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
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
EPIDEMIOLOGIC DATA demonstrate that
perioperative and postoperative venous thrombosis are common in high-risk
surgical patients.1-5 In the absence of
thromboprophylaxis, this disorder occurs in 40% to 60% of patients undergoing
hip arthroplasty.5, 6 Prophylactic regimens
include warfarin and subcutaneous low-molecular-weight heparin.5, 6
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, 7-29
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, 13-16, 18, 21-24, 26-29 The European
approach recognizes that deep vein thrombosis typically originates perioperatively
and that preoperative prophylaxis may optimize antithrombotic effectiveness.30-32 Delayed initiation
(12-24 hours postoperatively) of low-molecular-weight heparin prophylaxis is
standard practice in North America to minimize bleeding risk.7, 12, 17, 19, 20, 33 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
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, 12, 20 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
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 Recently, 2
published studies evaluated low-molecular-weight heparin prophylaxis
administered either immediately preoperatively25, 34 or early
postoperatively34 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 The first 10 criteria
assess methodologic rigor, and the last 5 assess the scientific basis of
treatment recommendations.35 We systematically
identified articles for inclusion in this analysis, described variations in
study design and execution, evaluated study quality,36 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
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, 21, 25, 34 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 
coefficient38 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 procedure39 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 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: one41 did not use
phlebographic evidence of deep vein thrombosis as the end point, one42 used unilateral
rather than bilateral phlebography and included a twice-daily administered
low-molecular-weight heparin group, and one43 addressed the
postphlebographic outcome of patients for a trial already included in our
analysis. Interrater agreement for study eligibility was 100% ( = 1.0). These articles were published between 1994 and
2000.
DESCRIPTION OF VARIATION IN
STUDY METHODS
Table 1
displays study design characteristics and methodologic quality among the 4
included studies. The low-molecular-weight heparins evaluated were tinzaparin
sodium,17 nadroparin
calcium,21 and dalteparin
sodium.25, 34 Initiation of
low-molecular-weight heparin prophylaxis was 18 to 24 hours postoperatively in
one study,17 the evening of
the preoperative day in one study,21 and 2 hours
preoperatively in another study.25 The remaining study34 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).
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, 34 and the postoperative
regimen initiated prophylaxis using half the usual high-risk dose shortly after
surgery.34 Full high-risk
doses were resumed the day after surgery. Two studies17, 21 used weight-adjusted
doses of low-molecular-weight heparin, and 225, 34 used fixed doses.
Initiation of oral anticoagulant prophylaxis in
the control group occurred the day before surgery in 2 studies21, 25 and on the evening of
the day of surgery in 2 studies17, 34 (Table 1).
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 70% by day 4 in
another,21 66% by day 2
in a third,25 and 86% by day
6 in the remaining study.34 The day phlebography
was performed after surgery varied among the studies, ranging from 5.734 to 10 days21 (Table 1).
ASSESSMENT OF STUDY QUALITY
All studies used proper randomization techniques and objective methods for the
detection of deep vein thrombosis (Table 1).
Two studies17, 34 were double blinded,
and 221, 25 were single blinded.
One single-blinded study21 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 study25 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.
A summary of clinical characteristics of the patient populations is reported in
Table 2.
DATA ANALYSIS
Individual study findings for all and proximal deep vein thrombosis are shown
in Table 3
and in Figure 1
and Figure 2.
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.
A large absolute risk reduction was observed in the 2 trials25, 34 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 surgery25, 34 or 4 to 6 hours after
surgery.34 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 surgery21 or 18 to 24 hours
after surgery.17
Individual study findings for major bleeding are
shown in Table 3
and Figure 4.
Major bleeding was significantly more frequent in only one study34; 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 A mixed-effects
analysis indicated that a significant (P
= .008) decrease in deep vein thrombosis rates in the studies25, 34 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 study42 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 
2
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.
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.
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 postoperatively25, 34 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, 21 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 bleeding34 (Table 3).
