min [7]; those requiring
therapeutic anticoagulation; those who had received more than 2
doses of heparin in the ICU; and those with a contraindication to
heparin or blood products. Patients underwent centralized
telephone randomization to receive either dalteparin 5000 IU QD
and placebo QD SC or UFH 5000 IU BID SC to conceal allocation.
We stratified patients by center and by medical vs surgical
admission status because surgical ICU patients may have a higher
risk of VTE than medical patients. Moreover, our Canadian cross-
sectional study showed differences in UFH prophylaxis prescribing
between medical and surgical patients in that 1 to 2 doses of
heparin were often deferred or omitted immediately
postoperatively when patients were still mechanically ventilated
[8]. In addition, surgical patients who have an epidural catheter
may have been withheld of the study drug out of concern about
epidural bleeding associated with LMWH at the time of catheter
removal. Patients, families, ICU staff, ultrasound technologists,
and research personnel were all blinded to drug allocation. The
study pharmacist at each center was the only person who was not
blinded. Trough anti-Xa levels were sampled from all patients
whose calculated creatinine clearance declined to lower than 30
mL/min. Peak and trough anti- Xa levels were drawn every
Tuesday and Thursday regardless of serum creatinine level in 5
centers participatingin an anti-Xa screening substudy, and anti-Xa
levelswere also drawn if patients had a bleeding event.
Mechanical thromboprophylaxes (antiembolic stockings and
pneumatic compression devices) were not used except in the
setting of prespecified conditions (severe thrombocytopenia
366 D.J. Cook et al.
[platelet count, V50 _ 109/L]), coagulopathy [international
normalized ratio of N2_ ULN or partial thromboplastin time of N2_
ULN], bleeding, and suspected or serologically proven [by
serotonin release assay] HIT [9]). We disallowed mechanical
thromboprophylaxis under other circumstances because no
randomized trial has been performed in the ICU, published studies
are of poor quality [10], standards for appropriate fitting and
methods to monitor compliance do not exist, and use of
mechanical thromboprophylaxis is uncommon in Canada [5,6,8].
Patients who developed suspected or serologically proven HIT had
the study drug discontinued, all other heparin exposures were
stopped, and danaparoid sodium or
argatroban was administered. To diagnose proximal DVT, we
performed bilateral lower limb venous compression ultrasounds
within 48 hours of each patients enrollment, twice weekly, on
suspicion of DVT, and 7 days after ICU discharge to diagnose
proximal DVT. This required noncompressibility of one or more
deep venous segments during ultrasound examination at 6
conventional sites: (1) the trifurcation of the deep calf veins; (2)
distal popliteal; (3) proximal popliteal; (4) distal superficial
femoral; (5) mid superficial femoral; and (6) common femoral. To
ensure a standardized approach, we developed an operations
manual and conducted an ultrasound reliability study in one
center, documenting excellent agreement between 2
ultrasonographers blinded to each others reading. Suspected PE
was evaluated with a protocol including bilateral lower limb
ultrasound if this had not been performed already and computed
tomographic angiogram in patients without any contraindication
to intravenous contrast or transport to the radiology suite.
Pulmonary embolus was diagnosed in the presence of an
intraluminal filling defect in the main, lobar, or segmental
branches of a pulmonary artery. Nondiagnostic computed
tomographic angiogram required one or more of the
following: a ventilation-perfusion lung scan in patients with
normal chest x-ray, serial compression ultrasound, or pulmonary
angiography findings, depending on the specific situation.
Bleeding was defined as major or minor as per the participating
center. In addition, all VTE and bleeding outcomes were
adjudicated blinded to study medication using prespecified
criteria. By design, the PROTECT Pilot Study was not powered to
determine the relative benefit of LMWH vs UFH on the
development of DVT. This important scientific question will be
answered by the larger multicenter trial. We designed this pilot
study on 120 patients to estimate the proportion of patients who
would meet our feasibility criteria using confidence intervals. For
example, if 110 of the 120 patients received every dose of their
study drug, then the estimated rate would be 91.7% (95%
confidence interval, 85.2%- 95.9%). We also considered it
imperative to conduct a multicenter rather than a single-center
pilot trial. Based on our experience with prior studies conducted
through the Canadian Critical Care Trials Group [11], we projected
that an enrollment of 120 patients and a minimum recruitment of
3 patients in each center would be sufficient to streamline
screening and consent procedures, to refine protocol adherence
and data collection methods, and to maximize the chance of
identifying unforeseen barriers to the conduct of a larger trial
across multiple centers. We conducted an intention-to-treat
analysis maintaining the blinded
group allocation.
