Timing of Initial Administration of Low-Molecular-Weight Heparin Prophylaxis
Against Deep Vein Thrombosis in Patients Following Elective Hip Arthroplasty
A Systematic Review
Arch Intern Med. 2001;161:1952-1960
Author Information
<http://archinte.ama-assn.org/issues/v161n16/rfull/#aainfo> Russell D.
Hull, MBBS; Graham F. Pineo, MD; Paul D. Stein, MD; Andrew F. Mah, BSc;
Susan M. MacIsaac, MSc; Ola E. Dahl, MD, PhD; William A. Ghali, MD, MPH;
Matthew S. Butcher, BSc; Rollin F. Brant, PhD; David Bergqvist, MD, PhD;
Karly Hamulyák, MD; Charles W. Francis, MD; Victor J. Marder, MD; Gary E.
Raskob, PhD
Background Perioperative and postoperative venous thrombosis are common in
patients undergoing elective hip surgery. Prophylactic regimens include
subcutaneous low-molecular-weight heparin 12 hours or more before or after
surgery and oral anticoagulants. Recent clinical trials suggest that
low-molecular-weight heparin initiated in closer proximity to surgery is
more effective than the present clinical practice. We performed a systematic
review of the literature to assess the efficacy and safety of
low-molecular-weight heparin administered at different times in relation to
surgery vs oral anticoagulant prophylaxis.
Methods Reviewers (A.F.M. and S.M.M.) identified studies by searching
MEDLINE, reviewing references from retrieved articles, scanning abstracts
from conference proceedings, and contacting investigators and pharmaceutical
companies. Randomized trials comparing low-molecular-weight heparin
administered at different times relative to surgery with oral anticoagulants
in patients undergoing elective hip arthroplasty, evaluated using contrast
phlebography, were selected. Two reviewers (A.F.M. and S.M.M.) extracted
data independently.
Results The literature review identified 4 randomized trials meeting
predefined inclusion criteria. The results indicate that
low-molecular-weight heparin initiated in close proximity to surgery
resulted in absolute risk reductions of 11% to 13% for deep vein thrombosis,
corresponding to relative risk reductions of 43% to 55% compared with oral
anticoagulants. Low-molecular-weight heparin initiated 12 hours before
surgery or 12 to 24 hours postoperatively was not more effective than oral
anticoagulants. Low-molecular-weight heparin initiated postoperatively in
close proximity to surgery at half the usual dose was not associated with a
clinically or statistically significant increase in major bleeding rates (P
= .16).
Conclusions The timing of initiating low-molecular-weight heparin
significantly influences antithrombotic effectiveness. The practice of
delayed initiation of low-molecular-weight heparin prophylaxis results in
suboptimal antithrombotic effectiveness without a substantive safety
advantage.
Arch Intern Med. 2001;161:1952-1960
IRA10035
EPIDEMIOLOGIC DATA demonstrate that perioperative and postoperative venous
thrombosis are common in high-risk surgical patients. 1-5
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r1> In the absence of
thromboprophylaxis, this disorder occurs in 40% to 60% of patients
undergoing hip arthroplasty. 5
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r5> , 6
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r6> Prophylactic
regimens include warfarin and subcutaneous low-molecular-weight heparin. 5
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r5> , 6
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r6>
Oral anticoagulant prophylaxis is a common practice in the United States and
Canada for patients undergoing elective total hip replacement. The
requirement for laboratory monitoring to maintain a therapeutic
international normalized ratio has led investigators to search for
alternative therapies. Low-molecular-weight heparin prophylaxis is a
standard regimen in Europe and is widely accepted in the United States and
Canada. 5 <http://archinte.ama-assn.org/issues/v161n16/rfull/#r5> , 7-29
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r7>
Clinical practice differs in North America and Europe regarding the
initiation time of antithrombotic prophylaxis in surgical patients. In
Europe, low-molecular-weight heparin is usually initiated 12 hours
preoperatively. 8-11 <http://archinte.ama-assn.org/issues/v161n16/rfull/#r8>
, 13-16 <http://archinte.ama-assn.org/issues/v161n16/rfull/#r13> , 18
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r18> , 21-24
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r21> , 26-29
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r26> The European
approach recognizes that deep vein thrombosis typically originates
perioperatively and that preoperative prophylaxis may optimize
antithrombotic effectiveness. 30-32
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r30> Delayed initiation
(12-24 hours postoperatively) of low-molecular-weight heparin prophylaxis is
standard practice in North America to minimize bleeding risk. 7
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r7> , 12
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r12> , 17
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r17> , 19
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r19> , 20
