META-ANALYSIS
Optimal Timing of Perioperative Chemical Thromboprophylaxis
in Elective Major Abdominal Surgery
A Systematic Review and Meta-analysis
Christopher Klonis, BBiomedSc, MD,* Hamza Ashraf, MD,†
Carlos S. Cabalag, MBBS, PhD,*†‡ Darren J. Wong, PhD, FRACP,‡§
Sean G. Stevens, MSurgEd, FRACS,*†‡ and David S. Liu, PhD, FRACS*†‡∥✉
Objective: To investigate the effect of the timing of chemoprophylaxis on
venous thromboembolisms (VTEs) and bleeding rates in patients
undergoing major abdominal surgery.
Background: Postoperative bleeding and VTE incur significant morbid-
ity, mortality, and health care costs. Chemoprophylaxis is used routinely
to prevent VTEs but increases bleeding risk. The perioperative timing of
chemoprophylaxis initiation may influence both VTE and bleeding risks.
The optimal window for commencing chemoprophylaxis in the
perioperative period is unclear.
Methods: MEDLINE, EMBASE, Cochrane Library, and Web of
Science databases were searched using PRISMA guidelines. Randomized
trials and cohort studies published between January 1, 2000 to May 10,
2022, which reported on chemoprophylaxis timing as well as the
incidence of VTE and bleeding after elective abdominal surgery were
meta-analyzed.
Results: From 6175 studies, 14 (24,922 patients) were meta-analyzed.
Bariatric (4 studies), antireflux (1 study), hepato-pancreatic-biliary
(5 studies), colorectal (1 study), ventral hernia (1 study), and major intra-
abdominal surgeries (2 studies) were included. Chemoprophylaxis was
initiated before skin closure in 10,403 patients, and postoperatively in
14,519 patients. Both symptomatic [risk ratios (RR), 0.81; 95% CI, 0.45-
1.43; P = 0.460] and overall (RR, 0.74; 95% CI, 0.45-1.24; P = 0.250)
VTE rates were comparable between study groups. Compared with
postoperative chemoprophylaxis, early usage increased the risk of all
bleeding (RR, 1.56; 95% CI, 1.13-2.15; P = 0.007), major bleeding (RR,
From the *Department of Surgery, The University of Melbourne, Austin
Precinct, Austin Health, Heidelberg, VIC, Australia; †Division of Sur-
gery, Anesthesia, and Procedural Medicine, Austin Health, Heidelberg,
VIC, Australia; ‡Department of Surgery, General and Gastrointestinal
Surgery Research Group, The University of Melbourne, Austin Precinct,
Austin Health, Heidelberg, VIC, Australia; §Department of Gastro-
enterology and Hepatology, Austin Health, Heidelberg, VIC, 3084,
Australia; and ∥Division of Cancer Surgery, Peter MacCallum Cancer
Centre, Melbourne, VIC, Australia.
✉ liu.davidsh@gmail.com.
C.K. and H.A. are joint first authors.
C.K.: study design, data collection, analysis and interpretation, drafting of
article, and final approval. H.A.: study design, data collection, analysis and
interpretation, drafting of article, and final approval. C.S.C.: study design,
data analysis and interpretation, drafting of article, and final approval.
S.G.S.: study conception and design, data analysis and interpretation,
drafting of article, final approval, and study supervision. D.J.W.: data
analysis and interpretation, drafting of article, and final approval. D.S.L.:
study conception and design, data analysis and interpretation, drafting of
article, final approval, and study supervision.
The authors report no conflicts of interest.
Supplemental Digital Content is available for this article. Direct URL citations
are provided in the HTML and PDF versions of this article on the journal’s
website, www.annalsofsurgery.com.
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0003-4932/23/27706-0904
DOI: 10.1097/SLA.0000000000005764
904 | www.annalsofsurgery.com
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1.63; 95% CI, 1.16-2.28; P = 0.005), blood transfusion (RR, 1.48; 95%
CI, 1.24-1.76; P < 0.001), and reintervention (RR, 1.94; 95% CI, 1.19-
3.18; P = 0.008).