In contrast, the close-proximity preoperative regimen (<2 hours before
surgery), although highly effective, resulted in increased major bleeding.34
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, 12, 17, 19, 20 European practice has
largely used low-molecular-weight heparin 12 hours preoperatively,8-11, 13-16, 18, 21-24, 26-29 recognizing that
deep vein thrombosis typically commences perioperatively.30-32, 44 The findings of the
randomized trials25, 34 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);
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
data45-47 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 trials18, 29 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 postoperatively48-50; these
close-proximity regimens were more effective. Furthermore, studies32, 51-55 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, 57 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, 59 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
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]).
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.
REFERENCES
1.
Anderson FA, Wheeler HB, Goldberg RJ, et al.
A population-based perspective of the hospital incidence and case-fatality
rates of deep vein thrombosis and pulmonary embolism.
Arch Intern Med.
1991;151:933-938.
MEDLINE
2.
Anderson FA, Wheeler HB, Goldberg RJ, Hosmer DW, Forcier A.
The prevalence of risk factors for venous thromboembolism among hospital
patients.
Arch Intern Med.
1992;152:1660-1664.
MEDLINE
3.
Nordstrom M, Lindblad B, Bergqvist D, Kjellstrom T.
A prospective study of the incidence of deep-vein thrombosis within a defined
urban population.
J Intern Med.
1992;232:155-160.
MEDLINE
4.
Salzman EW, Hirsh J.
Prevention of venous thromboembolism.
In: Colman RW, Hirsh J, Marder VJ, et al, eds. Hemostasis
and Thrombosis: Basic Principles and Clinical Practice. 3rd ed.
Philadelphia, Pa: JB Lippincott; 1994:1332.
5.
Geerts WH, Heit JA, Clagett GP, et al.
Prevention of venous thromboembolism.
Chest.
1998;114(suppl):531S-560S.
MEDLINE
6.
Nicolaides AN, Bergqvist D, Hull RD, et al.
Prevention of venous thromboembolism: International Consensus Statement.
Int Angiol.
1997;16:3-38.
MEDLINE
7.
Turpie AGG, Levine MN, Hirsh J, et al.
A randomized controlled trial of a low-molecular-weight heparin (enoxaparin) to
prevent deep-vein thrombosis in patients undergoing elective hip surgery.
N Engl J Med.
1986;315:925-929.
MEDLINE
8.
Planes A, Vochelle N, Mazar F, et al.
Prevention of postoperative venous thrombosis: a randomized trial comparing
unfractionated heparin with low molecular weight heparin in patients undergoing
total hip replacement thrombosis and haemostasis.
Thromb Haemost.
1988;60:407-410.
MEDLINE
9.
Danish Enoxaparin Study Group.
Low-molecular weight heparin (enoxaparin) vs dextran 70: the prevention of
postoperative deep vein thrombosis after total hip replacement.
Arch Intern Med.
1991;151:1621-1624.
MEDLINE
10.
Lassen MR, Borris LC, Christiansen HM, et al.
Prevention of thromboembolism in 190 hip arthroplasties.
Acta Orthop Scand.
1991;62:33-38.
MEDLINE
11.
Eriksson BI, Kälebo P, Anthmyr BA, Wadenvik H, Tengborn L, Risberg B.
Prevention of deep vein thrombosis and pulmonary embolism after total hip
replacement.
J Bone Joint Surg Am.
1991;73:484-493.
MEDLINE
12.
Levine MN, Hirsh J, Gent M, et al.
Prevention of deep vein thrombosis after elective hip surgery: a randomized
trial comparing low molecular weight heparin with standard unfractionated
heparin.
Ann Intern Med.
1991;114:545-551.
MEDLINE
13.
Leyvraz PF, Bachmann F, Hoek J, et al.
Prevention of deep vein thrombosis after hip replacement: randomized comparison
between unfractionated heparin and low molecular weight heparin.
BMJ.
1991;303:543-548.
MEDLINE
14.
