European Journal of Internal Medicine 88 (2021) 73–80

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European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Weight-adjusted versus fixed dose heparin thromboprophylaxis in

hospitalized obese patients: A systematic review and meta-analysis
Davide Ceccato a, 1, *, Angelo Di Vincenzo b, 1, Claudio Pagano a, Raffaele Pesavento a,
Paolo Prandoni c, Roberto Vettor a
a
Department of Internal Medicine, University of Padua, Padua, Italy
b
Camposampiero Hospital, Camposampiero, Italy
c
Arianna Foundation on Anticoagulation Bologna, Padua, Italy

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Fixed dose unfractionated or low molecular weight heparin is the recommended treatment for
Thromboprophylaxis venous thromboembolism (VTE) prevention in hospitalized patients. However, its efficacy has been questioned in
Venous thromboembolism obese population. Results of previous studies on weight-adjusted doses of heparin for VTE prevention are con­
Obesity
tradictory. Different anticoagulant regimens are used in clinical practice, but their role remains to be elucidated.
Heparin
Aims: To clarify the efficacy and safety of weight-adjusted dose heparin for VTE prevention in obese subjects
Anti-Xa levels
hospitalized for medical and surgical conditions.
Methods: Twelve studies were identified as reporting VTE occurrence, major or minor bleeding and anti-Xa
levels. A random-effect meta-analysis was conducted to derive odds ratios (OR) comparing fixed vs weight
adjusted-doses heparins on VTE occurrence, bleeding, anti-Xa levels. Medical and surgical patients, prospective
vs retrospective and quality of studies were extracted for moderators and meta-regression analysis.
Results: Weight-adjusted dose heparin administration was not associated with reduced VTE occurrence (6320/
13317 patients, OR 1.03, 95% C.I. 0.79 to 1.35), nor increased bleeding (5840/10906 patients, OR 0.84, 95% C.I.
0.65 to 1.08), but it was associated with higher anti-Xa levels (284/294 patients, ES 2.04, 95% C.I. 1.16 to 2.92,
p<0.0001). A significant heterogeneity was present for comparison of anti-Xa levels (I2=94%, p=0.0001) but not
for VTE occurrence or bleeding (I2=7.6% and 12.8% respectivel). None of the moderators explained the het­
erogeneity of the results among primary studies.
Conclusion: Weight-adjusted dose as compared to fixed-dose of heparins in the prevention of VTE in obese
patients was not associated with a lower risk of VTE nor a higher risk of bleeding.

Introduction
Venous thromboembolism (VTE) is a multi-factorial disease with
high morbidity and mortality rates. As it has been reported to occur in
about 100–200 cases/100,000 inhabitants per year [1], VTE qualifies as
the third most common cardiovascular disease worldwide. Although it
can develop in the absence of risk factors of thrombosis, VTE is
commonly associated with several conditions, in particular acute med­
ical illnesses requiring hospitalization. Age, reduced mobility, recent
surgery, respiratory and heart failure increase the risk of VTE in in­
patients [2], as well as diabetes, smoking and obesity [3,4,5].
Among these conditions, obesity (defined as a body mass index (BMI)
≥ 30Kg/m2) leads to 2-3 fold higher risk of VTE both in men and women
[6]. This risk is expected to further increase when the BMI exceeds 40
Kg/m2. Although an impaired balance of hemostatic factors, such as
fibrinogen level, factor VIII or D-dimer, has been reported in obese in­
dividuals [7,8,9], there is still uncertainty on the mechanisms by which
obesity predisposes to VTE development. Reduced mobility, impaired
venous return with a decrease blood velocity, and a low-grade inflam­
matory state are likely to account for the increased risk of VTE in obese
subjects [10,11].
Thromboprophylaxis has been demonstrated to reduce the incidence
of inhospital VTE in patients at high risk [12,13]. However, in obese
subjects the efficacy of fixed dose strategy has often been questioned

* Corresponding author at: University of Padova, Via Giustiniani 2, 35128Padova, Italy.