Conclusions: Our findings advocate for initiating chemoprophylaxis
postoperatively in elective abdominal surgery to minimize bleeding risk
without compromising VTE protection.
Keywords: abdominal, chemoprophylaxis, surgeryvenous thromboemb-
olism, timing
(Ann Surg 2023;277:904–911)
P atients undergoing major abdominal surgery are at risk of
hospital-acquired venous thromboembolisms (VTEs). VTE,
which includes deep vein thrombosis and pulmonary embolism,
incurs significant morbidity, mortality, and health care costs.1 The
risk of VTE can be reduced through both mechanical and chemical
approaches. Mechanical thromboprophylaxis includes graduated
compression stockings or sequential compression devices. Chem-
ical thromboprophylaxis includes anticoagulants and antiplatelet
agents such as unfractionated heparin, low molecular weight
heparin, warfarin or aspirin.2 However, these chemical measures
are associated with a risk of minor and major bleeding
complications.3 This risk needs to be considered in the perioper-
ative period and balanced against the risk of developing VTE.
Consensus guidelines recommend the use of both mech-
anical and chemical thromboprophylaxis in the perioperative
period for patients undergoing major abdominal surgery.4 How-
ever, the optimal window for commencing chemoprophylaxis is
unknown. Consequently, chemoprophylaxis timing is frequently
based on personal experience and surgical dogma, leading to sig-
nificant and often irrational variability in practice.5 Notably, evi-
dence in other fields, such as orthopedic surgery, suggests that
preoperative initiation of chemoprophylaxis confers no additional
benefit for reducing VTE risk compared with postoperative.6 In
addition, in several general surgery cohorts, initiation before skin
closure increased the risk of postoperative bleeding.7 Therefore,
variations in the timing of chemoprophylaxis may translate to
harm through increased rates of either bleeding or VTE, prompt-
ing a need for further investigation and standardization in practice.
McAlpine et al8 recently conducted a meta-analysis on the
timing of perioperative thromboprophylaxis across multiple
surgical specialties. Notably, these authors combined data from
orthopedic, thoracic, cardiac, breast, obstetric, and abdominal
surgeries. These procedures have very different VTE and
bleeding risk profiles,9–12 and likely explain the author’s con-
clusion that perioperative timing of chemoprophylaxis had no
significant impact on bleeding and VTE rates. Moreover, the
Annals of Surgery  Volume 277, Number 6, June 2023
Annals of Surgery  Volume 277, Number 6, June 2023
applicability of these findings to patients undergoing major
abdominal surgery is unclear.
This systematic review and meta-analysis investigated the
effect of the timing of perioperative chemoprophylaxis initiation
on VTE and bleeding rates in elective major abdominal surgery.
METHODS
Study Identification
We performed a systematic review and meta-analysis
according to the preferred reporting items for systematic reviews and
meta-analyses (PRISMA) guidelines.13 We conducted a compre-
hensive search of 4 databases (MEDLINE, EMBASE, Cochrane
Library, and Web of Science) to identify eligible studies published
between January 1, 2000 and May 10, 2022. We incorporated
search terms that focused on chemoprophylaxis, VTE, postoperative
bleeding, and the most common abdominal wall and intra-
abdominal pathologies encountered in abdominal surgery and their
associated procedural names. The MESH and EMTREE terms
used for MEDLINE and EMBASE can be found in Supplemental
Table 1 (Supplemental Digital Content 1, http://links.lww.com/SLA/
E354). MESH terms were used in the Cochrane library and Web of
Science databases.
FIGURE 1. PRISMA flow diagram.
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Chemoprophylaxis Timing in Abdominal Surgery
Screening Process
References were imported into EndNote X8 and dupli-
cates were removed. References were manually screened by 2
authors (C.K. and H.A.) by title and abstract for inclusion.