Planes A, Vochelle N, Fagola M, Feret J, Bellaud M.
Prevention of deep vein thrombosis after total hip replacement: the effect of
low-molecular-weight heparin with spinal and general anaesthesia.
J Bone Joint Surg Br.
1991;73:418-423.
MEDLINE
15.
Torholm C, Broeng L, Jorgensen PS, et al.
Thromboprophylaxis by low-molecular-weight heparin in elective hip surgery: a
placebo controlled study.
J Bone Joint Surg Br.
1991;73:434-438.
MEDLINE
16.
The German Hip Arthroplasty Trial (GHAT) Group.
Prevention of deep vein thrombosis with low molecular-weight heparin in
patients undergoing total hip replacement: a randomized trial.
Arch Orthop Trauma Surg.
1992;111:110-120.
MEDLINE
17.
Hull RD, Raskob GE, Pineo GF, et al.
A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium
for prophylaxis against deep-vein thrombosis after hip or knee implantation.
N Engl J Med.
1993;329:1370-1376.
MEDLINE
18.
Planes A.
Comparison of antithrombotic efficacy and haemorrhagic side effects of Clivarin
versus enoxaparin in patients undergoing total hip replacement surgery.
Blood Coagul Fibrinolysis.
1993;4(suppl 1):S33-S38.
MEDLINE
19.
Spiro TE, Johnson CJ, Christie MJ, et al.
Efficacy and safety of enoxaparin to prevent deep venous thrombosis after hip
replacement surgery.
Ann Intern Med.
1994;121:81-89.
MEDLINE
20.
Colwell CW Jr, Spiro TE, Trowbridge AA, et al, for the Enoxaparin Clinical
Trial Group.
Use of enoxaparin, a low-molecular-weight heparin, and unfractionated heparin
for the prevention of deep venous thrombosis after elective hip replacement: a
clinical trial comparing efficacy and safety.
J Bone Joint Surg Am.
1994;76:3-14.
MEDLINE
21.
Hamulyák K, Lensing AW, van der Meer J, Smid WM, van Ooy A, Hoek JA, for the
Fraxiparine Oral Anticoagulant Study Group.
Subcutaneous low-molecular-weight heparin or oral anticoagulants for the
prevention of deep-vein thrombosis in elective hip and knee replacement?
Thromb Haemost.
1995;74:1428-1431.
MEDLINE
22.
Bergqvist D, Benoni G, Bjorgell O, et al.
Low-molecular-weight heparin (enoxaparin) as prophylaxis against venous
thromboembolism after total hip replacement.
N Engl J Med.
1996;335:696-700.
MEDLINE
23.
Planes A, Vochelle N, Darmon JY, Fagola M, Bellaud M, Huet Y.
Risk of deep-venous thrombosis after hospital discharge in patients having
undergone total hip replacement: double-blind randomized comparison of
enoxaparin versus placebo.
Lancet.
1996;348:224-228.
MEDLINE
24.
Dahl OE, Andreassen G, Aspelin T, et al.
Prolonged thromboprophylaxis following hip replacement surgery: results of a
double-blind prospective, randomized, placebo-controlled study with dalteparin
(Fragmin).
Thromb Haemost.
1997;77:26-31.
MEDLINE
25.
Francis CW, Pellegrini VD Jr, Totterman S, et al.
Prevention of deep-vein thrombosis after total hip arthroplasty: comparison of
warfarin and dalteparin.
J Bone Joint Surg Am.
1997;79:1365-1372.
MEDLINE
26.
Eriksson B, Wille-Jorgensen P, Kalebo P, et al.
A comparison of recombinant hirudin with a low-molecular-weight heparin to
prevent thromboembolic complications after total hip replacement.
N Engl J Med.
1997;337:1329-1335.
MEDLINE
27.
Samama CM, Clergue F, Barre J, Montefiore A, Ill P, Samii K.
Low molecular weight heparin associated with spinal anaesthesia and gradual
compression stockings in total hip replacement surgery.
Br J Anaesth.
