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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 1  |  Issue : 1  |  Page : 3-9

Comparison of the effectiveness and safety of enoxaparin vs. unfractionated heparin for venous thromboembolism (VTE) prophylaxis in critically ill medical patients


1 Department of Pharmaceutical Care, King Abdulaziz Medical City; College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences; King Abdullah International Medical Research Center; Saudi Critical Care Pharmacy Research (SCAPE) Platform, Riyadh, Saudi Arabia
2 Department of Pharmaceutical Care, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
3 Department of Statistics, European Organization for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium
4 Intensive Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia
5 Department of Clinical Pharmacy, Taif University, Taif, Saudi Arabia
6 Department of Pharmaceutical Care, King Fahad Hospital, Baha, Saudi Arabia
7 Saudi Critical Care Pharmacy Research (SCAPE) Platform, Riyadh; Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia

Date of Submission15-Sep-2021
Date of Acceptance17-Feb-2022
Date of Web Publication30-Mar-2022

Correspondence Address:
Dr. Khalid Al Sulaiman
King Abdulaziz Medical City (KAMC), Ministry of National Guard Health Affairs (MNGHA), King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, PO Box 22490, 11426 Riyadh
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjcp.SJCP_1_21

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  Abstract 

Critically ill patients are more likely to acquire venous thromboembolism (VTE) due to various underlying factors, including severe illness, mechanical ventilation, sedative medications, and extended immobility. Thromboprophylaxis is a crucial component in critically ill patients’ management because of their high risk of VTE. However, there is uncertainty about the appropriate type of pharmacological VTE prophylaxis in critically ill patients admitted to the medical intensive care units (ICUs). Therefore, our study aims at evaluating the effectiveness and safety of standard dosing regimens (Enoxaparin vs. unfractionated heparin (UFH)) as a VTE prophylaxis in those populations. This is a retrospective cohort study included medical ICU patients aged ≥ 18 years with a normal body mass index (BMI) who received either Enoxaparin 40 mg daily or UFH 5000 Unit three times daily as a VTE prophylaxis between January 1, 2018 and December 31, 2018. The primary outcome was VTE and any case of thrombosis, and the secondary outcomes included complications during the ICU stay (i.e., major bleeding, minor bleeding, RBC transfusion during ICU stay, HAT, and HIT). A total of 1866 patients were screened; 311 patients were included in the study. The differences in VTE (OR 0.47; 95% CI 0.10–4.10; P = 0.49) and any case of thrombosis (OR 0.43;95%CI 0.14–1.32; P = 0.14) during ICU were similar between the two groups and not statistically significant. Conversely, patients who received enoxaparin have a higher incidence of major bleeding, specifically GI bleeding, compared with UFH (OR 3.30; 95% CI 0.85–12.61; P = 0.08); however, it is not statistically significant. Standard dosing of enoxaparin in critically ill medical patients was not associated with thrombosis benefit, but it is linked with higher odds of GI bleeding.

Keywords: Critically ill, DVT prophylaxis, enoxaparin, unfractionated heparin (UFH), intensive care units (ICUs), medical ICUs, VTE prophylaxis


How to cite this article:
Al Sulaiman K, Alshehri A, Vishwakarma R, Bakhsh U, Kharbosh A, Mokali A, Aljuhani O. Comparison of the effectiveness and safety of enoxaparin vs. unfractionated heparin for venous thromboembolism (VTE) prophylaxis in critically ill medical patients. Saudi J Clin Pharm 2022;1:3-9

How to cite this URL:
Al Sulaiman K, Alshehri A, Vishwakarma R, Bakhsh U, Kharbosh A, Mokali A, Aljuhani O. Comparison of the effectiveness and safety of enoxaparin vs. unfractionated heparin for venous thromboembolism (VTE) prophylaxis in critically ill medical patients. Saudi J Clin Pharm [serial online] 2022 [cited 2022 Jul 6];1:3-9. Available from: http://www.sjcp.org/text.asp?2022/1/1/3/341438


  Introduction Top


Venous thromboembolism (VTE) includes deep vein thrombosis (DVT) and pulmonary embolism (PE). DVT is the formation/presence of a thrombus in the deep veins.[1] However, PE is an obstruction of the pulmonary artery or its branches by a thrombus.[1] The most likely source of thrombus in pulmonary arteries is an embolization from deep veins of the legs, occurring in one-third of patients with DVT. Many studies showed that VTE is a leading cause of death and disability worldwide that requires immediate medical attention.[2]