Studies passing the initial screen underwent full-text review. Any
uncertainties were resolved by consultation with senior authors
(D.S. L. and S.G.S.).
Eligibility Criteria
Studies selected for final review contained patients
> 18 years of age that underwent elective major abdominal
procedures, including ventral hernia repair, bariatric, upper
gastrointestinal, hepato-pancreatic-biliary, and colorectal sur-
geries. We included all randomized controlled trials (RCT) and
cohort studies with no language restrictions. Studies were
excluded if there was no comparison between early (before skin
closure) and postoperative (after skin closure) chemoprophylaxis
use with regard to our primary and secondary outcomes.
Outcomes and Definitions
Our outcomes included the rate of symptomatic and all
(symptomatic and asymptomatic) VTE, as well as the incidence of
postoperative bleeding, the need for hemostatic reintervention,
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Klonis et al
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TABLE 1. Study Characteristics

Time to first
Early Postoperative Intraoperative postoperative
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Author name, chemoprophylaxis chemoprophylaxis mechanical chemoprophylaxis

year Place Study design Specialty Operations Complexity agent agent prophylaxis (h)
Abdelsalam, Egypt Single blinded Bariatric Sleeve Gastrectomy Simple LMWH LMWH SCD < 24
et al, 202115 RCT
Ainoa, et al, UK Retrospective HPB Hepatectomy Complex LMWH LMWH SCD 4–6
202116 cohort
Altieri, et al, USA Retrospective Bariatric Sleeve gastrectomy Simple UFH or LMWH UFH or LMWH — —
201817 cohort Roux-en-Y gastric bypass
Doughtie, et al, USA Single blinded HPB Hepatectomy Simple LMWH LMWH SCD < 24
202118 RCT Cholecystectomy
Pancreatectomy
Pancreaticoduodenectomy
Fong, et al, USA Retrospective HPB Pancreatectomy Complex UFH UFH — —
202019 cohort Pancreaticoduodenectomy
Hamad et al, USA Retrospective Bariatric Sleeve gastrectomy Simple LMWH LMWH — < 24
200520 cohort Roux-en-Y gastric bypass
Vertical gastroplasty
Kakkar, et al, UK Double Major Laparotomy Complex LMWH LMWH — 7–13
201421 blinded RCT abdominal
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Liu, et al, 20207 Australia Retrospective HPB Laparoscopic cholecystectomy Simple UFH or LMWH UFH or LMWH SCD and TEDS Median 10.2
cohort
Liu, et al, 202222 Australia Retrospective Major Esophago-gastrectomy Complex UFH or LMWH UFH or LMWH SCD and TEDS Median 8.4

Annals of Surgery
cohort abdominal Hepatectomy
Splenectomy
Pancreaticoduodenectomy
Small bowel resection
Colectomy
Proctectomy
PROTECTinG, Australia Prospective ARS Fundoplication Simple UFH or LMWH UFH or LMWH SCD and TEDS Median 8.2
202223 cohort +/− hiatus hernia repair


PROTECTinG, Australia Retrospective VHS Ventral hernia repair Simple UFH or LMWH UFH or LMWH SCD and TEDS Median 9.2

Volume 277, Number 6, June 2023

202224 cohort
Reinke, et al, USA Retrospective HPB Pancreatectomy Complex UFH UFH SCD —
201225 cohort Pancreaticoduodenectomy
Steele, et al, USA Double Bariatric Sleeve gastrectomy Simple LMWH LMWH SCD and TEDS 6
201526 blinded RCT Roux–en–Y gastric bypass
Zaghiyan, et al, USA Nonblinded Colorectal Major colorectal surgery Complex UFH UFH SCD 8
201627 RCT
ARS indicates antireflux surgery; HPB, hepato-pancreatic-biliary; LMWH, low molecular weight heparin; RCT, randomized controlled trials; SCD, sequential compression device; TEDS, thromboembolic
deterrent stockings; UFH, unfractionated heparin; VHS, ventral hernia surgery.