E-mail address: davide.ceccato@aopd.veneto.it (D. Ceccato).
1
First co-authors for this paper

https://doi.org/10.1016/j.ejim.2021.03.030
Received 27 January 2021; Received in revised form 1 March 2021; Accepted 24 March 2021
Available online 19 April 2021
0953-6205/© 2021 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
D. Ceccato et al.
Fig. 1. Selection process of studies for the meta-analysis.
[14]. On the other hand, the evidence in support of a greater efficacy of a
weight-adjusted thromboprophylaxis strategy in obese patients is still
matter of discussion [15]. In some studies, the administration of
weight-adjusted doses of low molecular weight heparins (LMWH) in
obese patients was found to be associated with higher anti-Xa circulating
levels compared with fixed doses [16,17], thus suggesting a higher
protective effect against VTE events. However, there is no clear evidence
coming from clinical trials that an increased dose of heparin yields a
reduction of VTE risk during hospitalization among obese. Therefore,
whether adjusting the (LMW) heparin doses according to body weight in
patients with obesity confers a higher efficacy without increasing the
bleeding risk remains controversial.
In order to assess the benefit/risk profile of weight-adjusted versus
standard doses of LMWH or UFH in obese subjects undergoing hospi­
talization for either medical or surgical conditions, we performed a
systematic review and meta-analysis of available comparative studies.
Materials and methods
Study selection
The search strategy was conducted according to the Preferred
Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)
guidelines [18]. We performed a search in MEDLINE, Scopus and Google
Scholar, from January 2005 to August 2020, using the following key­
words and Medical Subject Headings in various combinations to identify
clinical studies that evaluated the effect of different doses of heparins in
obese patients: “obesity”, “overweight”, “thrombosis prophylaxis”,
“thromboprophylaxis”, “heparin”, “venous thromboembolism”, “deep
vein thrombosis”, “pulmonary embolism”, “bariatric surgery”, “sur­
gery”, “medically ill”. Only studies published in English were
considered.
Two reviewers (DC and ADV) independently screened titles and
abstracts of the search. Data from each study were extracted indepen­
dently by the authors using the same criteria, and disagreements were
solved by discussion and consensus with other authors (CP, RV and RP).
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European Journal of Internal Medicine 88 (2021) 73–80
We included prospective observational, retrospective, non-
randomized and randomized controlled trials evaluating the effects of
standard versus adjusted doses of different heparin molecules (LMWH or
UFH) in obese hospitalized patients. Weight-adjusted thromboprophy­
lactic LMWH or UFH dosing was defined as the use of a higher than the
standard recommended dose, corresponding to the subcutaneous (sc)
once daily administration of enoxaparin 40 mg, bemiparin 3500 IU,
parnaparin 4250 IU or the sc administration of UFH 5000 units every 8-
12 hours.
Outcomes
Selected studies were included in the meta-analysis if they reported
the following outcomes: occurrence of VTE, major or minor bleeding,
and anti-Xa circulating levels (anti-Xa). VTE was defined when at least
one of the following events had occurred: superficial vein thrombosis,
deep vein thrombosis or pulmonary embolism as confirmed by
compressive ultrasound, computerized pulmonary angiography, or ICD-
9 coding (VTE events diagnosis codes from 453.8 to 453.89 and 415.1,
V12.51, 673.8) in retrospective studies.
According to the ISTH criteria, bleeding was defined as clinically
overt bleeding associated with one or more of the following: transfusion
of at least two units of packed red blood cells; intracranial or retroper­
itoneal bleeding or bleeding involving a body cavity; bleeding-related
death; ICD-9 coding (bleeding-events diagnosis codes 287.4, 287.3,
287.39, 287.5, 289.82, 287.1 and 289.84).
Data collection and management
In addition to the above mentioned outcomes, the following infor­
mation was extracted from each study when available: publication type,
study design, length of follow-up, type of population (medically ill,
general surgery patients, bariatric surgery patients, pregnant women),
BMI, type of heparin, number of patients, age, country, number of males,
year of publication. We extracted and displayed data according to the
PRISMA criteria (Fig. 1).
D. Ceccato et al. European Journal of Internal Medicine 88 (2021) 73–80

Table 1
Summary of the selected studies.
Author, year (reference) N Outcome Heparin regimen Country Design Mean Population Male Age
BMI (%) (yrs)