Critically ill patients are at higher VTE risk due to underlying severe illness, sedative drugs, invasive lines, and prolonged immobilization.[3] Further, PE incidence in the ICU was clinically suspected in 0.4% to 2.3% of medical ICU patients; the incidence increased to 3.2% in post-traumatic ICU patients, despite the use of pharmacological thromboprophylaxis.[4] A randomized control trial evaluating the efficacy and safety of heparin thromboprophylaxis vs. placebo in 7,226 medical-surgical patients in the ICU, Alhazzani et al.[5] found that heparin thromboprophylaxis has significantly reduced the rate of DVT (risk ratio, 0.51 [95% CI, 0.41, 0.63]; (P < 0.0001)) and PE (risk ratio, 0.52 [95% CI, 0.28, 0.97]; (P = 0.04)). Therefore, thromboprophylaxis is a crucial component of critically ill patients because of their high risk of VTE.[6] The American society of hematology (ASH) guideline panel recommends using UFH or LMWH over no pharmacological VTE prophylaxis, as those populations are at a high risk for developing VTE.[7]

There is uncertainty about the appropriate type of pharmacological VTE prophylaxis. A prospective cohort study that was conducted on 798 medical-trauma-surgical ICU patients by Al-Dorzi, et al.[8] found that there was no difference in VTE incidence during ICU stay between patients who received enoxaparin (8.0%) and patients who received UFH (7.5%). However, this study was limited by the heterogenicity of the patients which included medical, trauma, and surgical ICU patients.

There is a lack of studies that evaluate the safety and effectiveness of different types of VTE prophylaxis, specifically in standard dosing (UFH 5000 U q8h vs. Enoxaparin 40 mg q24h) for critically ill medical patients. Therefore, our study aimed to evaluate the effectiveness and safety of standard dosing for different types of VTE prophylaxis in this population.


  Materials and Methods Top


Study design

A retrospective cohort study was conducted, including adult critically ill medical patients admitted to the ICU between January 1, 2018 and December 31, 2018. All patients who met inclusion criteria during the time period were included in this study [Figure 1]. Eligible patients were then categorized into two groups based on the type of standard dosing of DVT prophylaxis (i.e., Enoxaparin 40 mg Q24 h vs. Heparin 5000 Units Q8 h). We used propensity score adjustment between the two groups based on the patient’s APACHE II score, serum creatinine baseline, INR baseline, and cancer as coexisting illnesses. The study was approved by King Abdullah International Medical Research Center (KAIMRC)-Institutional Review Board (Study Number: NRC21R/188/04).
Figure 1: Inclusion/exclusion criteria

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Participants

Patients were eligible if they were critically ill medical patients aged ≥ 18 years with a BMI between 18.5 and 30. Patients were excluded if they were non-medical patients (e.g., Burn, Surgical, Trauma), had a history of VTE, systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and heparin-induced thrombocytopenia (HIT), on anticoagulation treatment dose for other indication (s) (e.g., Afib.); or had bleeding within 24 h of ICU admission. In addition, patients who had acute kidney injury (AKI) within 24 h of ICU admission, were known to have chronic kidney disease (CKD) on dialysis, creatinine clearance (Crcl) <30ml/min, ICU length of stay (LOS) ≤ 1 day, or death within 24 h of ICU admission were excluded [Figure 1].

Setting

This study was conducted in the adult medical ICUs at King Abdulaziz Medical City (KAMC), a tertiary-care academic referral hospital in Riyadh, Saudi Arabia. The ICU admits medical patients and operates as a closed unit with 24/7 onsite coverage by critical care board-certified intensivists.

Data collection

Demographic and clinical data, including age, gender, weight, BMI, associated comorbidities, severity scores within 24 h of ICU admission (APACHE II, and SOFA), Padua score, type/dose of pharmacological DVT prophylaxis, and nonpharmacological DVT prophylaxis, were collected. Moreover, laboratory tests within 24 h of ICU admission (e.g., renal profile, liver function tests (LFTs), coagulation profile (i.e., INR, aPTT, fibrinogen)) were recorded for the eligible patients. In addition, complications during ICU stay (bleeding, thrombosis, HIT, heparin-associated thrombocytopenia (HAT)), and RBCs transfusion requirement were collected.