3.1.1. Measurement of protocol adherence and recruitment
A priori, we specified that the 5 feasibility objectives for the
PROTECT Pilot Study would be considered successful if all of the
following were met:
1. 115 of the 120 (98.5%) patients received the study drug within
12 hours of randomization;
2. 110 of the 120 (91.7%) patients received every scheduled dose
of the study drug in a blinded manner;
3. 110 of the 120 (91.7%) patients had lower limb compression
ultrasounds within 48 hours of ICU admission, 110 of the 120
(91.7%) patients had Monday and Thursday ultrasounds within 24
hours, and 90% or more of all surviving patients had a postICU
discharge ultrasound within 7 to 10 days;
4.more than 90% of necessary dose adjustments were made
appropriately in response to anti-Xa levels; and
5. 2 patients per month, on average, were randomized in each
participating center.
3.1.2. Evaluation of eligibility
To reevaluate the exclusion criteria for the PROTECT Pilot, we
reviewed the first 9 months of screening. Over this period, we
randomized 86 patients and excluded 575 patients. The most
frequent reasons for exclusion from the PROTECT
Pilot Study were the following: (1) creatinine clearance of lower
than 30 mL/min (n = 193; 33.6% of reasons); (2) therapeutic
anticoagulation (n = 123; 21.4%); (3) hemorrhage on ICU
admission (n = 119; 20.7%); (4) platelet count of less than
100_109/L (n = 122; 21.2%); (5) coagulopathy (n = 71; 12.3%);
and (6) more than 2 doses of heparin in the ICU (n = 62; 10.8%).
We then reevaluated the exclusion criteria and delineated those
criteria that could be modified to maximize enrollment and the
generalizability of the results.
3.1.3. Assessment of workload before protocol implementation
To document all research activities in the participating centers
before recruitment, pairs of one research coordinator and the
investigator at the 7 participating centers retrospectively reported
their activities related to the startup of the pilot from the time of
protocol receipt until the commencement of screening. Each pair
reported startup activities independent from other pairs. These
activities were classified into 8 categories that we established
previously [12]: reviewing the protocol; individualizing the
protocol to The Prophylaxis of Thromboembolism in Critical Care
Trial 367 each research ethics board (REB) specification; adapting
consent forms to each institution; having meetings and
correspondence with relevant disciplines on logistics; procuring
REB signature; responding (written) to scientific and ethical REB
comments; having in-services; and holding other activities.
3.2. Research ethics
The PROTECT Pilot Study received REB approval from all
participating centers. We obtained written informed consent from
patients next of kin. The PROTECT Pilot was funded by a peer
reviewgranting agency, the Canadian Institutes of Health
Research (200202MCT-98778), which had no influence on the
design, conduct, analysis, interpretation, and write-up of the
study.
4. Results
We randomized 129 patients to test trial procedures fully in each
center. The mean age of the randomized patients was 59.7 (SD,
14.8) years, with an APACHE II score of 20.9 (SD, 7.3); 42.2% were
female; and 67.2% were medical patients. Of the cohort, 6
patients (4.7%) had a previous malignancy, 19 (14.8%) had an
active malignancy, and, because 1 patient had both a history of
malignancy and an additional active malignancy, 24 (18.75%)
patients had malignancy overall. In addition, 108 patients (84.4%)
required mechanical ventilation and 56 (43.8%) required
inotropes or vasopressors. The baseline characteristics were
comparable between groups. In this pilot study, the primary and
secondary outcomes were analyzed on the entire cohort of
enrolled patients rather than according to the 2 treatment groups.
We found that 11 (8.6%) patients had a lower limb DVT.