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r20> , 33
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r33> This difference in
clinical practice has led to the expressed need (by the International
Consensus Statement) for a level 1 randomized trial evaluating the time of
initiation of low-molecular-weight heparin thromboprophylaxis. 6
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r6>
Low-molecular-weight heparin prophylaxis has been administered once daily in
patients undergoing elective hip surgery, except in the United States, where
the most common regimen has been twice daily. Clinical practice in the
United States reflects initial regulatory agencies approval of a twice-daily
low-molecular-weight heparin regimen. 7
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r7> , 12
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r12> , 20
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r20> Subsequently,
once-daily administration of low-molecular-weight heparin was approved
because similar outcomes were observed by direct comparison with the
twice-daily regimen in a double-blind randomized trial. 19
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r19>
It is possible that low-molecular-weight heparin administered in closer
proximity to surgery, either immediately preoperatively or early
postoperatively once daily, may be more effective than the present clinical
practice. This just-in-time concept harmonizes with the understanding that
the risk of thrombosis starts perioperatively. 30-32
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r30> Recently, 2
published studies evaluated low-molecular-weight heparin prophylaxis
administered either immediately preoperatively 25
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r25> , 34
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r34> or early
postoperatively 34 <http://archinte.ama-assn.org/issues/v161n16/rfull/#r34>
vs oral anticoagulant prophylaxis.
In light of these studies, we performed a systematic review of the
literature to assess the efficacy and safety of low-molecular-weight heparin
administered at different times in relation to surgery vs the classic
reference standard, oral anticoagulant prophylaxis.
MATERIALS AND METHODS
To ensure high methodologic quality, we adhered to the 15 criteria outlined
by McAlister et al. 35
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r35> The first 10
criteria assess methodologic rigor, and the last 5 assess the scientific
basis of treatment recommendations. 35
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r35> We systematically
identified articles for inclusion in this analysis, described variations in
study design and execution, evaluated study quality, 36
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r36> and quantified the
relative benefits of prophylaxis with low-molecular-weight heparin vs oral
anticoagulants with respect to preoperative and postoperative initiation
time in proximity to surgery. 37
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r37>
STUDY IDENTIFICATION
All published and unpublished randomized trials comparing prophylaxis using
low-molecular-weight heparin vs oral anticoagulants in patients undergoing
hip arthroplasty were identified. A strategy was developed for locating all
published studies in the MEDLINE database:
1. S1 keyword (kw) (LMWH or "low-molecular-weight heparin" or clexane
or clivarin or CY 216 or CY 222 or dalteparin or enoxaparin or fragmin or
fraxiparine or logiparin certoparin or nadroparin or parnaparin or reviparin
or tinzaparin) and kw (OAC or warfarin or coumadin).
2. S2 (S1 and kw prophylaxis).
3. S3 (S2 and kw hip).
4. S4 (S3 and kw (DVT or "deep-vein thrombosis" or "deep-venous
thrombosis" or "venous thromboembolism" or "proximal vein thrombosis")).
5. S5 (S4 and kw (randomized or randomised or randomly)).
6. S6 (S5 and kw (venograms or venography or phlebography)).
We augmented our MEDLINE search by manually reviewing the reference lists of
original articles and review articles. We also reviewed abstracts from
conference proceedings and contacted investigators and pharmaceutical
companies. Abstracts reporting full methods and results were eligible for
inclusion.
STUDY ELIGIBILITY
Two investigators (A.F.M. and S.M.M.) independently evaluated studies for
inclusion; disagreements were resolved by discussion. Investigators were not
blinded to journal, author, or institution. Studies were included if they
(1) enrolled patients undergoing elective hip arthroplasty, (2) randomly
assigned patients to treatment groups, (3) investigated the efficacy and
safety of once-daily subcutaneous low-molecular-weight heparin compared with
oral anticoagulants in the prevention of deep vein thrombosis, (4)
objectively documented the presence or absence of deep vein thrombosis and
proximal vein thrombosis by bilateral ascending contrast phlebography, and
(5) used objective methods for assessing major bleeding complications. Deep
vein thrombosis was defined as the presence of constant intraluminal filling
defects in the deep veins; and proximal vein thrombosis, as constant
intraluminal filling defects in the popliteal or more proximal deep veins.
