Safety and efficacy of low-molecular-weight heparins in prophylaxis of deep vein thrombosis in postoperative/ICU patients: A comparative study

Abstract

Venous thromboembolism (VTE), although a very common problem in everyday clinical practice, remains asymptomatic in most cases. Clinical diagnosis helps identify those who are going to have thromboembolic episode. A combination of clinical scoring systems like Wells' score and D-dimer assay provide a useful diagnostic tool. Trauma (surgical or accidental) and critically ill patients are found to have greatest risk. Enoxaparin and dalteparin are amongst the most common low-molecular-weight heparins (LMWHs) used for deep venous thrombosis (DVT) prophylaxis in such patients.
The present study is designed to compare their role in preventing DVT in postoperative or critically ill patients and to determine their relative safety profiles.
The study included 36 critically ill adult patients. All the patients were allocated into three groups of 12 patients each. Group I patients received no prophylaxis, group II received inj. enoxaparin s/c 0.6-0.8 mg/kg twice daily, and group III received inj. dalteparin s/c 125-250 units/kg once daily. Routine investigations and coagulation profile were recorded on admission to intensive care unit (ICU) and at every third day thereafter. Patients were daily assessed for pretest probability of DVT using Wells' scoring, and D-dimer test was done on the 7(th) day. Occurrence of any bleeding (visible or occult) was noted, and incidence of DVT was determined in each group using positive results of D-dimer test and the clinical assessment with Wells' score.
A significant difference in Wells' score (P < 0.05) was found between groups I and III on day 5 and day 7. A lower, but insignificant difference in the incidence of DVT was found between the study and control groups. No significant difference in major bleeding or other side effects was found. Better hemodynamic status and arterial blood gases in the study groups may indirectly refer to absence of asymptomatic DVT or silent pulmonary embolism in this group.
The present study suggests that LMWHs, namely, enoxaparin and dalteparin, provide effective means of preventing DVT in high-risk, critically ill or postoperative patients, without causing any significant increase in the risk of bleeding or other side effects. Dalteparin appears to be unaffected by low creatinine clearance as explained by its clearance by a non-saturable mechanism. Still, a more extensive study with larger population is needed to make the outcomes worthwhile.

Full text

197
Journal of Natural Science, Biology and Medicine | January 2013 | Vol 4 | Issue 1
Safety and efcacy of low‑molecular‑weight
heparins in prophylaxis of deep vein thrombosis in
postoperative/ICU patients: A comparative study
Abstract
Background: Venous thromboembolism (VTE), although a very common problem in everyday clinical practice, remains asymptomatic
in most cases. Clinical diagnosis helps identify those who are going to have thromboembolic episode. A combination of clinical scoring
systems like Wells’ score and D-dimer assay provide a useful diagnostic tool. Trauma (surgical or accidental) and critically ill patients
are found to have greatest risk. Enoxaparin and dalteparin are amongst the most common low‑molecular‑weight heparins (LMWHs)
used for deep venous thrombosis (DVT) prophylaxis in such patients. Aim: The present study is designed to compare their role in
preventing DVT in postoperative or critically ill patients and to determine their relative safety proles. Materials and Methods: The
study included 36 critically ill adult patients. All the patients were allocated into three groups of 12 patients each. Group I patients
received no prophylaxis, group II received inj. enoxaparin s/c 0.6‑0.8 mg/kg twice daily, and group III received inj. dalteparin s/c
125‑250 units/kg once daily. Routine investigations and coagulation prole were recorded on admission to intensive care unit (ICU)
and at every third day thereafter. Patients were daily assessed for pretest probability of DVT using Wells’ scoring, and D-dimer test
was done on the 7th day. Occurrence of any bleeding (visible or occult) was noted, and incidence of DVT was determined in each
group using positive results of D-dimer test and the clinical assessment with Wells’ score. Results: A signicant difference in Wells’
score (P < 0.05) was found between groups I and III on day 5 and day 7. A lower, but insignicant difference in the incidence of DVT
was found between the study and control groups. No signicant difference in major bleeding or other side effects was found. Better
hemodynamic status and arterial blood gases in the study groups may indirectly refer to absence of asymptomatic DVT or silent
pulmonary embolism in this group. Conclusion: The present study suggests that LMWHs, namely, enoxaparin and dalteparin, provide
effective means of preventing DVT in high‑risk, critically ill or postoperative patients, without causing any signicant increase in the
risk of bleeding or other side effects. Dalteparin appears to be unaffected by low creatinine clearance as explained by its clearance
by a non‑saturable mechanism. Still, a more extensive study with larger population is needed to make the outcomes worthwhile.
