Critically ill patients are significantly more likely to develop venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), due to factors like immobility from hospitalization, high severity of illness, inflammation, sedation exacerbating immobility, and the use of indwelling venous catheters. The occurrence of VTE in intensive care unit (ICU) patients varies widely, with rates reported from 10% based on clinical findings to over 90% in autopsy studies. Particularly, patients undergoing major surgery or trauma are at the highest risk. The mortality rate from PE in ICU patients is estimated to be up to 12%, leading to a low threshold among clinicians to investigate suspected VTE cases.
To mitigate the risk of VTE, critically ill patients usually receive prophylactic treatment, such as pharmacologic or mechanical therapy, or a combination of both. Prophylaxis is recommended for medical and surgical critically ill patients, and not administering thromboprophylaxis within the first 24 hours after ICU admission has been associated with a higher mortality rate. However, there remains uncertainty regarding the most effective agents or combination of agents for VTE prevention in critically ill patients, leading to variation in practice. Antithrombotic medications such as unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are preferred, but these drugs can be associated with significant adverse effects, like major bleeding. Mechanical devices have been suggested for patients with contraindications to antithrombotic agents, like those at a high risk of bleeding.
In this post, we focus on evaluating the evidence supporting various strategies for venous thromboembolism (VTE) prophylaxis in critical care practice. We explore the effectiveness of pharmacological therapies, such as low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH), alongside mechanical interventions like intermittent pneumatic compression. Our discussion includes an analysis of multiple studies, trials, and a network meta-analysis that compares the efficacy of these preventive measures. Our goal is to provide valuable, evidence-based insights that can guide optimal VTE prophylaxis in critical care.
Heparin versus Placebo
In a study published in the critical care medicine journal in 1982, 119 critically ill patients were randomized to receive low dose heparin prophylaxis (5000 units subcutaneousely twice a day) compared to placeb. The incidence of deep vein thrombosis (DVT) was 13% in those receiving subcutaneous heparin at a dose of 5000 units, whereas the control group had an incidence of 29% (P value <0.05) [1].
LMWH versus Placebo
In a study involving 223 mechanically ventilated patients with acute, decompensated chronic obstructive pulmonary disease, randomization to treatment with subcutaneous nadroparin adjusted for body weight (0.4 ml, equivalent to 3,800 AXa IU, or 0.6 ml, equivalent to 5,700 AXa IU) or placebo was conducted. The average treatment duration was 11 days. The incidence of deep vein thrombosis (DVT) in the nadroparin group was significantly lower than that in the placebo group (15.5% versus 28.2%; p = 0.045) [2].
PROTECT Trial: LMWH VS UFH
A multicenter trial compared the efficacy of dalteparin, a low-molecular-weight heparin, with that of unfractionated heparin in preventing proximal leg deep-vein thrombosis (DVT) in critically ill patients. In total, 3764 patients were randomly assigned to receive either dalteparin or unfractionated heparin while they were in the intensive care unit. The primary outcome measured was the incidence of DVT, as diagnosed via compression ultrasonography.
The results showed no significant difference in the rate of DVT between the two groups; 5.1% of patients receiving dalteparin and 5.8% of those receiving unfractionated heparin developed DVT. However, dalteparin was found to significantly reduce the occurrence of pulmonary emboli compared to unfractionated heparin (1.3% vs 2.3%). Rates of major bleeding and in-hospital death were similar between the two groups. Additionally, fewer patients receiving dalteparin developed heparin-induced thrombocytopenia.
The study concluded that while dalteparin did not demonstrate superiority over unfractionated heparin in reducing the incidence of DVT in critically ill patients, it showed benefits in reducing the occurrence of pulmonary emboli and heparin-induced thrombocytopenia [3].
Mechanical Versus Chemical Prophylaxis
A retrospective study was conducted on nonsurgical patients undergoing mechanical ventilation, comparing the effectiveness of chemical prophylaxis (CP) in 329 patients and mechanical prophylaxis (MP) in 419 patients. The incidence of venous thromboembolism (DVT, PE or both) was significantly lower in the CP group, with a rate of 0.3%, compared to 3.1% in the MP group. The odds ratio was calculated to be 9.9, indicating a substantial difference favoring chemical prophylaxis.
Additionally, the mortality rate in the CP group was 34.3%, while it was higher at 50.6% in the MP group. These findings suggest that chemical prophylaxis may be more effective in reducing the incidence of thromboembolic events and potentially associated with a lower mortality rate compared to mechanical prophylaxis in nonsurgical patients on mechanical ventilation [4].
What is the preferred agent for chemical prophylaxis for the prevention of VTE in your ICU
Heparin 5000 units every 8 hours
Heparin 5000 units SC every 8 hours
LMWH (i.e. enoxaparin 40 mg SC daily)
PREVENT Trial: Mechanical & Chemical Prophylaxis
This study examined whether the use of adjunctive intermittent pneumatic compression could reduce the incidence of deep-vein thrombosis in critically ill patients who were already receiving pharmacologic thromboprophylaxis. Adult patients in ICUs were randomly assigned to either receive intermittent pneumatic compression in addition to pharmacologic thromboprophylaxis (the pneumatic compression group) or pharmacologic thromboprophylaxis alone (the control group). The primary outcome was the occurrence of new proximal lower-limb deep-vein thrombosis.