Beall J et al., 2016 [20] 2378 Clinical SD: heparin 5000u q8h USA Retrospective NA BMI > 30 (ICD- 54 56
AD: heparin 7500u q8h 9)
Borkgren-Okonek MG et al., 223 Clinical + SD: enoxaparin 40 mg/d USA Prospective 50.4 Bariatric surgery 25 44
2007 [21] anti-Xa AD: enoxaparin 60 mg q12h
Freeman A et al., 2012 [22] 30 Clinical + SD: enoxaparin 40 mg/d USA Prospective 61.3 BMI > 60 31 44
anti-Xa AD: enoxaparin 0.4-0.5 mg/d
Frezza E et al., 2006 [23] 155 Clinical SD: hep 7000u/d or enoxaparin USA Retrospective 46.9 Bariatric surgery 1 39
2 mg/d
AD: hep 7000u q12h or
enoxaparin 2 mg/q12h
Imberti D et al., 2014 [24] 258 Clinical SD: parnaparin 4250 IU/d Italy RCT 44 Bariatric surgery 20 40
AD: parnaparin 6400 IU/d
Miranda S et al., 2017 [17] 91 Clinical + SD: enoxaparin 40 mg/d France RCT 37.8 BMI > 30 46 70
anti-Xa AD: enoxaparin 60 mg/d
Reynolds PM et al., 2019 6300 Clinical SD: heparin 5000u q12h USA Retrospective NA BMI > 30 (ICD- NA NA
[25] AD: heparin 7500u q8h 9)
Rottenstreich A et al., 2018 60 Clinical + SD: enoxaparin 40 mg/d Israel Prospective 38 Obese pregnant 0 36
[26] anti-Xa AD: enoxaparin 60 mg/d
Steib C et al., 2015 [27] 164 Clinical + SD: enoxaparin 40 mg/d France RCT 49 Bariatric surgery 24 39
anti-Xa AD: enoxaparin 60 mg/d or
4000 q12h
Vavken P et al., 2009 [28] 750 Clinical SD: bemiparin 3500 IU/d USA RCT NA Bariatric surgery 60 55
AD: bemiparin 5000 IU/d
Wang TF et al., 2014 [29] 9241 Clinical SD: heparin 5000u q8h or enoxa USA Retrospective 39* BMI 30-40 and > 56* 56*
40 mg/d 40
AD: heparin 7500u q8h or
enoxaparin 60 mg/d

Abbreviations: BMI: body mass index; SD: standard dose; AD: adjusted dose; USA: United States of America; RCT: randomized clinical trial; NA : non available; hep:
heparin; enoxa: enoxaparin
* % refers on cohort who developed VTE events

Assessment of the quality of the studies

Table 2
The Newcastle-Ottawa Scale (NOS) for the assessing the quality of studies.
Two independent investigators completed the assessment of the
quality of the studies according to the Newcastle-Ottawa Scale (NOS), Study Selection Comparability Outcome NOS
Score
which was specifically developed to assess the quality of non-
randomized observational studies. The scoring system includes the Beall J et al., 2016 ** * * * * Medium
following eight items: clear definition of the study sample, selection, Borkgren-Okonek MG ** * * * * * Medium
et al., 2007 ** * * * Low
interventions, outcomes, adequate assessment of the outcome, analyses Freeman A et al., 2012 ** * * * Low
for comparability, adequate length of follow-up, and appropriate Frezza E et al., 2006 ** ** * * * High
interpretation of results. If an item was adequately addressed, 1 point Imberti D et al., 2014 ** * * * * * Medium
each was awarded for the first seven specific items and 2 points for Miranda S et al., 2017 ** * * * * Medium
Reynolds PM et al., ** * * * Low
analyses for comparability. This results in a quality score between 0 and
2019 ** * * * ** Medium
9. Studies with a score ≥7 were considered of high quality, medium Rottenstreich A et al., ** * * * * Medium
quality for scores between 4 and 6, and low quality for scores ≤3 [19]. 2018 ** * * * * * High
Steib C et al., 2015
Vavken P et al., 2009
Meta-analysis
Wang TF et al., 2014

Data were synthesized using meta-analytic method. Selected out­

comes were VTE, bleeding occurrence and anti-Xa levels. Effect size (ES)
was calculated comparing groups of obese patients treated with stan­
dard heparin or weight-adjusted doses. Calculations were based on bi­
nary data, means and standard deviations, p values and sample sizes of
the groups according to data reported in the primary studies. Data were
statistically pooled by the standard meta-analysis approach, meaning
that studies were weighted by the inverse of the sampling variance. The
random effect model was used as a conservative approach to account for
different sources of variation among studies. The Q statistic was used to
assess heterogeneity among primary studies, with a significant value
indicating the lack of homogeneity of findings between the studies.
Categorical characteristics such as experimental design (retrospective vs
prospective), surgical vs medical conditions, and quality of study were
treated as moderators, and effect sizes were compared across subgroups
formed by these moderators, while continuous variables (percent of
female patients, mean BMI and age) were examined as covariates using
random effects (method of moments) meta-regression. Very few or none
of the studies reported data on the duration of the treatment and pre­
vious VTE, which were not considered in the meta-regression.
Publication bias was assessed using the Funnel plot, Egger’s t test and
Begg’s test. Based on conventional standards, ES of 0.20, 0.50 and 0.80
were considered small, medium and large, respectively. ProMeta3
software (Internovis.a.s., Cesena, Italy) was used for statistical analysis
and reporting of data conformed to the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) statements.
Results
Study identification and selection
As shown in Fig. 1, of the 1006 potentially eligible studies 995 were
excluded, leaving 11 articles for our meta-analysis. The main charac­
teristics of these 11 studies are summarized in Table 1. One article re­
ported study on different populations that were treated separately and