Safety was evaluated by documenting the frequency of bleeding complications.
VARIATION IN STUDY DESIGN AND EXECUTION
Two investigators (A.F.M. and S.M.M.) collected data on the following
study-level factors: (1) type of low-molecular-weight heparin used, (2)
timing of administration of low-molecular-weight heparin before or after
surgery, (3) timing and adequacy of warfarin, (4) whether
low-molecular-weight heparin dosing was fixed or weight adjusted, (5)
whether a high-risk dose approved by regulatory agencies was used, and (6)
the interval after surgery when phlebography was performed.
OTHER SOURCES OF POTENTIAL VARIABILITY
Two investigators (A.F.M. and S.M.M.) collected data on other variables
potentially affecting study outcomes. These included patient characteristics
on enrollment into the study, primary or revision hip replacement,
anesthesia type (general and/or regional), and use of graduated pressure
stockings.
ASSESSMENT OF STUDY QUALITY
Four key issues were reviewed to assess the quality and strength of the
studies. They include (1) proper randomization derived from the use of a
randomized numbers table or a computer program; (2) masking of the
allocation sequences from the investigators, staff, and patients involved in
the study; (3) use of double blinding; and (4) determining the proportion of
patients who underwent successful phlebography. Two investigators (A.F.M.
and S.M.M.) extracted these data from the primary studies. When details were
not reported in the articles, additional information was requested from the
authors.
DATA EXTRACTION
Two investigators (A.F.M. and S.M.M.) independently extracted data on the
frequency of the major outcomes: (1) all deep vein thrombosis, (2) proximal
vein thrombosis, and (3) major bleeding complications as defined by the
investigators. 17 <http://archinte.ama-assn.org/issues/v161n16/rfull/#r17> ,
21 <http://archinte.ama-assn.org/issues/v161n16/rfull/#r21> , 25
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r25> , 34
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r34> Data for other
variables, such as minor bleeding, wound hematomas, and thrombocytopenia,
were also recorded. The selections of studies for inclusion in the analysis
by the 2 investigators were compared, and the percentage agreement and
kappacoefficient 38 <http://archinte.ama-assn.org/issues/v161n16/rfull/#r38>
between the 2 investigators were calculated. Investigator disagreements were
resolved by discussion.
DATA ANALYSIS AND STATISTICAL ANALYSIS
For each of the major outcomes in the individual studies, we calculated
absolute risk reduction, relative risk reduction, odds ratio, number needed
to treat to prevent one thromboembolic event, and number needed to harm to
cause one major bleeding event. We considered P<.05 to be statistically
significant for all statistical tests. P values, number needed to treat, and
number needed to harm are reported when the comparison is significant.
Analyses were performed using the Metan procedure 39
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r39> of Stata, release
6.0. To assess the validity of combining results from individual studies, we
used the Mantel-Haenszel test for statistical heterogeneity. 40
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r40> We did not perform
statistical analyses to pool results across studies because of heterogeneity
(see the "Interstudy Analysis" subsection of the "Results" section).
Funnel plots were examined to evaluate interstudy variation in odds ratios
for the 3 major outcomes in relation to sample size to assess the
possibility that publication bias might be a contributing factor. Logistic
regression methods were used in conjunction with analysis of deviance to
assess other potential sources of heterogeneity. Linear mixed-effects models
were applied to the variance-stabilized (arcsine-transformed) event rates to
test the effect of close proximity administration of prophylaxis on these
rates, and to the odds ratios to obtain the quadratic fit. By incorporating
oral anticoagulant group event rates as controls in this analysis, it was
possible to take into account the contribution of nonsystematic
between-study variation.
A secondary analysis was performed including the one study that used a
unilateral phlebogram; the effects of including the once-daily
low-molecular-weight group from this study on heterogeneity, funnel plots,
and logistic regression analysis were evaluated.