Key words: D-dimer, deep vein thrombosis, low-molecular-weight heparin, venous thromboembolism
Arpita Saxena,
Apurva Mittal,
Arya S. K.,
Deepak Malviya,
Uma Srivastava
Department of Anesthesiology and Critical Care, B. R. D. Medical College, Gorakhpur,
Uttar Pradesh, India
Address for correspondence:
Dr. Arpita Saxena, Department of Anesthesia and Critical Care, B. R. D. Medical College, Gorakhpur,
Uttar Pradesh, India. E-mail: apoorvsn@yahoo.com
INTRODUCTION
Deep vein thrombosis (DVT) commonly affects the
leg veins or the deep veins of the pelvis. In high-risk
hospitalized patients, most deep vein thrombi occur in
the small calf veins, are asymptomatic, and are rarely
detected, even if symptomatic. Vague aching pain,
tenderness along the distribution of the veins, edema,
and erythema are nonspecic and vary in frequency
and severity. Tenderness, swelling of the whole leg,
>3 cm difference in circumference between calves,
pitting edema, and collateral supercial veins are the
most specic signs. A combination of ≥3 signswith the
absence of another likelydiagnosis makes DVT more
probable
Although many thrombi are initially asymptomatic, in many
cases, the affected extremity may be painful, swollen, red,
and warm, with engorged supercial veins. In up to 25%
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DOI:
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Original Article
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Saxena, et al.: Comparison of low molecular weight heparins for DVT prophylaxis
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Journal of Natural Science, Biology and Medicine | January 2013 | Vol 4 | Issue 1
of all hospitalized patients, there may be some form of
DVT, which often remains clinically inapparent (unless
pulmonary embolism develops).[1] In fact, pulmonary
embolism remains the most common preventable cause
of death in hospital.[2]
To identify clinically important thrombi in patients, Wells’
score[3] for DVT have been developed. It combines many
clinical parameters to increase the sensitivity. Recently,
the revised Geneva score[4] has been introduced for
determination of probability of pulmonary embolism.
Along with these scoring systems, D-dimer assay is
validated as a diagnostic tool to safely exclude the presence
of venous thromboembolism (VTE) due to its high
negative predictive value (NPV).[5,6]
Prophylaxis is preferred to treatment in patients at high
risk of developing DVT. The present study was designed
to assess and compare the efcacy of enoxaprin and
dalteparin in preventing DVT in medical or post-surgical
patients admitted to intensive care unit (ICU) and to
determine their relative safety margins.
MATERIALS AND METHODS
The present study was conducted in the ICU of
Department of Anesthesiology, Nehru Hospital, B. R. D.
Medical College, Gorakhpur. Adult patients of either sex
admitted to the ICU were included in this study.
Exclusion criteria included:Active bleeding, congenital/
acquired bleeding disorders or therapeutic anticoagulation,
hemorrhagic stroke, brain/spinal/ocular surgery in
≤6 months, pregnancy/lactation, hypersensitivity to study
drugs, or thrombocytopenia < 100 × 109/L.
A total of 36 patients were included in the study. All
patients were routinely investigated and their coagulation
prole was done on admission to ICU and at every third
day thereafter. Serial hemoglobin concentration was
obtained by daily arterial blood gas (ABG) analysis. Patients
were assessed and scored for pretest probability (PTP) of
DVT using Wells’ scoring on admission and daily for ten
consecutive days thereafter. Patients were continuously
monitored for pulse rate, respiratory rate, non-invasive
blood pressure (NIBP), temperature, electrocardiography,
SpO2, and urine output.
All the patients were randomly allocated into three groups
of 12 patients each and received prophylaxis with one of
the following dosing regimens:
• Group I: Patients receiving no prophylaxis (control
group)
• Group II: Patients receiving enoxaparin s/c
0.6–0.8 mg/kg twice daily
• Group III: Patients receiving dalteparin s/c
125–250 units/kg once daily
Patients received prophylaxis for adequate duration, but
the study period was the rst 10 days of admission. The
rst dose was given 12–24 h after surgery in postoperative
patients. In non-surgical patients, prophylaxis was started
on the day of admission. In all the patients, therapy
was continued as per dosing regime being followed for
DVT prophylaxis based on the Eighth American College
of Chest Physicians (ACCP) Consensus Conference
recommendations.[7]
The patients were daily assessed for the occurrence of
any bleeding from the surgical site or any visible or occult
bleeding. Thromboprophylaxis was stopped in case of
bleeding, and International Normalized Ratio (INR) and
platelet counts were repeated.