1997;78:660-665.
MEDLINE
28.
Lassen MR, Borris LC, Andersen BS, et al.
Efficacy and safety of prolonged thromboprophylaxis with a low-molecular-weight
heparin (dalteparin) after total hip-arthroplasty: the Danish Prolonged
Prophylaxis (DaPP) Study.
Thromb Res.
1998;89:281-287.
MEDLINE
29.
Planes A, Samama M, Lensing A, et al.
Prevention of deep vein thrombosis after total hip replacement: comparison
between two low-molecular-weight heparins, tinzaparin and enoxaparin.
Thromb Haemost.
1999;81:22-25.
MEDLINE
30.
Sharnoff JG, DeBlasio G.
Prevention of fatal postoperative thromboembolism by heparin prophylaxis.
Lancet.
1970;2:1006-1007.
MEDLINE
31.
Dahl OE, Aspelin T, Lyberg T.
The role of bone traumatization in the initiation of proximal deep vein
thrombosis during cemented hip replacement surgery in pigs.
Blood Coagul Fibrinolysis.
1995;6:709-717.
MEDLINE
32.
Gallus AS, Hirsh J, Tuttle RJ, et al.
Small subcutaneous doses of heparin in prevention of venous thrombosis.
N Engl J Med.
1973;288:545-551.
MEDLINE
33.
Kearon C, Hirsh J.
Starting prophylaxis for venous thromboembolism postoperatively.
Arch Intern Med.
1995;155:366-372.
MEDLINE
34.
Hull RD, Pineo GF, Francis C, et al, for the North American Fragmin Trial
Investigators.
Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to
surgery vs warfarin in hip arthroplasty patients: a double-blind, randomized
comparison.
Arch Intern Med.
2000;160:2199-2207.
ABSTRACT
| FULL TEXT
| PDF
| MEDLINE
35.
McAlister FA, Clark HD, van Walraven C, et al.
The medical review article revisited: has the science improved?
Ann Intern Med.
1999;131:947-951.
MEDLINE
36.
Schultz KF, Chalmers I, Hayes RJ, Altman DG.
Empirical evidence of bias: dimensions of methodological quality associated
with estimates of treatment effects in controlled trials.
JAMA.
1995;273:408-412.
MEDLINE
37.
Lau J, Ioannidis P, Schmidt CH.
Quantitative synthesis in systematic reviews.
Ann Intern Med.
1997;127:820-826.
MEDLINE
38.
Jekel JF, Elmore J, Katz DL.
Epidemiology, Biostatistics, and Preventive
Medicine.
Philadelphia, Pa: WB Saunders Co; 1997:95-97.
39.
Bradburn MJ, Deeks JJ, Altman DG.
Metan: an alternative meta-analysis command [technical bulletin].
College Station, Tex: Stata Corp; 1998. Bulletin 44.
40.
Petitti D.
Meta-analysis, Decision-Analysis, and
Cost-effectiveness Analysis: Methods for Quantitative Synthesis in Medicine.
New York, NY: Oxford University Press Inc; 1994.
41.
Colwell CW Jr, Collins DK, Paulson R, et al.
Comparison of enoxaparin and warfarin for the prevention of venous
thromboembolic disease after total hip arthroplasty: evaluation during
hospitalization and three months after discharge.
J Bone Joint Surg Am.
1999;81:932-940.
MEDLINE
42.
RD Heparin Arthroplasty Group.
RD heparin compared with warfarin for prevention of venous thromboembolic
disease following total hip or knee arthroplasty.
J Bone Joint Surg Am.
1994;76:1174-1185.
MEDLINE
43.
Hull RD, Pineo GF, Francis C, et al, for the North American Fragmin Trial
Investigators.
Low-molecular-weight heparin prophylaxis using dalteparin extended out-of-hospital
vs in-hospital warfarin/out-of-hospital placebo in hip arthroplasty patients: a
double-blind, randomized comparison.
Arch Intern Med.
2000;160:2208-2215.