RESULTS
STUDY IDENTIFICATION AND SELECTION
Our MEDLINE and manual search strategies identified 149 potentially relevant
studies. One hundred forty-two of these articles were excluded after
reviewing their titles and abstracts: 62 were unrelated to
thromboprophylaxis in patients undergoing hip arthroplasty, 60 were reviews
or letters to the editor, 4 were surveys of physician practice, 9 were
cost-effectiveness analyses, 4 were meta-analyses, and 3 were not randomized
controlled trials. The remaining 7 articles were original studies of
low-molecular-weight heparin used for prophylaxis against deep vein
thrombosis in patients undergoing hip arthroplasty and were retained for
further evaluation.
Of these 7 articles, 3 were subsequently excluded from our analysis because
they did not meet the a priori eligibility criteria outlined in the "Study
Eligibility" subsection of the "Materials and Methods" section: one 41
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r41> did not use
phlebographic evidence of deep vein thrombosis as the end point, one 42
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r42> used unilateral
rather than bilateral phlebography and included a twice-daily administered
low-molecular-weight heparin group, and one 43
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r43> addressed the
postphlebographic outcome of patients for a trial already included in our
analysis. Interrater agreement for study eligibility was 100% (kappa = 1.0).
These articles were published between 1994 and 2000.
DESCRIPTION OF VARIATION IN STUDY METHODS
Table 1
<http://archinte.ama-assn.org/issues/v161n16/fig_tab/ira10035_t1.html>
displays study design characteristics and methodologic quality among the 4
included studies. The low-molecular-weight heparins evaluated were
tinzaparin sodium, 17
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r17> nadroparin
calcium, 21 <http://archinte.ama-assn.org/issues/v161n16/rfull/#r21> and
dalteparin sodium. 25
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r25> , 34
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r34> Initiation of
low-molecular-weight heparin prophylaxis was 18 to 24 hours postoperatively
in one study, 17 <http://archinte.ama-assn.org/issues/v161n16/rfull/#r17>
the evening of the preoperative day in one study, 21
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r21> and 2 hours
preoperatively in another study. 25
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r25> The remaining
study 34 <http://archinte.ama-assn.org/issues/v161n16/rfull/#r34> evaluated
separate randomized groups for preoperative (within 2 hours of surgery) and
postoperative (4-6 hours after surgery) low-molecular-weight heparin
initiation.
The specific doses used for each low-molecular-weight heparin evaluated were
the high-risk doses with demonstrated effectiveness in patients undergoing
elective hip arthroplasty and approved by regulatory agencies ( Table 1
<http://archinte.ama-assn.org/issues/v161n16/fig_tab/ira10035_t1.html> ).
For the 2 studies that initiated prophylaxis in close proximity to surgery,
the preoperative regimens initiated prophylaxis using a split dose (half the
usual high-risk dose given just before surgery and half given shortly after
surgery) 25 <http://archinte.ama-assn.org/issues/v161n16/rfull/#r25> , 34
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r34> and the
postoperative regimen initiated prophylaxis using half the usual high-risk
dose shortly after surgery. 34
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r34> Full high-risk
doses were resumed the day after surgery. Two studies 17
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r17> , 21
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r21> used
weight-adjusted doses of low-molecular-weight heparin, and 2 25
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r25> , 34
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r34> used fixed doses.
Initiation of oral anticoagulant prophylaxis in the control group occurred
the day before surgery in 2 studies 21
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r21> , 25
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r25> and on the evening
of the day of surgery in 2 studies 17
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r17> , 34
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r34> ( Table 1
<http://archinte.ama-assn.org/issues/v161n16/fig_tab/ira10035_t1.html> ). In
all studies, the oral anticoagulant dose was adjusted daily to maintain
equivalence with an international normalized ratio between 2.0 and 3.0. Each
study achieved therapeutic international normalized ratios in many patients:
76% by day 3 in one study, 17
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r17> 70% by day 4 in
another, 21 <http://archinte.ama-assn.org/issues/v161n16/rfull/#r21> 66% by
day 2 in a third, 25
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r25> and 86% by day 6
in the remaining study. 34
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r34> The day
phlebography was performed after surgery varied among the studies, ranging
from 5.7 34 <http://archinte.ama-assn.org/issues/v161n16/rfull/#r34> to 10
days 21 <http://archinte.ama-assn.org/issues/v161n16/rfull/#r21> ( Table 1
<http://archinte.ama-assn.org/issues/v161n16/fig_tab/ira10035_t1.html> ).