Aim of study and outcomes

This study evaluates the safety and effectiveness of standard dosing of pharmacological VTE in critically ill patients admitted to medical ICUs in a tertiary-care hospital in Riyadh. The primary outcome was VTE and any case of thrombosis. During ICU stay, both VTE and any thrombotic event were identified by using radiological findings (lateral or bilateral US for DVT; or chest CT scan for PE) and based on documentation using an electronic medical records system during ICU stay. The secondary outcomes included complication (s) during the ICU stay (i.e., major bleeding, minor bleeding, RBCs transfusion, HAT, and HIT).

Definition (s)

  • Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction mediated by platelet-activating antibodies that target complexes of platelet factor 4 and heparin.[9] HIT was confirmed by using platelet factor 4 (PF4) antibody level in the blood.[10]
  • Heparin-associated thrombocytopenia (HAT) is non-immune HAT that is characterized by a mild, transient decline in platelet count that occurs one to four days after initiating heparin; it is relatively benign and usually resolves spontaneously despite the continuation of heparin.[11]
  • Acute kidney injury (AKI) is defined by using the AKIN) definition, which is a sudden decrease of renal function within 48 h; it is defined by an increase in absolute SCr of at least 26.5 mmol/L (0.3 mg/dL) or by a percentage increase in SCr 50% (1.5× baseline value), or by a decrease in the urine output (UOP) (documented oliguria <0.5 mL/kg/h for more than 6 h).[12]
  • Major bleeding is defined as clinically overt bleeding with at least one of the following: fatal, symptomatic intracranial hemorrhage, retroperitoneal hemorrhage, intraocular hemorrhage leading to significant vision loss, a decrease in hemoglobin of >3.0 g/dl (with each blood transfusion unit counting for 1.0 g/dl of HB) and requiring transfusion of two or more units of red blood cells or the equivalent of whole blood.[13]
  • Minor bleeding is defined as clinically significant bleeding not meeting the definition of major and leading to an interruption of a study drug, surgical intervention or transfusion of 1 unit of blood.[13]


Data management and statistical analysis

We presented continuous variables as mean and standard deviation (SD), or median and interquartile range (IQR), and categorical variables as number (percentage) as appropriate. The normality assumptions were assessed for all numerical variables by using a statistical test (i.e., Shapiro–Wilk test) and graphical representation (i.e., histograms and Q-Q plots). We compared categorical variables by using the chi-square or Fisher exact test. We compared the normally distributed continuous variables by using the unpaired student t-test and other non-normally distributed continuous variables with the Mann-Whitney U test. Baseline characteristics, baseline severity, and outcome variables were compared between the two groups.

Propensity score (PS) adjustment was used for patients who received a standard dose of UFH (Control) to patients who received a standard dose of enoxaparin (Active). Multivariable regression analysis and negative binomial regression were used, adjusting for the generated propensity score based on the patient’s APACHE II score, serum creatinine baseline, INR baseline, and cancer as coexisting illness. The odds ratios (OR) and estimates with the 95% confidence intervals (CI) were reported as appropriate. No imputation was made for missing data, as the cohort of patients in our study was not derived from random selection. We considered a P value of <0.05 statistically significant and used SAS version 9.4 for all statistical analyses.


  Results Top


Among the 1866 patients initially screened, a total of 311 medical critically ill patients who received pharmacological VTE prophylaxis at ICU admission were included in the study [Figure 1]. Standard dose regimen of unfractionated heparin (UFH) was given to 224 patients (72.0%), whereas 87 patients (28.0%) received enoxaparin as pharmacological VTE prophylaxis. After propensity score adjustment based on the selected criteria, a total of 275 patients were included.

Demographic and clinical characteristics

Patients’ demographics data, relevant laboratory tests, and VTE risk factors (as presented in [Table 1]) are described in [Table 1]. Patients who received enoxaparin were younger, and they had higher APCHE II score, INR, and a lower serum creatinine. Moreover, the enoxaparin cohort slightly included more patients with hypothyroidism (3.5% vs. 2.3%), ischemic heart disease (11.8% vs. 9.6%), cancer (8.2% vs. 4.5%), and liver disease (3.5% vs. 1.4%) compared with the UFH prophylaxis arm. There were no significant differences in baseline characteristics between the two cohorts after adjustment by using the propensity score.
Table 1: Summary of demography and baseline characteristics