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D. Ceccato et al. European Journal of Internal Medicine 88 (2021) 73–80

Fig. 2.. Forest plots of VTE occurrence and bleeding in fixed versus weight-adjusted doses.

Fig. 3.. Forest plot of anti-Xa factor levels.

then a total of 12 primary studies were extracted. Table 2 shows the
assessment of methodological quality for the 11 studies included in the
systematic review.
Effect of standard vs adjusted dose of heparins on VTE, bleeding and anti-
Xa circulating levels
Forest plots of the odds ratio of fixed versus weight-adjusted doses of
heparins on VTE (OR 1.03, 0.79 to 1.35, k=14, p=ns) and bleeding (OR
0.84, 0.65 to 1.08, k=14, p=ns) are reported in Fig. 2. Forest plot of the
effect size of fixed versus weight-adjusted dose of heparins on anti-Xa
levels is reported in Fig. 3. Anti-Xa levels were significantly higher in
adjusted dose treatment (Hedges’s g: 2.04, 1.16 to 2.92, k=7,
p<0.0001).
Heterogeneity analysis and publication bias
Heterogeneity statistics did not show any significant heterogeneity
for VTE occurrence (Q=14.07, I2=7.60, p=ns) and bleeding (Q=14.92,
I2=12.89, p=ns), while a significant degree of heterogeneity was
observed for the ES on anti-Xa levels (Q=107.30, I2=94.41, p<0.0001).
Publication bias was not significant for VTE occurrence (Egger’s test:
p=ns; Begg’s test p=ns) and bleeding (Egger’s test: p=ns; Begg’s test
p=ns), while being significant for anti-Xa levels (Egger’s test: p=0.024;
Begg’s test p=0.051).
Moderators analysis comparing outcomes defined as VTE occurrence
and bleeding events in surgical vs medical conditions, low vs medium
quality and prospective vs retrospective studies did not show any dif­
ference between groups (both p>0.30), as reported in Figs. 4, 5 and 6.

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Fig. 4. Moderators analysis comparing outcomes in surgical vs medical and different quality of studies.
Also continuous variables (percent of female patients, age and mean
BMI) did not show any statistical significance. Due to a high heteroge­
neity of “standard” dose and “weight-adjusted” dose in both heparin and
low molecular weight heparin group, a moderator comparison analysis
was not performed.
Discussion
This systematic review and meta-analysis aims to clarify, using data
extracted from 11 studies, the management of thromboprophylaxis in
obese inpatients. After comparing different strategies including standard
dose and weight-adjusted regimen of heparin, none has been shown to
be superior in terms of reduction in VTE related-events nor in bleeding
events. In addition, according to the results of our data, the efficacy and
safety of standard doses for VTE prevention in patients with obesity is
maintained both in the surgical and in the medical ward settings.
Although the use of weight-adjusted heparin doses achieves a higher
peak of anti-Xa levels, there is no clinical correlation between laboratory
data and clinical outcomes.
Obesity is an independent and well established risk factor for VTE
(Ageno et al estimated an OR of 2.3 VTE in obese patients [30] and VTE
recurrence [31], even if the mechanisms behind this causal relationship
remain unclear. Different elements can play a role in this pro-thrombotic
hemostatic balance. On one hand, obesity results in venous stasis and
less degree of mobility; on the other hand, it induces a low grade chronic
inflammatory state created by the adipose tissue. Indeed, adipocytes
dysfunction is responsible for the production of pro-inflammatory mol­
ecules such as IL-6 and TNF-α, and the recruitment of macrophages, with
consequent activation of prothrombotic signaling pathways in vascular
cells and impaired fibrinolysis. Additionally, surgery itself promotes
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European Journal of Internal Medicine 88 (2021) 73–80
oxidative stress and endothelial dysfunction in the early post-operative
period, with particular relevance in the case of bariatric procedures.
Data from several studies illustrate that an increasing BMI has a strong
linear association with the development of VTE events [32,33].
Accordingly, adult patients with greatest BMI are exposed to an increase
risk of pulmonary embolism (PE) and deep vein thrombosis (DVT).
However, in most pharmacodynamic and clinical studies of thrombo­
prophylaxis using heparins agents, obese and morbidly obese (BMI ≥40
kg/m2) patients have been under-represented. A surrogate value for
estimating heparin concentration is the anti-factor Xa level (eg for
enoxaparin between 0.32 and 0.54 IU/mL). ACCP guidelines point out
that there is a negative correlation between total body weight (TBW)
and anti-factor Xa levels in overweight patients. Consequently, obese
and morbid obese patients are unlikely to receive an adequate throm­
boprophylaxis because of decreased anti-factor Xa levels [34,35,36].
As far as we know, for the first time in the literature our meta-
analysis points out that in obese and morbid obese inpatients standard
doses of heparin for thromboprophylaxis are effective and safe. An
increased efficacy of a weight-adjusted strategy was observed from
Borkgren-Okonek et al [21], who first proposed in bariatric patients a
BMI-stratified strategy Our results differ from those reported, but are
consistent with those obtained by Ikesaka et al [28] and by Imberti et al
[29] in the same clinical setting Of interest, the results of our
meta-regression analysis apply to both medical and surgical inpatients.
They are consistent with those coming from the ITOHENOX trial, where
two regimens of enoxaparin were adopted in 91 obese inpatients [17]
and with those from two large retrospective studies [37,25], both sup­
porting the lack of an association between heparin dosage and rate of
VTE events during hospitalization in obese patients. These results may
confirm the concept of a “therapeutic threshold” for heparins in VTE
D. Ceccato et al. European Journal of Internal Medicine 88 (2021) 73–80