Annals of Surgery  Volume 277, Number 6, June 2023 Chemoprophylaxis Timing in Abdominal Surgery

TABLE 2. Patient Characteristics

BMI
Sex (kg/m2), Length-of- Therapeutic
Age (y), (F) mean Smoking; Surgery time stay (d), anticoagulation; Antiplatelets;
References Study arms Patients mean (SD) (%) (SD) n (%) (min), mean (SD) mean (SD) n (%) n (%)
Abdelsalam, et al15 Early 50 33.8 (9.4) 80 48.8 (5.6) NA NA NA NA NA
Postoperative 50 34.0 (9.7) 80 48.0 (5.5) NA NA NA NA NA
Ainoa, et al16 Early 253 62.9 (12.8) 47.8 26.3 (5.1) NA 206.0 (95.0) 6† (5-7) NA 46 (18.2)
Postoperative 259 63.2 (13.1) 40.5 26.1 (5.6) NA 226.0 (90.0) 6† (5-7) NA 36 (14.0)
Altieri, et al17 Early 3280 NA 80 NA NA NA NA NA NA
Postoperative 4593 NA 81.2 NA NA NA NA NA NA
Doughtie, et al18 Early 93 NA NA 27.6* NA NA NA NA NA
Postoperative 130 NA NA 27.9* NA NA NA NA NA
Fong, et al19 Early 1062 NA 51.1 NA NA NA NA NA NA
Postoperative 386 NA 48.9 NA NA NA NA NA NA
Hamad et al20 Early 100 39.5 (9.1) 75 47.0 (7.4) 12 (12.0) NA 2.3 (0.9) NA NA
Postoperative 444 NA NA NA 37 (8.3) NA NA NA NA
Kakkar, et al21 Early 2177 62.0† 43.2 25.4† NA 164.0 (82.0) NA NA NA
Postoperative 2175 62.0† 43.4 25.4† NA 162.0 (84.0) NA NA NA
Liu, et al7 Early 847 48.5 (16.2) 71.9 30.5 (6.9) NA 84.3 (36.3) 1.4 (2.8) 16 (1.9) 68 (8.0)
Postoperative 573 52.7 (16.8) 65.4 29.8 (9.7) NA 88.4 (44.3) 1.7 (2.0) 13 (2.3) 45 (7.9)
Liu, et al22 Early 265 62.0 (14.1) 48.7 28.3 (6.3) NA 358.4 (172.0) 8.0† (6–14) 19 (7.2) 29 (10.9)
Postoperative 680 64.0 (12.3) 50 28.2 (6.2) NA 257.8 (123.3) 7.0† (5–11) 44 (6.5) 103 (15.1)
PROTECTinG- Early 1099 57.2 (15.3) 61 30.4 (5.4) NA 135.3 (59.7) 3.4 (3.8) 59 (5.4) 122 (11.1)
ARS23
Postoperative 3202 60.4 (14.8) 63.4 29.8 (4.9) NA 128.1 (69.0) 3.4 (5.3) 130 (4.1) 304 (9.5)
PROTECTinG- Early 856 58.7 (13.5) 55.3 32.9 (7.2) NA 109.5 (70.1) 3.3 (6.5) 49 (5.7) 121 (14.1)
VHS24
Postoperative 1701 59.4 (13.2) 51.3 32.2 (6.6) NA 112.1 (63.6) 3.2 (4.2) 93 (5.5) 244 (14.3)
Reinke, et al25 Early 39 66.6 31 27.3* NA 240* NA 8 (20.5) NA
Postoperative 34 69.7 62 27.0* NA 234* NA 6 (17.6) NA
Steele, et al26 Early 98 41.8 (9.0) 83.7 45.7 (5.2) 14 (16.9) 183.0 (51.0) 2.4 (0.8) NA NA
Postoperative 100 40.4 (10.2) 84 45.1 (5.5) 17 (19.8) 187.0 (49.0) 2.5 (0.8) NA NA
Zaghiyan, et al27 Early 184 51.7 (16.9) 50.4 24.9 (6.1) 12 (6.5) 199.5† (141–252) 4.5† (3–7) NA 22 (12.0)
Postoperative 192 53.6 (18.2) 52.6 25.8 (6.3) 14 (7.3) 189.0† (144–260) 5.0† (4–7) NA 27 (14.1)
*No SD recorded.