The study included 2003 patients, with 991 in the pneumatic compression group and 1012 in the control group. Pneumatic compression was applied for a median of 22 hours each day for a median of 7 days. The main outcome occurred in 3.9% of patients in the pneumatic compression group and 4.2% in the control group, a difference that was not statistically significant.
Furthermore, venous thromboembolism occurred in 10.4% of patients in the pneumatic compression group and 9.4% in the control group, while death from any cause at 90 days occurred in 26.1% and 26.7% of patients respectively. Again, these differences were not statistically significant.
The study concluded that in critically ill patients already receiving pharmacologic thromboprophylaxis, the use of adjunctive intermittent pneumatic compression did not significantly reduce the incidence of proximal lower-limb deep-vein thrombosis [5].
How do you use mechanical devices for VTE prophylaxis in your ICU?
0%As adjuvant to chemical prophylaxis
0%As a primary method for VTE
0%Only in patients with high risk or active bleeding
2012 ACCP Guidelines for VTE
The 2012 guidelines by the American College of Physicians (ACP) provide recommendations on venous thromboembolism (VTE) prophylaxis for critically ill patients. According to these guidelines, the ACP suggests the use of low-molecular-weight heparin (LMWH) or low-dose unfractionated heparin (LDUH) for VTE prevention in these patients. This recommendation is made with a Grade 2C level of evidence, which suggests a weak recommendation with moderate-quality evidence.
For patients who are currently bleeding or those at high risk for significant bleeding, the ACP recommends employing mechanical thromboprophylaxis methods. These methods could include graduated compression stockings or intermittent pneumatic compression. This recommendation should be followed until the risk of bleeding decreases, and this suggestion is also supported by a Grade 2C level of evidence, suggesting moderate-quality evidence for a weak recommendation [6].
A Network Meta-analysis!
This analysis encompassed 13 randomized trials and included a total of 9619 critically ill patients, provided key insights into the effectiveness of various thromboprophylaxis methods. One standout finding was that low-molecular-weight (LMW) heparin significantly reduced the incidence of all deep vein thrombosis (DVT). Specifically, when compared with control treatment - a combination of no prophylaxis, placebo, or the use of compression stockings only - LMW heparin reduced the occurrence of DVT with an odds ratio (OR) of 0.59 and a 95% confidence interval (CI) of 0.33-0.90. This evidence was of high certainty, making LMW heparin a compelling choice for thromboprophylaxis.
Further, the analysis suggested that LMW heparin could potentially be more effective than unfractionated heparin (UFH) in preventing DVT, with an OR of 0.72 and a 95% CI of 0.46-0.98. However, the certainty of this evidence was moderate, indicating that further investigation may be required for a conclusive comparison. Conversely, mechanical methods of thromboprophylaxis, such as intermittent compressive devices, appeared to be the least effective, yielding an OR of 0.85 and a 95% CI of 0.50-1.50 with low certainty. Furthermore, the impact of using combination therapy, which includes both pharmacological and mechanical methods, remained unclear, highlighting a need for further exploration in this area [7].
Conclusion:
LMW heparin reduced DVT incidence significantly compared to control treatments, and it appears to be more effective than UFH. In contrast, mechanical methods of thromboprophylaxis are the least effective.
References
Cade JF. High risk of the critically ill for venous thromboembolism. Crit Care Med. 1982 Jul;10(7):448-50. doi: 10.1097/00003246-198207000-00006. PMID: 7044682. Link
Fraisse F, Holzapfel L, Couland JM, Simonneau G, Bedock B, Feissel M, Herbecq P, Pordes R, Poussel JF, Roux L. Nadroparin in the prevention of deep vein thrombosis in acute decompensated COPD. The Association of Non-University Affiliated Intensive Care Specialist Physicians of France. Am J Respir Crit Care Med. 2000 Apr;161(4 Pt 1):1109-14. doi: 10.1164/ajrccm.161.4.9807025. PMID: 10764298. Link
PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group; Cook D, Meade M, Guyatt G, Walter S, Heels-Ansdell D, Warkentin TE, Zytaruk N, Crowther M, Geerts W, Cooper DJ, Vallance S, Qushmaq I, Rocha M, Berwanger O, Vlahakis NE. Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med. 2011 Apr 7;364(14):1305-14. doi: 10.1056/NEJMoa1014475. Epub 2011 Mar 22. PMID: 21417952. Link
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Kahn SR, Lim W, Dunn AS, Cushman M, Dentali F, Akl EA, Cook DJ, Balekian AA, Klein RC, Le H, Schulman S, Murad MH. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e195S-e226S. doi: 10.1378/chest.11-2296. PMID: 22315261; PMCID: PMC3278052. Link
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