Fig. 5. Moderators analysis comparing outcomes in low vs high quality of studies.

Fig. 6. Moderators analysis comparing outcomes in prospective vs retrospective studies.

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D. Ceccato et al.
prophylaxis, not requiring a weight-adjusted dosage. However, the lack
of standardization of studies design and the small amount of good data
represent a limitation of our analysis.
What is true for obese may not be true for morbidly obese patients.
Some authors have proposed that anti-Xa monitoring might be of value
to guide doses of prophylactic parenteral anticoagulants in patients who
are morbidly obese. However, even if clinical trials have demonstrated
that an increased dosage of heparin provides a higher control of anti-Xa
levels [38,39], none were able to observe a greater efficacy in terms of
reduction of VTE events. These conclusions are supported by the
sub-group analysis of our data. However, the number of morbidly obese
patients may not have been large enough to exclude a clinically mean­
ingful advantage of higher doses of heparin in this subgroup of patients.
Besides this limitation, we acknowledge the heterogeneity of obesity
definition, not always reported as BMI ≥30 Kg/m2, the limited number
of randomized controlled trials, the heterogeneity of the outcomes (re­
ported as clinical events, anti-Xa levels or, retrospectively, as ICD-9
code), and the failure to access individual patients data. In addition,
the low to moderate average quality of the studies, may have introduced
bias into the analysis, along with the results of studies with LMWH and
UFH.along
Because of these limitations, there is the need for confirmatory large
prospective clinical trials addressing the comparison between different
heparin regimens on primary VTE prevention in obese and morbidly
obese patients are warranted. Furthermore, it will be of interest to
evaluate the role of the direct oral anticoagulants in this setting.
Conclusion
Despite the common use in clinical practice of higher heparin doses
among obese hospitalized patients, a weight-adjusted thromboprophy­
laxis does not reduces the risk of VTE respect to a fixed-dose strategy,
nor increases the risk of major bleeding. This data confirms the concept
of a therapeutic threshold for heparins in VTE prophylaxis, not requiring
a weight-adjusted strategy. Thus, a fixed-dose heparin should be used for
VTE prophylaxis irrespective BMI levels[a1] . [a1]Conclusion para­
graph as suggested by Reviewer #3.
Author Contributions
Study design, data analysis, and draft writing, D.C., A.D.V.,C.P. and
R.P.; data collection and interpretation, R.P., C.P., P.P., D.C. and A.D.V.;
data collection and management, D.C., C.P.; critical revision of the
article for important intellectual content, D.C., A.D.V., P.P., R.V. All
authors have read and agreed to the published version of the
manuscript.
Declaration of Competing Interest
The authors of this manuscript have no conflicts of interest.
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