Secondary outcome results were as follows: 2 (1.6%) patients had
a PE, 6 (4.7%) had clinically important bleeds, 23 (18%) had
minor bleeds, 4 (3.1%) had at least one platelet count of less than
50 _ 109/L, and 2 (1.6%) had a positive HIT test by serotonin
release assay, 1 of whom had a bilateral DVT from the trifurcation
extending distally.
4.1. Measurement of protocol adherence and recruitment
1. Timely drug administration occurred for all patients within 12
hours of their randomization.
2. Complete study drug administration occurred for 97.8% of
scheduled doses. Every dose of study medication was blinded, as
reported by each center. However, in one center in which 2
patients were randomized the same day, the study pharmacist
reported that study medication was switched in error for 24 hours.
3. The first ultrasound was performed within 48 hours of
enrollment for 98.4% of the patients; subsequent ultrasounds
occurred as scheduled without exception.
4. We did not observe bioaccumulation of heparin when
administered in prophylactic doses in these critically ill patients
with a range of renal dysfunction. In the 7 patients overall who
developed a creatinine clearance of lower than 30 mL/min, trough
anti-Xa levels were very low (0.1 IU/mL [interquartile range, b0.1-
0.1]). These results and data from the substudy patients [13]
contributing to anti-Xa levels (4-hour peak, trough, and in the
event of bleeding) are presented in Table 1. Only one dose
adjustment was necessary according to an anti-Xa level done in a
center participating in the substudy of anti-Xa level screening.
The peak anti- Xa level of 0.51 IU/mL occurred on study day 2 in a
patient weighing 40 kg who had not developed a creatinine
clearance of lower than 30 mL/min. The subsequent dose was
changed from 5000 to 2500 IU for remaining doses; the patient
was transferred to another institution on study day 4 and study
medication was discontinued. This led us to plan to include
patients weighing 45 kg or heavier in the Table 1 Anti-Xa level
results Allocation Trough levels in patients with creatinine
clearance V30 mL/min Trough levels in all patients on Tuesdays
and Thursdays Peak levels in all patients on Tuesdays and
Thursdays Bleeding levels in patients at the time of bleeding
events Group A [median (interquartile range); IU/mL] Eight tests
in 2 patients Seventeen tests in 9 patients
Seventeen tests in
9 patients
Seven tests in
4 patients
0.1 (b0.1-0.1) b0.1 (b0.1-0.13) 0.11 (b0.1-0.27) 0.1 (b0.1-0.29)
Group B [median
(interquartile range); IU/mL]
Twenty-three tests in
5 patients
Forty-six tests in
12 patients
Forty-six tests in
12 patients
Ten tests in
8 patients
b0.1 (b0.1-0.1) b0.1 (b0.1-0.1) b0.1 (b0.1-0.1) b0.1 (b0.1-0.1)
Shown are the anti-Xa levels for patients undergoing anti-Xa
testing for 4 reasons in a small substudy of the PROTECT Pilot.
Trough anti-Xa levels in this
range of 0.1 IU/mL are very low, indicating no evidence of
bioaccumulation. Peak Anti-Xa levels in the range of 0.2 to 0.3
IU/mL are in the usual
prophylactic range, approximately 4 hours postinjection; these
results do not indicate excessive anticoagulant effects in either
group. Overall, we found no
difference between the UFH and LMWH groups (results remain
blinded).
368 D.J. Cook et al.
larger trial, as is customary in many thromboprophylaxis
trials.
5. Projected recruitment for the future PROTECT is
at least 2 patients/center per month and likely 3 to
4 patients per month after modifying 3 exclusion
criteria [14,15] as described in the succeeding
subsection.