†Data reported as (median ± interquartile range).
ARS indicates antireflux surgery; BMI, body mass index; NA, not available (data); VHS, ventral hernia surgery.

and blood transfusion. VTE was defined by digital subtraction
venography, magnetic resonance venography, ultrasound duplex
scans of upper and lower limbs, ventilation/perfusion (V/Q),
and computed tomography pulmonary angiogram scans of the
lung. Overall bleeding was defined as hematoma on clinical
examination or imaging, frank blood from drain output, a return-
to-theater for hemostasis, or a need for blood transfusion. Major
bleeding was defined as any bleeding that required blood trans-
fusion, reintervention in theater, or > 20 g/L fall in hemoglobin
from baseline.7 Minor bleeding was defined as any bleeding that
did not meet major bleeding criteria.
Data Extraction and Statistical Analysis
Data were extracted independently by 2 authors (C.K. and
H.A.) using a standardized electronic proforma, and meta-ana-
lyzed by a third author (C.S.C.). Extracted data points include
author, country, year of publication, study design, surgical
specialty, types of operation, number of patients in control and
treatment arms, types of anticoagulation, age, sex, body mass
index, length of operation, therapeutic anticoagulation, anti-
platelet therapy, length-of-stay, procedural complexity as well as
primary and secondary endpoints. Procedural complexity was
defined as simple if the expected length of stay was <3 days and
complex if this duration was longer.
Meta-analysis was performed using Review Manager v5.4
(The Cochrane Collaboration, 2020) comparing those who
received chemoprophylaxis early (administered preoperatively
and intraoperatively) versus those postoperatively. The random
effects model was used to calculate pooled risk ratios (RR) for
primary and secondary outcomes. Study heterogeneity was
assessed using I2, where > 50% was considered significant het-
erogeneity. P < 0.05 were considered statistically significant.
Assessment of Bias
Two authors (C.K. and H.A.) each evaluated all studies
using the methodological index for non-randomized studies
(MINORS) score; a validated assessment tool for evaluating
the quality and rigor of surgical studies.14 The highest possible
score for comparative studies is 24 (Supplemental Table 2,
Supplemental Digital Content 1, http://links.lww.com/SLA/
E354).
RESULTS
Study Selection and Characteristics
Our systematic review identified a total of 6175 studies
(Fig. 1 and Supplemental Table 3, Supplemental Digital Content
1, http://links.lww.com/SLA/E354). After screening, 14 were meta-
analyzed (Table 1). Eight were retrospective cohort studies, 2 were
prospective cohort studies, and 4 were RCTs. Based on an inde-
pendent assessment by 2 authors (Supplemental Table 2, Supple-
mental Digital Content 1, http://links.lww.com/SLA/E354), the

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Klonis et al
FIGURE 2. Meta-analysis comparing the rate of symptomatic VTE between early versus postoperative chemoprophylaxis. VTE
indicates venous thromboembolism.
median (interquartile range) MINORS score was 21 (20–24). This
suggests that the studies included in this meta-analysis are of high
quality. In total, these reports included 24,922 patients who
underwent bariatric (4 studies, 8715 patients),15,17,20,26 antireflux
(1 study, 4301 patients),23 colorectal (1 study, 376 patients),27
hepato-pancreatic-biliary (5 studies, 3676 patients),7,16,18,19,25 ven-
tral hernia (1 study, 2557 patients),24 and major intra-abdominal
(2 studies, 5297 patients)21,22 surgeries. Twelve studies used
unfractionated heparin, enoxaparin, or dalteparin as their pre-
ferred chemoprophylactic agent. One study used semuloparin,
whereas another used fondaparineux.21,26 Eleven studies reported
on their time to the first postoperative dose of chemoprophylaxis.