ABSTRACT
| FULL TEXT
| PDF
| MEDLINE
44.
Hull RD, Brant RF, Pineo GF, Stein PD, Raskob GE, Valentine KA.
Preoperative vs postoperative initiation of low-molecular-weight heparin
prophylaxis against venous thromboembolism in patients undergoing elective hip
replacement.
Arch Intern Med.
1999;159:137-141.
ABSTRACT
| FULL TEXT
| PDF
| MEDLINE
45.
Francis CW, Marder VJ, Evarts CM, Yaukoolbodi S.
Two-step warfarin therapy: prevention of postoperative venous thrombosis
without excessive bleeding.
JAMA.
1983;249:374-378.
MEDLINE
46.
Francis CW, Pellegrini VD, Marder VJ, et al.
Comparison of warfarin and external pneumatic compression in prevention of
venous thrombosis after hip replacement.
JAMA.
1992;267:2911-2915.
MEDLINE
47.
Francis CW, Pellegrini VD, Leibert KM, et al.
Comparison of two warfarin regimens in the prevention of venous thrombosis
following total knee replacement.
Thromb Haemost.
1996;75:706-711.
MEDLINE
48.
Eriksson B, Wille-Jorgensen P, Kalebo P, et al.
A comparison of recombinant hirudin with a low-molecular-weight heparin to
prevent thromboembolic complications after total hip replacement.
N Engl J Med.
1997;337:1329-1335.
MEDLINE
49.
Lassen MR.
The EPHESUS Study: comparison of the first synthetic factor Xa inhibitor with low-molecular-weight
heparin (LMWH) in the prevention of venous thromboembolism (VTE) after elective
hip replacement surgery [abstract].
Blood.
2000;96:490a.
50.
Turpie G.
The Pentathlon 2000 Study: comparison of the first synthetic factor Xa
inhibitor with low-molecular-weight heparin in the prevention of venous
thromboembolism (VTE) after elective hip replacement surgery [abstract].
Blood.
2000;96:491a.
51.
Nicolaides AN, Dupont PA, Desai S, et al.
Small doses of subcutaneous sodium heparin in preventing deep venous thrombosis
after major sugery.
Lancet.
1972;2:890-893.
MEDLINE
52.
Kakkar VV, Corrigan T, Spindler J, et al.
Efficacyof low doses of heparin in prevention of deep-vein thrombosis after
major surgery: a double-blind, randomized trial.
Lancet.
1972;2:101-106.
MEDLINE
53.
Kakkar VV, Corrigan TP, Fossard DP, et al.
Prevention of fatal postoperative pulmonary embolism by low doses of heparin:
an international multicentre trial.
Lancet.
1975;2:45-51.
MEDLINE
54.
Gallus AS, Hirsh J, O'Brien SE, McBride JA, Tuttle RJ, Gent M.
Prevention of venous thrombosis with small, subcutaneous doses of heparin.
JAMA.
1976;235:1980-1982.
MEDLINE
55.
Clagett GP, Reisch JS.
Prevention of venous thromboembolism in general surgical patients.
Ann Surg.
1988;208:227-240.
MEDLINE
56.
Lumpkin MM.
FDA alert: FDA public health advisory.
Anesthesiology.
1998;88:27A-28A.
MEDLINE
57.
Horlocker TT, Heit JA.
Low molecular weight heparin: biochemistry, pharmacology, perioperative
prophylaxis regimens and guidelines for regional anesthetic management.
Anesth Analg.
1997;85:874-885.
MEDLINE
58.
Dahl OE.
Thromboembolism and thromboprophylaxis in high-risk surgery: facts and
assumptions
a topic for emotions?
Eur J Anaesthesiol.
2000;17:343-347.
MEDLINE
59.
Horlocker TT, Wedel DJ.
Neuraxial block and low-molecular-weight heparin: balancing perioperative
analgesia and thromboprophylaxis.
Reg Anesth Pain Med.
1998;23:164-177.
MEDLINE
Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.