4.2. Evaluation of eligibility
To address impediments to recruitment, we modified
3 criteria for the large trial: creatinine clearance of lower
than 30 mL/min, platelet count of less than 100 _ 109/L,
and more than 2 doses of previous heparin. To clarify
whether it was necessary to exclude ICU patients from the
PROTECT based on low creatinine clearance, we began a
second pilot study to determine whether bioaccumulation of
LMWH occurs in patients with renal insufficiency receiving
low-dose thromboprophylaxis (Dalteparins Influence on
Renal Insufficiency in Critical Care Trial [DIRECT]). The
main concern about bioaccumulation of LMWH in patients
with renal failure is among those who receive therapeutic,
not prophylactic, doses. If bioaccumulation does not occur,
we will enroll patients in the PROTECT with a creatinine
clearance of lower than 30 mL/min. Second, after informal
consultation with the Canadian Critical Care Trials Group
community, we reduced the exclusion for low platelet
counts to less than 75 _ 109/L. Third, we are planning to
recruit patients on weekends using an on-call system for
research coordinators because 52% of patients excluded for
reasons of prior heparin administration were identified on a
Monday morning. We anticipate that these 3 modifications
to the pilot study exclusion criteria will increase monthly
accrual in the future PROTECT 2-fold to 3-fold [16].
4.3. Assessment of workload before protocol
implementation
We identified a range of generic and site-specific activities
to help operationalize the PROTECT Pilot protocol
before the accrual of patients. These data are reported as the
median hours per center (Table 2). Before screening
patients for potential recruitment, we found that a mean
of 65.6 hours per center was spent in these 7 centers.
Research coordinators accounted for 70% of these
prerandomization
activities; site investigators, for 30%. Translating
REB applications and consent forms into French
resulted in a small increase in unanticipated workload [17].
5. Discussion
We designed the PROTECT Pilot Study with specific
feasibility objectives to replicate most, if not all, aspects of
the future trial across multiple sites. We conclude that a
randomized clinical trial comparing the efficacy of LMWH
with that of UFH for VTE prevention in medical-surgical
ICU patients is feasible. The proximal DVT rates remained
high in these medical-surgical ICU patients despite
universal heparin thromboprophylaxis, underscoring the
need for further research to guide improvements in
thromboprophylaxis for critically ill patients.
The first goal of the PROTECT Pilot Study was to
evaluate our 4 specific feasibility objectives. Had delayed or
missed drug administration occurred often, we would have
had to analyze the process involving the study pharmacist,
ICU pharmacist, bedside ICU nurse, and ICU team and then
modify our approach accordingly. If centers had been unable
to conduct ultrasound evaluations, then fewer events would
be detected over the course of the trial, increasing the risk
that the larger trial would be underpowered. Had there been
inattention to anti-Xa levels and dose adjustments, we
would have analyzed and improved the drug delivery
system to ensure its safety. Had we not recorded a
conservative recruitment rate through careful documenting
of screening efforts in relation to recruitment [18] in this
multicenter pilot study, we may have fallen into the common
trap of overestimating patient accrual, thereby risking trial
fatigue, and the threat of inappropriate early stopping [19].
Although safety issues must remain paramount in
practice and clinical research, common overstringent exclusion
criteria may increase perceived trial safety yet limit the
generalizability of trial results and delay answers to
Table 2 Prerandomization activities
Site A Site B Site C Site D Site E Site F Site G Median (interquartile
range) hours Range
Protocol review 9 12 51 6 7 8 18 9 (7-18) 6-51
REB preparation 9 9 27 3 1 9 7 9 (3-9) 1-27
Consent adaptation 5 5 1 6 11 4.5 3 5 (3-6) 1-11
Meetings 23 19 17 10 4 16 14 16 (10-19) 4-23
Signatures 7 1 1 1 2 2 1.5 1.5 (1-2) 1-7
REB responses 10.5 3 2 4 6 5 1 4 (2-6) 1-10.5
In-services 19.5 5 2 4 6 11 24 6 (4-19.5) 2-24
Others 13 6 2 2 6 0 1.5 2 (1.5-6) 0-13
Total time 96 60 103 36 43 55.5 70 36-103
Total = 463.5 h (mean 66.2 h/site)
Shown are the types of research activities engaged in by research
coordinators and investigators before patients were randomized
in the PROTECT Pilot.