ASSESSMENT OF STUDY QUALITY
All studies used proper randomization techniques and objective methods for
the detection of deep vein thrombosis ( Table 1
<http://archinte.ama-assn.org/issues/v161n16/fig_tab/ira10035_t1.html> ).
Two studies 17 <http://archinte.ama-assn.org/issues/v161n16/rfull/#r17> , 34
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r34> were double
blinded, and 2 21 <http://archinte.ama-assn.org/issues/v161n16/rfull/#r21> ,
25 <http://archinte.ama-assn.org/issues/v161n16/rfull/#r25> were single
blinded. One single-blinded study 21
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r21> reviewed efficacy
and safety outcomes by a central adjudication committee that was unaware of
treatment allocation, the patients' clinical findings, or the results of
other diagnostic tests. The other single-blinded study 25
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r25> reviewed all lung
scans and pulmonary angiograms by an independent third-party evaluator who
did not have knowledge of the treatment group assignment. The proportion of
patients undergoing successful phlebography is reported in Table 1
<http://archinte.ama-assn.org/issues/v161n16/fig_tab/ira10035_t1.html> . A
summary of clinical characteristics of the patient populations is reported
in Table 2
<http://archinte.ama-assn.org/issues/v161n16/fig_tab/ira10035_t2.html> .
DATA ANALYSIS
Individual study findings for all and proximal deep vein thrombosis are
shown in Table 3
<http://archinte.ama-assn.org/issues/v161n16/fig_tab/ira10035_t3.html> and
in Figure 1
<http://archinte.ama-assn.org/issues/v161n16/fig_tab/ira10035_f1.html> and
Figure 2
<http://archinte.ama-assn.org/issues/v161n16/fig_tab/ira10035_f2.html> . The
effect of the time from surgery when prophylaxis was initiated on the rate
of deep vein thrombosis for the low-molecular-weight heparin groups from
each study is shown in Figure 3
<http://archinte.ama-assn.org/issues/v161n16/fig_tab/ira10035_f3.html> . A
large absolute risk reduction was observed in the 2 trials 25
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r25> , 34
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r34> initiating
low-molecular-weight heparin at half the usual high-risk dose in close
proximity to surgery. These close-proximity regimens administered
prophylaxis less than 2 hours before surgery 25
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r25> , 34
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r34> or 4 to 6 hours
after surgery. 34 <http://archinte.ama-assn.org/issues/v161n16/rfull/#r34>
This large absolute risk reduction was not observed in patients receiving
low-molecular-weight heparin administered using the conventional timing of
12 to 24 hours before surgery 21
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r21> or 18 to 24 hours
after surgery. 17 <http://archinte.ama-assn.org/issues/v161n16/rfull/#r17>
Individual study findings for major bleeding are shown in Table 3
<http://archinte.ama-assn.org/issues/v161n16/fig_tab/ira10035_t3.html> and
Figure 4
<http://archinte.ama-assn.org/issues/v161n16/fig_tab/ira10035_f4.html> .
Major bleeding was significantly more frequent in only one study 34
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r34> ; this occurred in
the group administered low-molecular-weight heparin preoperatively in close
proximity to surgery. The frequencies of minor bleeding, thrombocytopenia,
and wound hematomas were similar and low for each study across randomized
groups (data not shown).
INTERSTUDY ANALYSIS
Statistical tests detected heterogeneity between studies for total and
proximal deep vein thrombosis (P<.20 for each outcome). Consequently, the
results for these studies were not pooled. Indeed, a pooled analysis would
have masked the impact of the time of administration of low-molecular-weight
heparin prophylaxis.
A separate examination of the low-molecular-weight heparin and oral
anticoagulant arms revealed significant interstudy variability
(low-molecular-weight heparin, P = .004; and oral anticoagulants, P = .01).
Among the oral anticoagulant arms, heterogeneity was attributable to the low
event rate in one study. 21
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r21> A mixed-effects
analysis indicated that a significant (P = .008) decrease in deep vein
thrombosis rates in the studies 25
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r25> , 34
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r34> using close
proximity to surgery prophylaxis protocols accounted for the heterogeneity
between low-molecular-weight heparin arms.