Of these, all patients received postoperative chemoprophylaxis
within 24 hours of skin closure. Baseline patient characteristics
from each study are detailed in Table 2.
Timing of Chemoprophylaxis Does Not Significantly
Impact Venous Thromboembolisms Rates
Eleven studies reported symptomatic VTE rates. Compared
with postoperative initiation (1.3%), early chemoprophylaxis
(1.4%) did not significantly affect the incidence of symptomatic
VTE (RR, 0.81; 95% CI, 0.45-1.43; P = 0.460, I2, 66%). (Fig. 2).
We also performed further subgroup analyses of the overall VTE
rate stratified by RCTs (RR, 0.81; 95% CI, 0.61-1.07; P = 0.140,
I2, 0%) and non-RCTs (Supplemental Fig. 1, Supplemental Dig-
ital Content 1, http://links.lww.com/SLA/E354), as well as surgical
complexity (Supplemental Fig. 2, Supplemental Digital Content 1,
http://links.lww.com/SLA/E354) and surgeries for benign con-
ditions (Supplemental Fig. 3, Supplemental Digital Content 1,
http://links.lww.com/SLA/E354). In addition, we compared rates
FIGURE 3. Meta-analysis comparing the overall rate of bleeding between early versus postoperative chemoprophylaxis.
908 | www.annalsofsurgery.com
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Annals of Surgery  Volume 277, Number 6, June 2023
of deep vein thrombosis (Supplemental Fig. 4, Supplemental
Digital Content 1, http://links.lww.com/SLA/E354) and pulmo-
nary embolism (Supplemental Fig. 5, Supplemental Digital Con-
tent 1, http://links.lww.com/SLA/E354) between early versus
postoperative chemoprophylaxis groups. All these subgroup
analyses were consistent with the main finding that the timing of
chemoprophylaxis does not significantly affect VTE rates after
major abdominal surgery.
Early Chemoprophylaxis Significantly Increases
Postoperative Bleeding Rates
Eight studies reported overall postoperative bleeding
rates. Compared with postoperative chemoprophylaxis (2.9%),
early initiation (5.0%) significantly increased the rate of bleeding
(RR. 1.56; 95% CI, 1.13-2.15; P = 0.007; I2, 67%) (Fig. 3), par-
ticularly major bleeding (RR, 1.63; 95% CI, 1.16-2.28; P = 0.005;
I2, 66%) after major abdominal surgery (Supplemental Fig. 6,
Supplemental Digital Content 1, http://links.lww.com/SLA/
E354). Further subgroup analyses of overall bleeding stratified
by RCTs (RR, 1.37; 95% CI, 1.06-1.79; P = 0.020; I2, 0%) and
non-RCTs (Supplemental Fig. 7, Supplemental Digital Content
1, http://links.lww.com/SLA/E354), as well as surgical com-
plexity (Supplemental Fig. 8, Supplemental Digital Content 1,
http://links.lww.com/SLA/E354) and surgeries for benign path-
ology (Supplemental Fig 9, Supplemental Digital Content 1,
http://links.lww.com/SLA/E354) were consistent with the main
finding that early chemoprophylaxis initiation, compared with
postoperative usage only, significantly increases the risk of
bleeding after major abdominal surgery.
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Annals of Surgery  Volume 277, Number 6, June 2023
FIGURE 4. Meta-analysis comparing blood transfusion rate between early versus postoperative chemoprophylaxis.