The Prophylaxis of Thromboembolism in Critical Care Trial 369
important clinical questions. Reevaluation of the PROTECT
Pilot exclusion criteria will facilitate timely completion and
enhance the applicability of the larger PROTECT study in
several ways. The PROTECT Pilot indicated the need for
another pilot study (DIRECT) to determine the safety of
dalteparin 5000 IU SC OD among patients with severe renal
insufficiency (creatinine clearance, b30 mL/min). We
assessed this by measuring the proportion of patients with
trough anti-Xa levels greater than 0.40 IU/mL after 3 F 1,
10 F 1, and 17 F 1 days of dalteparin prophylaxis treatment
and by estimating the risk of major bleeding during the
treatment period. We considered DIRECT to be a valuable
contribution to the literature because experts recommend
anti-Xa level measurement when patients with renal
insufficiency receive treatment doses of LMWH [20], and
our observations do not suggest that this is necessary for
prophylactic doses of LMWH. Furthermore, our systematic
review of observational studies on LMWH thromboprophylaxis
in nonICU patients with dialysis-independent
renal insufficiency showed that evidence supporting the
need to monitor anti-Xa levels at a creatinine clearance of
30 mL/min or lower is neither strong nor consistent [21].
Reexamination of the PROTECT Pilot Study exclusion
criteria underscores the importance of unhurried, careful
planning before embarking on a large multicenter trial so
that the ultimate study enrolls the most broadly suitable type
of patients.
Attention to detail of the research administration during
the PROTECT Pilot provided several useful findings:
foremost was the diverse range of time and costconsuming
activities necessary before starting to recruit
patients into this trial. Documenting prerandomization
research activity can help plan project timelines, justify
costs incurred for prerecruitment activities, and identify
where such funding should be allocated. Strengths of the
approach to examining prerandomization activities were
the documentation of a full range of research activities and
independent blinded data collection methods in geographically
diverse centers. We subsequently presented our data
on prerandomization activities for the PROTECT Pilot in
the grant application for the future PROTECT. However,
these activities were retrospectively self-reported and
unverified, thus subject to random error and recall bias.
Our data reflect the activities of only one pilot trial;
however, we hope that the methods may serve as a template
for analyzing other pilot studies with different designs in
other settings [22].
The term pilot study is an informal term describing an
investigation that serves to prepare for future clinical [23] or
economic [24] studies. Pilot studies can be distinguished
from pilot work in that the latter type is less likely to be
standardized (ie, protocol) and less likely to lead to
generalizable, published knowledge. Examples of pilot, or
preparatory, work include reliability testing of survey
instruments, focus groups to generate potential end points
in long-term outcome studies, and refinement of complex
interventions in preparation for randomized trials. Examples
of pilot studies are investigations testing hypotheses about
mechanisms of action [25], surveys of stated practice [26],
chart reviews to estimate the burden of illness of a target
condition [27], prospective observational studies to estimate
expected event rates [28], a series of multicenter observational
studies [23] to inform the design of a large
randomized trial, systematic reviews of prior randomized
trials to estimate relative risk reductions [29], and more
useful multicenter randomized trials with specific feasibility
objectives to replicate most, if not all, aspects of the future
trial across several sites.
The objectives of pilot studies vary widely, in keeping
with their diverse designs. Examples of pilot study
objectives are to estimate the safety of LMWH for stroke
patients [30], to document the diagnostic accuracy of
myocardial infarction for prehospital thrombolysis [31],
and to learn about end-of-life informational needs and
decision-making preferences through interviewing elderly
acutely ill hospitalized patients [32]. To test the feasibility
of rapid enrollment, recruitment efficiency, and 6-month
retention, the CRASH investigators randomized 1000
patients in 52 emergency departments in 14 hospitals to
thoroughly test their international emergency medicine
megatrial protocol [33]. Pilot studies may promote clinical
research ethics by maximizing the chance that future studies
are designed rigorously, conducted safely and efficiently,
and completed as planned.
We conclude that pilot studies with explicit feasibility
objectives and a priori success criteria are important
foundation steps in preparing for large trials [23],
for megatrials [33,34], and for research programs [35].
Ongoing formal review of the multifaceted issues inherent
in the design and conduct of pilot studies can
provide invaluable feasibility and scientific data for
clinical trialists. We endorse completion of comprehensive
pilot studies in preparation for multicenter randomized
trials, particularly in light of the large number of
international peer review ICU collaborations planned in
the future [36,37].