For proximal deep vein thrombosis, results were heterogeneous, with the
timing of initiation of prophylaxis accounting for a statistically
significant (P = .004) component of variability. There was no strong
indication of heterogeneity in the results for major bleeding events.
One hip arthroplasty prophylaxis study 42
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r42> was not included
in our primary review because it did not meet the inclusion criteria of
having performed bilateral phlebography (unilateral phlebography was
performed). The study included a once- and a twice-daily
low-molecular-weight heparin group. The results of including both study
groups and the once-daily group alone were consistent with the results
arising from the main data set.
Inverted funnel plots of study odds ratios vs study sample size were
uninformative because of the similarity of the sample sizes among the
studies and are, therefore, not presented.
INTRASTUDY ANALYSIS AND THE QUADRATIC FUNCTION
An analysis using the chi2 test, the Fisher exact test, and the t test found
that the clinical characteristics of patients were comparable across
treatment groups within each study.
An intrastudy analysis of the comparative frequencies of deep vein
thrombosis expressed as relative odds is shown in Table 3
<http://archinte.ama-assn.org/issues/v161n16/fig_tab/ira10035_t3.html> . The
relationship between the odds ratios for deep vein thrombosis occurrence for
each trial and the time of administration based on a quadratic function is
shown in Figure 3
<http://archinte.ama-assn.org/issues/v161n16/fig_tab/ira10035_f3.html> . A
visual understanding of the findings derived from within each clinical trial
is provided by the quadratic figure; the peak efficacy for
low-molecular-weight heparin ranges between 2 hours preoperatively and 6 to
8 hours postoperatively.
COMMENT
Our analysis identifies that the interval between surgery and the first
administration of low-molecular-weight heparin is a critical variable that
significantly influences the occurrence of deep vein thrombosis in patients
undergoing elective hip arthroplasty. Low-molecular-weight heparin begun in
close proximity to hip arthroplasty either preoperatively or postoperatively
25 <http://archinte.ama-assn.org/issues/v161n16/rfull/#r25> , 34
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r34> initiated at half
the usual high-risk dose was more effective than low-molecular-weight
heparin regimens that were administered 12 hours preoperatively or 12 to 18
hours postoperatively. 17
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r17> , 21
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r21> The just-in-time
postoperative regimen (low-molecular-weight heparin administered 4-6 hours
after surgery) provided superior efficacy vs oral anticoagulant treatment
without significantly increased overt bleeding 34
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r34> ( Table 3
<http://archinte.ama-assn.org/issues/v161n16/fig_tab/ira10035_t3.html> ). In
contrast, the close-proximity preoperative regimen (<2 hours before
surgery), although highly effective, resulted in increased major bleeding.
34 <http://archinte.ama-assn.org/issues/v161n16/rfull/#r34>
Traditionally in North America, low-molecular-weight heparin prophylaxis for
patients undergoing hip arthroplasty has been delayed postoperatively for at
least 12 to 24 hours to minimize bleeding. 7
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r7> , 12
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r12> , 17
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r17> , 19
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r19> , 20
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r20> European practice
has largely used low-molecular-weight heparin 12 hours preoperatively, 8-11
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r8> , 13-16
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r13> , 18
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r18> , 21-24
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r21> , 26-29
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r26> recognizing that
deep vein thrombosis typically commences perioperatively. 30-32
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r30> , 44
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r44> The findings of
the randomized trials 25
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r25> , 34
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r34> that administered
low-molecular-weight heparin in a modified regimen (the initial dose was
half the usual high-risk dose) in close proximity to surgery indicate the
need to administer prophylaxis close to the time of surgery. The aggregate
data suggest that either 12 hours preoperatively or 18 to 24 hours
postoperatively is temporally too distant from the time of perioperative
initiation of venous thrombosis. The just-in-time postoperative
low-molecular-weight heparin regimen administered in close proximity to
surgery, unlike the immediate preoperative regimen, did not sacrifice
safety.
Our findings are unlikely to be due to differences in the patient
characteristics ( Table 1
<http://archinte.ama-assn.org/issues/v161n16/fig_tab/ira10035_t1.html> );
these were comparable within each study for the randomized groups. The
interval to phlebography and the duration of prophylaxis were also
comparable within each study.