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Primary outcome

In crude analysis, enoxaparin prophylaxis was associated with a slightly, but nonsignificant, reduced rate of pulmonary embolism (0.0% vs. 1.02%, p-value:0.37), and deep vein thrombosis (1.3% vs. 1.5%, p-value:0.87). The incidence of VTE among the enoxaparin group was numerically lower compared with the standard dose of UFH (1.3 vs. 2.6%); however, it did not reach statistical significance (p-value:0.51). Moreover, any case of thrombosis during ICU was lower in patients who received enoxaparin compared with UFH (5.1% vs. 10.2%, p-value:0.51); but, it was not statistically significant. Results of multivariable logistic regression analysis showed a nonsignificant reduction in VTE (OR, 0.47; 95% CI, (0.1, 4.1); P = 0.49) and all thrombosis cases (OR, 0.43; 95% CI, (0.14, 1.32); P = 0.14) (as shown in [Table 2]).
Table 2: Regression analysis for the outcomesa

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Secondary outcomes

In patients who received standard-dose enoxaparin as DVT prophylaxis, major bleeding, specifically gastrointestinal (GI), was higher by 3.5 fold than a standard-dose of UFH; however, it did not reach statistical significance (OR, 3.30; 95% CI, (0.85, 12.6); P = 0.08). Moreover, RBCs transfusion requirement was slightly higher, but it was nonsignificant in patients who received enoxaparin (Estimate:0.05; 95% CI, (-0.43, 0.52); P = 0.85). On the flip side, the proportion of minor bleeding was 26.6% in the patients who received enoxaparin compared with 30.6% in the UFH group; however, it was not statistically significant (OR, 0.83; 95% CI, (0.46, 1.50); P = 0.54).

The study cohort (enoxaparin vs UFH prophylaxis arms) has shown a comparable figure (2.5% vs. 2.6%, p-value=0.99) for HIT. Moreover, HAT was not statistically significant between the two groups (OR, 1.19; 95% CI, (0.70, 2.04); P = 0.52). In addition, platelets transfusion requirement was similar in the enoxaparin compared with the UFH group (Estimate: -0.73; 95% CI, (-2.58, 1.12); P = 0.44) (as shown in [Table 2]).


  Discussion Top


In this study, we aimed to evaluate the effectiveness and safety of standard dosing of Enoxaparin vs. UFH as a pharmacological VTE prophylaxis in critically ill medical patients. We found no significant difference in the VTE incidence or any case of thrombosis between the two groups after adjustment. However, we reported that patients who received enoxaparin as VTE prophylaxis were at a significantly higher major bleeding risk, specifically GI, than patients on a standard-dose regimen of UFH. Our findings support prior research on chemothromboprophylaxis with LMWH or UFH, which has been demonstrated to reduce the risk of VTE in medical and nonmedical critically ill patients; nonetheless, it is linked with a significant risk of adverse effects (mainly bleeding and thrombocytopenia).[14]

Regarding our primary findings, the enoxaparin group has numerically lower VTE incidence and any case of thrombosis (1.3% compared with the standard dose of UFH (2.6%) and (5.1% vs. 10.2%, p-value:0.51), respectively). Both enoxaparin and UFH showed a comparable efficacy in our cohort of critically medically ill patients. However, this could limit the generalizability of our findings to other critically ill patients, including surgical, trauma, neurocritical, and morbidly obese patients. Nonetheless, our results are consistent with previous research. Similar findings were reported by a single-center, retrospective cohort study of 460 ICU patients, which evaluated the safety and efficacy of prophylactic enoxaparin versus UFH in ICU patients with renal impairment. They found no difference in the rates of VTE (4.3% vs. 3.5%; P = 0.64) between the two groups.[15] Unlike our results, the PREVAIL trial aimed at comparing the efficacy and safety of enoxaparin with unfractionated heparin in 1762 patients with stroke. The PREVAIL trial reported that enoxaparin reduced the risk of VTE by 43% compared with unfractionated heparin (68 [10%] vs 121 [18%]; relative risk 0.57, 95% CI 0.44–0.76, P = 0.0001). It is worth noting that the PREVAIL trial included stroke patients, whereas ours included medically ill ICU patients; the stroke baseline condition accounted for limited number of patients in our group.[16]

In contrast to our results, a meta-analysis of eight RCTs included 5567 patients; which showed that LMWH compared with UFH reduced the risk of any DVT (RR 0.84, 95% CI 0.71–0.98, P = 0.03) and resulted in a net clinical benefit (RR 0.90, 95% CI 0.83–0.97, P = 0.01).[17] The controversy over the best VTE prophylaxis agent is still continuing, with trials showing mixed results in terms of VTE incidence and PE rates. LMWH might be superior to UFH in terms of PE reductions in high-risk populations with normal renal function. For acute medical illness patients who have a moderate to high VTE risk with an acceptable bleeding risk profile, the current guidelines recommend to use pharmacologic thromboprophylaxis (LMWH or UFH) rather than mechanical methods or no thromboprophylaxis at all.