The most important efcacy parameter was incidence
of VTE in the rst 10 days. The incidence of DVT was
determined in each group using positive results of D-dimer
test and the clinical assessment with Wells’ score.[8] Assay
was done on the 7th day. The patients developing DVT were
treated with anticoagulating doses of low-molecular-weight
heparin (LMWH).
Other safety parameters included incidence of side
effects like ecchymoses, skin rashes/pruritus, and
thrombocytopenia (<100 × 109/L) or more than 3 times
elevation in alanine aminotransferase (ALT) levels.
Statistical analysis
Statistical evaluation was done using independent variable
Student’s t-test and Chi-square test. Two software programs
were used, namely, Decision analyst, Inc 1998 version 1.1
and Javastat. Difference between variables was considered
as nonsignificant with P value >0.05, significant at
P value <0.05, highly signicant at P value <0.01, and very
highly signicant at P value <0.001.
RESULTS
All the three groups were comparable in their demographic
prole [Table 1]. Each group was composed of 58.33% and
41.67% each of medical and surgical patients, respectively.
Hemodynamic parameters like pulse rate, blood pressure,
respiratory rate, and PaO2 were taken into account as
indicators of asymptomatic DVT or silent pulmonary
embolism [Table 2]. Multiple readings were recorded
over 24-h period and their mean was calculated. Group I had
higher mean pulse rates as compared to groups II and III.
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Saxena, et al.: Comparison of low molecular weight heparins for DVT prophylaxis
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Journal of Natural Science, Biology and Medicine | January 2013 | Vol 4 | Issue 1
Group I had lower mean diastolic blood pressure. But
statistical comparison of study and control groups using
independent t-test showed no signicant difference in mean
pulse rates, systolic, diastolic pressures, respiratory rates, and
mean partial pressures of oxygen at different time intervals
(P > 0.05). Similarly, there was no signicant difference in
Wells’ scores on day 1 and day 3. But signicant difference
was found between groups I and III on day 5 (P < 0.05),
and a highly and very highly signicant difference on day
7 between groups I and III (<0.01) and between groups I
and II (P < 0.001), respectively. Study groups (groups II
and III) showed lower incidence of DVT (one patient each)
than group I (three patients), but statistical comparison
using Chi-square test showed no signicant difference in
the incidence of DVT (P > 0.05) [Table 3].
There was no mortality during the study period. Only
a single patient developed ecchymoses (group III). No
case of thrombocytopenia, skin rash, pruritus, or rise
in serum ALT level was seen. Group I had only a single
incidence of bleeding as indicated by sudden fall in
daily hemoglobin levels of >2 g/dl and required blood
transfusion. Group II had two patients showing fall
in serial hemoglobin and one patient with surgical site
bleeding. Group III similarly had two patients showing fall
in serial hemoglobin concentration and one patient with
hematuria. But statistical comparison of study and control
groups showed no signicant difference in hemoglobin
concentration, incidence of major bleeding, and INR at
different time intervals.
DISCUSSION
DVT is a common, but highly preventable complication
in hospitalized patients. If not provided prophylaxis,
nearly 40% of ICU patients; 30% of general surgical
patients; and 15% of general medical patients develop
DVT.[1] The most common risk factors are recent surgery
or hospitalization.
This study is aimed at determining the relative efcacies
of the two commonly used LMWHs, i.e. enoxaparin and
dalteparin, in ICU patients (medical/surgical) for DVT
prophylaxis and assessing and comparing their safety
margins.
Bounameaux et al. (2002)[9] studied the diagnostic approaches
to suspected DVT and pulmonary embolism and found
the strategy of using clinical probability and D-dimer as
rst-line screen to be a safe and cost-effective approach,
with a signicant reduction for the need of ultrasound
scans.Ten Cate‑Hoek et al. (2005)[10] have shown that the
approach of combining PTP with a modern D-dimer assay
can safely exclude disease in up to half of the patients with
suspected VTE, without the need for additional diagnostic
investigations. In concurrence with these studies, we used
Wells’ criteria and D-dimer assay for detecting DVT.
In the present study, the probability of developing DVT
during the study period, as assessed by Wells’ clinical scoring
system, was higher in the control group as compared to the
study groups. This refers to a reduction in the probability
of DVT in the study groups by LMWHs used for DVT
prophylaxis.