The time of initiation of oral anticoagulant prophylaxis did not influence
our findings. Indeed, independent clinical trial data 45-47
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r45> show similar
efficacy for this delayed onset of action prophylactic regimen, whether
given preoperatively or postoperatively.
The low-molecular-weight heparin regimens evaluated in this review for
in-hospital prophylaxis have been shown to be effective in multiple
randomized trials. The dose of low-molecular-weight heparin administered is
unlikely to be a significant variable, as high-risk doses based on
documented effectiveness and approved by the regulatory agencies were used.
The particular low-molecular-weight heparin used varied, but recent
randomized trials 18
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r18> , 29
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r29> suggest that
specific high-risk low-molecular-weight heparin regimens in patients
undergoing elective hip arthroplasty have similar effectiveness and safety
profiles.
Our findings are consistent with emerging results of clinical trials
evaluating newer antithrombotic regimens using the close proximity to
surgery prophylaxis approach. Regimens using either hirudin administered
immediately before or a pentasaccharide administered early after hip
arthroplasty were compared with low-molecular-weight heparin initiated 12
hours preoperatively or postoperatively 48-50
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r48> ; these
close-proximity regimens were more effective. Furthermore, studies 32
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r32> , 51-55
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r51> demonstrated that
low-dose unfractionated heparin was effective in at-risk patients; low-dose
heparin prophylaxis was administered 2 hours preoperatively. Our data
suggest that the best efficacy with heparin-derived compounds is obtained
between 2 hours preoperatively and 6 to 8 hours postoperatively.
Recently in the United States, there has been concern about the associated
use of neuraxial anesthesia and low-molecular-weight heparin prophylaxis
because of a cluster of spinal hematomas. 56
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r56> , 57
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r57> In Europe, there
has not been a reported cluster of spinal hematomas. This intriguing
difference between Europe and the United States in bleeding complications
may arise from local practice patterns, 58
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r58> , 59
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r59> with a predominant
tendency toward once-daily low-molecular-weight heparin prophylaxis in
Europe and twice-daily prophylaxis using a higher total daily dose in the
United States. Since half the usual high-risk dose of low-molecular-weight
heparin is administered using the close-proximity postoperative regimen and
the average time of initiation after spinal anesthesia was 9 hours, the
close-proximity postoperative regimen may be a safe approach in conjunction
with a spinal anesthesia. 34
<http://archinte.ama-assn.org/issues/v161n16/rfull/#r34>
In conclusion, our findings strongly suggest that the present practice in
the United States and Canada of delayed initiation of low-molecular-weight
heparin prophylaxis 12 to 24 hours postoperatively results in suboptimal
antithrombotic effectiveness without evidence of a substantive safety
advantage.
Author/Article Information
From the Thrombosis Research Unit (Drs Hull, Pineo, and Brant; and the
Department of Medicine (Dr Ghali), University of Calgary, Calgary, Alberta;
St Joseph Mercy Oakland, Pontiac, Mich; the Research Forum, Department of
Orthopaedics, Ullevaal University Hospital, Oslo, Norway (Dr Dahl); Uppsala
University, Uppsala, Sweden (Dr Bergqvist); the Department of Haemotology,
University Hospital Maastricht, Maastricht, the Netherlands (Dr Hamulyák);
the Vascular Medicine Unit, University of Rochester Medical Center,
Rochester, NY; Vascular Medicine Program, Los Angeles Orthopaedic
Hospital/University of California, Los Angeles (Dr Marder); and the
University of Oklahoma Health Sciences Center, Oklahoma City (Dr Raskob).
Corresponding author and reprints: Russell D. Hull, MBBS, Thrombosis
Research Unit, Foothills Hospital, Room 601 South Tower, 1403 29th St NW,
Calgary, Alberta, Canada T2N 2T9 (e-mail: [log in to unmask]
<mailto:[log in to unmask]> ).
Accepted for publication April 27, 2001.
We thank Adrian Jorgenson, BSc, Jeanne Sheldon, BA, Rita Biel, BSc, Vicki
Stagg, and Jennifer Ringrose, MSc, for their assistance.
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