Early Chemoprophylaxis Significantly Increases the
Need for Blood Transfusions
Eleven studies reported on blood transfusion rates. Com-
pared with postoperative chemoprophylaxis (2.4%), early initiation
(3.9%) significantly increased the need for blood transfusion (RR,
1.48; 95% CI, 1.24-1.76; P < 0.001; I2, 18%) after major abdominal
surgery (Fig. 4).
Early Chemoprophylaxis Significantly Increases the
Need for Reoperation
Seven studies reported on the rate of reintervention for
hemostasis. Compared with postoperative chemoprophylaxis
(0.7%), early initiation (1.3%) significantly increased the rate of
reintervention for bleeding (RR, 1.94; 95% CI, 1.19-3.18;
P = 0.008; I2, 11%) after major abdominal surgery (Fig. 5).
DISCUSSION
In this systematic review and meta-analysis, our key
findings were that chemoprophylaxis administered before skin
closure offered no additional protection against VTE but came
at the cost of increased bleeding, blood transfusion, and reop-
eration compared with postoperative initiation.
In a recent meta-analysis, McAlpine et al8 investigated
17,124 patients from 22 studies exploring the impact of chemo-
prophylaxis timing on postoperative VTE and bleeding rates.
They demonstrated no difference in VTE and bleeding rates
between early and postoperative cohorts. However, the authors
included patients who underwent orthopedic, thoracic, breast as
well as abdominal surgeries. These operations carry vastly
FIGURE5. Meta-analysis comparing RTT rate between early versus postoperative chemoprophylaxis. RTT indicates return-to-
theater.
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Chemoprophylaxis Timing in Abdominal Surgery
different VTE and bleeding risks, contributing to study hetero-
geneity and potentially leading to inconsistent results. It may
explain why their study did not identify a statistically significant
result. Moreover, it is difficult to apply their overall findings to
individual procedural types. In contrast, the present study
included only patients who underwent major abdominal surgery.
Our cohort is therefore more homogenous, with findings directly
translatable to this group of patients.
Fundamentally, chemoprophylaxis in the perioperative
period requires balancing the risk of bleeding and thromboembo-
lism. Despite evidence demonstrating that prophylactic doses of
anticoagulant carry an increased risk of intraoperative and post-
operative bleeding,3 many general surgeons still prefer pre or
intraoperative chemoprophylaxis based on their belief that VTE
occurs on-table.5,28 This concept has been largely driven by several
factors; Firstly, from early clinical trials, which showed that pre-
operative heparin reduced VTE in general surgical patients.28,29
Secondly, from studies, which reported that abdominal insufflation
during laparoscopic surgery altered lower limb venous blood flow
and may predispose to clot formation.30,31 Thirdly, from global
health campaigns over the last 4 decade, which was designed to
raise awareness of hospital-acquired VTE and the importance of
thromboprophylaxis in the perioperative period.2 In retrospect,
those early clinical trials did not include a postoperative chemo-
prophylaxis group, lacked minimally invasive techniques, and
did not utilize mechanical thromboprophylaxis, thus calling
into question their applicability to current surgical practices.
Furthermore, despite changes in venous hemodynamics during
laparoscopic surgery, it has never been proven to precipitate
thrombosis. In addition, although population-based strategies have
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Klonis et al
in general improved thromboprophylactic compliance within the
hospital setting,32 many surgeons default to surgical dogma, rather
than evidence, to decide when to start chemoprophylaxis in the
perioperative period.5 The ideal chemoprophylactic regimen is one
that minimizes bleeding risk while conferring maximal throm-
boembolic protection. Recently, there have been several studies
attempting to define this optimal regimen. Towards this goal, our
meta-analysis summarizes the available evidence and posits that
postoperative chemoprophylaxis mitigates the risk of anti-
coagulant-related bleeding while providing adequate protection
against VTE. Based on our data, the number needed to treat with
postoperative chemoprophylaxis to prevent 1 case of symptomatic
VTE is 368. Conversely, the number needed to harm with respect
to bleeding by using early chemoprophylaxis is 36.