In our study, we reported a higher major bleeding rate with enoxaparin (3.5 fold) than a standard-dose regimen of UFH; however, it did not reach a statistical significance (OR, 3.30; 95% CI, (0.85, 12.6); P = 0.08). In addition, no difference was noted in minor bleeding or RBCs transfusion requirement. These findings align with those reported by the PREVAIL trial, where the occurrence of any bleeding was similar with enoxaparin (69 [8%]) or unfractionated heparin (71 [8%]; P = 0.83).[14] However, it contrasts the findings of DeBiase et al.[13] as their single-center retrospective study showed a significant increase in major bleeding (OR: 1.84; 95% CI: 1.11 - 3.04; P = 0.02) after adjusting for confounding factors. It is important to note that patients with AKI and CKD were excluded from our study; nonetheless, DeBiase et al. study was limited by the inability to assess the causal association between drug exposure and bleeding events in ICU patients with renal impairment.

In our study, HIT (2.5% vs. 2.6%) and HAT (40.5% vs. 36.2%) were comparable, with no difference in platelet transfusion requirements (Estimate: -0.73; 95% CI, (-2.58, 1.12); P = 0.44). However, The PROTECT study compared LMWH dalteparin with UFH (a dose of 5000 IU Q12H) and included 3764 medical-surgical critically ill patients; a significant drop in HIT frequency was observed in the LMWH prophylaxis study arm. Contrary to our results, data from a systematic review by Ribic et al.,[18] which included 629 medical-surgical critically ill patients, have shown that thrombocytopenia occurred in 9.3% of medical-surgical ICU patients who received LMWH.

The significance of our study lies in the type of population that was included, as well as the strict BMI and standard dose criteria that allowed us to eliminate the most common and major confounders that could alter thromboprophylaxis efficacy or safety outcomes. However, our study could be limited by its retrospective nature, small sample size, and single center. In addition, the retrospective review captured only symptomatic patients and relied on the accuracy of medical documentation. Although we performed multivariable regression analysis to adjust for possible confounding variables, other residual confounders might be still existing. Further large, well-designed studies to further explore and to better describe the best practices for thromboprophylaxis in this patient population are needed. This will eventually assist the healthcare providers in developing optimal use of existing preventive interventions while maintaining patient’s safety and quality of care.


  Conclusion Top


Standard enoxaparin dosing in critically ill medical patients may reduce thrombosis, but it is associated with an increased risk of GI bleeding. VTE prophylaxis with enoxaparin may be considered in critically ill medical patients without risk factors for GI bleeding. To confirm our findings in those populations, more randomized clinical trials with a larger sample size are required.

Ethical policy and institutional review board statement

The study was approved in June 2021 by King Abdullah International Medical Research Center Institutional Review Board, Riyadh, Saudi Arabia (Ref.# NRC21R/188/04). Participants’ confidentiality was strictly observed throughout the study by using an anonymous unique serial number for each subject and restricting data only to the investigators. Informed consent was not required due to the research’s method as per the policy of the governmental and local research center.

Data availability statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Acknowledgement

The authors would like to acknowledge the investigators in the Saudi critical care pharmacy research (SCAPE) platform who participated in this project.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Al-Dorzi H, Tamim HM, Al Harbi S, Arabi Y Enoxaparin Versus unfractionated Heparin for Venous thromboembolism prophylaxis in critically ill patients: A propensity score-adjusted analysis. Middle East J Anesthesiol2018;25:103-12.  Back to cited text no. 8
    
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Lin CY, Chen YC Acute kidney injury classification: AKIN and RIFLE criteria in critical patients. World J Crit Care Med 2012;1: 40-5.  Back to cited text no. 12
    
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Boonyawat K, Crowther MA Venous thromboembolism prophylaxis in critically ill patients. Semin Thromb Hemost 2015;41:68-74.  Back to cited text no. 14
    
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DeBiase C, Giuliano CA, Doshi M, Ganoff M, Alexander Paxton R Enoxaparin versus unfractionated heparin for venous thromboembolism prophylaxis in renally impaired ICU patients. Pharmacotherapy 2021;41:424-9.  Back to cited text no. 15
    
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