Acknowledgments
This trial was funded by the Canadian Institutes for
Health Research (Ottawa, Ontario) and the Father Sean
OSullivan Research Center (Hamilton, Ontario). Study
medication was provided by Pharmacia, which played no
role in the design, conduct, analysis, or interpretation of
the results.
We are grateful to the expert PROTECT Pilot Study
research associates and Canadian Critical Care Trials Group
for their key role in this work. We thank Nicole Zytaruk for
her expert coordination of this study. We also thank John
Marshall, Kang-Hoe Lee, and Fun-Gee Chen for discussions
370 D.J. Cook et al.
about this pilot trial. D. Cook is the research chair of the
Canadian Institutes for Health Research; M. Meade, an
investigator of the Canadian Institutes for Health Research;
M. Crowther, a career investigator of the Heart and Stroke
Foundation of Ontario.
Appendix A
PROTECT Writing Committee: Deborah Cook,
Graeme Rocker, Maureen Meade, Jamie Cooper, Yoanna
Skrobik, Paul Hebert, and Martin Albert.
PROTECT Pilot Research Coordinators and Investigators:
Carlos Martinez and Sangeeta Mehta (Mount Sinai
Hospital, Toronto, Ontario); Andrea Matte-Martyn, Marilyn
Steinberg, Patrice Bret, Stephanie Wilson, and John Granton
(University Health Network, General Site, Toronto, Ontario);
Michelle Kho, Christine Wynne, Mark Duffett, Christopher
Caco, and Andreas Freitag (Hamilton Health Sciences-
McMaster University Medical Center, Hamilton, Ontario);
Ellen McDonald, Terry Minuk, and Graham Jones (Hamilton
Health Sciences-Henderson General Hospital, Hamilton,
Ontario); Ellen McDonald, France Clarke, David Schiff,
and Deborah Cook (St. Josephs Healthcare, Hamilton,
Ontario); Julia Gibson, Ian Doris, and Maureen Meade
(Hamilton Health Sciences-Hamilton General Hospital,
Hamilton, Ontario); Andrea McNeil, Susan Pleasance,
Derrick McPhee, and Graeme Rocker (Queen Elizabeth
Health Sciences Center, Halifax, Nova Scotia); Craig Dale,
Mel Keogh, Alan Moody, and Robert Fowler (Sunnybrook
and Womens Hospital); Johanne Harvey, Michel Dube,
Gaetan Barrette, Martine LeBlanc, and Yoanna Skrobik
(Maissoneuve Rosemont, Montreal, Quebec); Louise Provost,
Sylvie Groleau, and Germain Poirier (Charles
LeMoyne, Montreal, Quebec); Anik Rioux, Genevieve
Larouche, Jean-Marc Turcotte, Francois LeBlanc, and
Stephan Langevin (LEnfant Jesus, Quebec City, Quebec);
Carson Davidson, Irene Watpool, Tracy McArdle, and Paul
Hebert (Ottawa Hospital General Site, Ottawa, Ontario);
Mary-Jo Lewis, Julia Foxall, Bernard Lewandowski, and
Giuseppe Pagliarello (Ottawa Hospital Civic Site, Ottawa,
Ontario); Carole Sirois, Carole Nadon, Maria Danet, and
Martin Albert (Hopital Sacre-Coeur, Montreal, Quebec);
Catherine Harry, Kathryn Moulden, Samantha Ellis, and
Jamie Cooper (Alfred Hospital, Melbourne Australia); and
Julie Potter, Anne OConnor, Naresh Ramakrishnan, Charles
Fisher, Christopher Ward, and Simon Finfer (Royal North
Shore Hospital, Sydney, Australia).
PROTECT Methods Center: Nicole Zytaruk (Project
Coordinator), Suzanne Duchesne, Lauren Griffith, Christian
Rabbat, Shannon Bates, Diane Heels-Ansdell, and Stephen
Walter (McMaster University, Hamilton, Ontario).
PROTECT Pilot Steering Committee: Deborah Cook
(Principal Investigator), Mark Crowther, Maureen
Meade, Gordon Guyatt, and Lauren Griffith (McMaster
University, Hamilton, Ontario); David Anderson (Dalhousie
University, Halifax, Nova Scotia); and William Geerts
(University of Toronto, Toronto, Ontario).
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