From a bleeding perspective, a 2.1% absolute risk reduc-
tion observed in the postoperative chemoprophylaxis group
(early: 5.0% vs postoperative: 2.9%) has significant implications
at a population level. Given that over 13 million major
abdominal operations are undertaken globally each year,33
standardizing chemoprophylaxis to the postoperative period
potentially prevents over 273,000 patients from bleeding-related
complications per year.
Assessing each patient’s risks for bleeding and VTE is
important for the prescription of chemoprophylaxis. In this
regard, a universal risk stratified for bleeding and VTE was not
found across all studies. Some studies utilized the Caprini score
to gauge VTE risk within their own cohorts,5,7,15,22–24 whereas
others used the American College of Surgeons National Surgical
Quality Improvement Program scoring system to quantify VTE
and bleeding risks.25 Notably, in those studies that reported on
such risk assessments, their baseline risks were comparable
between early and postoperative chemoprophylaxis groups.
Furthermore, as evident in Table 2, patient characteristics were
largely similar between groups within each study. To enable risk
stratification across all studies, albeit rather crudely, we dicho-
tomized surgeries into simple and complex based on their
expected length of stay (simple <3 days and complex > 3 days).
This approach inherently reflects the extent of major abdominal
surgery, and by inference, their relative risk of postoperative
bleeding and VTE. Based on these subgroups, we found that for
complex surgeries, there was a tendency towards less VTE with
early anticoagulation (Supplemental Fig. 2, Supplemental Digi-
tal Content 1, http://links.lww.com/SLA/E354). However, these
comparisons did not reach statistical significance. Moreover, we
recently demonstrated that even in patients with high baseline
thromboembolic risk, the timing of perioperative chemo-
prophylaxis did not impact clinical VTE, but postoperative
chemoprophylaxis significantly decreased the risk of bleeding
when compared with early chemoprophylaxis.34
We recognize several limitations of this study. Firstly, due
to limited data, we cannot perform subgroup analyses based on
disease diagnosis, operative approach, patient positioning, and
surgical indications. Secondly, although we focused only on elec-
tive abdominal operations, different VTE and bleeding risk pro-
files may still exist within subspecialty procedures. Although there
were insufficient studies to meta-analyze each subspecialty sepa-
rately, we performed subgroup analyses of “simple” and “com-
plex” operations, as determined by their expected postoperative
length of stay, on the basis that they carry comparable VTE and
bleeding risk profiles. These analyses further support our main
findings. Thirdly, although there were insufficient studies to per-
form a meta-analysis consisting solely of RCTs, our sensitivity
analysis comparing RCTs and non-RCTs is also consistent with
our main findings. Fourthly, due to high heterogeneity, the
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Annals of Surgery  Volume 277, Number 6, June 2023
interpretation of symptomatic VTE and overall bleeding out-
comes should be undertaken with some level of caution. Based on
subgroup analyses, we found that this heterogeneity mainly
stemmed from non-RCT studies. In contrast, data from RCTs
were in fact highly homogenous (I2, 0%), and supported the main
conclusions (Supplemental Fig. 1, Supplemental Digital Content
1, http://links.lww.com/SLA/E354 and Supplemental Fig. 7,
Supplemental Digital Content 1, http://links.lww.com/SLA/E354).
Finally, publication bias may skew findings in any systematic
review. However, the symmetrical appearance of the funnel plot
(Supplemental Fig.10, Supplemental Digital Content 1, http://
links.lww.com/SLA/E354) suggests the low likelihood of pub-
lication bias affecting our study findings.
In this meta-analysis, we found that chemoprophylaxis
commenced before skin closure offers no additional protection
against VTE but led to higher rates of bleeding and the consequent
need for intervention compared with postoperative initiation.
Therefore, our findings advocate for postoperative chemo-
prophylaxis initiation as standard practice in elective major
abdominal surgery.
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