Similarly, results of D-dimer assay showed a higher
incidence (25% vs. 8.33%) of DVT in group I as compared
to study groups, but statistically it was not signicant.This
Table 1: Demographic data
Groups Male:Female
(n)
Age
(years)
Height
(m)
Weight
(kg)
BMI
(kg/m²)
I 6:6 58.2±11.9 1.5±0.1 53.7±7.2 23.1±4.6
II 7:5 57.7±11.1 1.6±0.6 55.5±5.8 23.8±4.3
III 7:5 58.6±10.9 1.5±0.1 53.7±5.2 23.7±3.2
Table 2: Comparison of various hemodynamic parameters
Pulse rate (per minute) Systolic blood
pressure (mmHg)
Diastolic blood
pressure (mmHg)
Respiratory rate PaO2
Day 5 Day 7 Day 5 Day 7 Day 5 Day 7 Day 5 Day 7 Day 5 Day 7
Group I 112.3±18.8 115.8±17.7 108.4±16.1 108.6±17.8 77.5±10.3 77.8±8.4 20.8±4.9 21.0±4.7 199.3±103.6 208.2±104.0
Group II 102.5±17.7 103.3±18.2 109.1±17.0 110.0±16.8 80.1±14.7 79.6±14.5 20.3±4.7 21.0±4.6 191.9±111.8 199.8±110.0
Group III 101.8±20.7 102.2±22.2 115.0±14.0 112.5±16.0 81.3±13.5 79.8±13.5 21.0±4.7 20.6±4.5 194.4±101.8 206.3±111.3
Table 3: Comparison of DVT and major bleeding
Wells’ scores D-dimer on day 7>0.05 mg/dl
or symptomatic DVT (n)
Incidence of major bleeding (n)
Day 5 Day 7
Group I 3.2±0.7 3.1±0.8 3 1
Group II 2.6±0.8 2.1±0.9* 1 3
Group III 2.3±0.9* 2.1±0.8* 1 3
*Statistically signicant on comparison with group I
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Journal of Natural Science, Biology and Medicine | January 2013 | Vol 4 | Issue 1
denotes the efcacy of LMWHs in reducing the incidence
of DVT in the study population, but signicant results
have not been found probably due to smaller group size.
Similar results were obtained by Theodore et al. (1994)[11]
who used different laboratory parameters to determine the
most effective and safest dose of enoxaparin for high-risk
surgical patients. They concluded that administration
of 30 mg of enoxaparin 12 hourly or 40 mg once daily
substantially reduced the incidence of DVT. In a similar
study, Ribic et al. (2008)[12] systematically reviewed the
effect of LMWH thromboprophylaxis in medical–surgical
critically ill patients in the ICU.They reviewed data like
LMWH use, clinical outcomes, laboratory outcomes, and
methodological quality. Thrombocytopenia occurred in
9.3% of patients receiving LMWH, as compared to none
in the present study. The frequency of VTE in patients
receiving LMWH ranged from 5.1 to 15.5% (8.33% in the
present study). Bleeding complications ranged from 7.2
to 23.1% (25% in the present study) and mortality ranged
from 1.4 to 7.4% (nil in the present study).
On comparison of study and control groups, no signicant
difference in major bleeding was found at different time
intervals (P ≥ 0.05). This indicates that using LMWHs
for DVT prophylaxis did not lead to an increase in the
incidence of bleeding. This is consistent with the ndings
of Theodore et al. (1994)[11] who found that incidence of
hemorrhagic episodes in the study groups was higher than
in the control group, but the overall incidence of major
hemorrhage was only 4–5%.
Further, on comparison of the study groups (II and III),
no difference was found in the incidence of DVT or
bleeding. But randomized trials in larger group are required
for nal inference. Likewise, in 2003, Chiou-Tan et al.,[13] in
a prospective study comparing dalteparin and enoxaparin
for DVT prophylaxis in patients with spinal cord injury,
found similar compliance, health status, DVT, and bleeding.
However, Cook et al. (2005)[14] studied the use of LMWH
for thromboprophylaxis in patients with renal impairment
and found that prophylactic doses of enoxaparin had to
be reduced from 30 mg twice daily to 40 mg once daily
for high-risk patients, while no such dose adjustment was
required for dalteparin.
To summarize, we found that use of LMWHs,
e.g. enoxaparin and dalteparin, is benecial in reducing
the incidence of DVT in postoperative/ICU patients,
without causing signicant side effects. However, studies
recruiting larger number of patients are required for any
recommendations.
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How to cite this article: Saxena A, Mittal A, Arya SK, Malviya D,
Srivastava U. Safety and efcacy of low‑molecular‑weight heparins in
prophylaxis of deep vein thrombosis in postoperative/ICU patients: A
comparative study. J Nat Sc Biol Med 2013;4:197-200.
Source of Support: Nil. Conict of Interest: None declared.
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