Compared with control treatment among critically ill adults, low-molecular-weight heparin (LMWH) reduces the incidence of deep vein thrombosis (DVT), according to a systematic review and network meta-analysis of randomized clinical trials (RCTs) published in CHEST. The analysis showed also that risk of DVT may be reduced by unfractionated heparin (UFH) and by mechanical compressive devices, although LMWH should be considered the primary pharmacologic agent for thromboprophylaxis.
Risk of venous thromboembolism (VTE), including DVT and pulmonary embolism (PE), is heightened in critically ill patients. VTE incidence is highest in major surgery and trauma patients, and mortality estimates from PE among intensive care unit patients are as high as 12%. Clinical practice guidelines recommend prophylaxis with pharmacologic agents over no prophylaxis in critically ill adults. Shannon M. Fernando, MD, of the University of Ottawa and colleagues examined the comparative efficacy and safety of various agents for VTE prophylaxis in critically ill patients through a review of 13 RCTs (9,619 patients) in six databases (Medline, PubMed, EMBASE, Scopus, Webof Science, and the Cochrane Database of Systematic Reviews). The ICU patients received a variety of therapies including pharmacologic, mechanical, or their combination for thromboprophylaxis. The control population consisted of a composite of no prophylaxis, placebo, or compression stockings only.
Indicative results
Analysis showed LMWH to reduce the incidence of DVT (odds ratio, 0.59; high certainty), while UFH may reduce the incidence of DVT (OR, 0.82; low certainty). Compared with UFH, LMWH probably reduces DVT (OR, 0.72; moderate certainty). Compressive devices, based on low-certainty evidence, may reduce risk of DVT, compared with control treatments (OR, 0.85).
The effect of combination therapy on DVT, compared with either therapy alone was unclear (very low certainty). The large-scale (2,000 patients) PREVENT trial in 2019, Dr. Fernando noted in an interview, found that adding compression therapy to pharmacologic therapy produced no reduction in proximal lower limb DVT.
“Ultimately, I think that, even if multiple RCTs and subsequent meta-analyses were performed, at best we would find that the incremental benefit of combination therapy is very minimal,” Dr. Fernando stated.
The findings provide evidence supporting LMWH and UFH use as compared with no pharmacologic prophylaxis for prevention of DVT, according to the researchers. While a similar certainty of effect in reducing PE was not found, evidence with moderate certainty suggested that LMWH and UFH probably reduce the incidence of any VTE, compared with no pharmacologic prophylaxis. Cost-effectiveness modeling that takes into account VTE incidence supports the practice. “If you’re reducing the incidence of DVT, it’s likely you’re similarly reducing incidence of PE, though I will agree that currently the data do not support this,” he said in an interview.
Noting that, while support in existing literature for any specific agent is controversial, the authors cite that American Society of Hematology guidelines suggest considering LMWH over UFH in critically ill patients, and that their findings lend support to that position. Regarding safety, pair-wise meta-analysis did not reveal clear major bleeding incidence differences between UFH and LMWH.
In and out of the ICU
Concordant with studies outside the ICU finding that heparin-induced thrombocytopenia (HIT) incidence is lower among patients receiving LMWH rather than UFH for VTE prophylaxis, the meta-analysis revealed a lower incidence of HIT among the critically ill receiving LMWH, but with evidence that was of low certainty.
Uncertainty around the optimal approach to VTE prophylaxis in the ICU along with wide variations in clinical practice persist despite recognition of the issue’s importance, note Major Michael J. McMahon, MD, of Honolulu and Colonel Aaron B. Holley, MD, of Bethesda, Md., authors of an accompanying editorial, “To generalize or not to generalize? The approach to VTE prophylaxis”. They acknowledge also that the Fernando et al. analysis yields important insights into VTE prevention in the ICU. Rhetorically raising the question, “Can we now say without doubt that LMWH is the preferred agent for all patients in the ICU?” – they responded, “probably.” Not entirely eliminated, they observe, is the possibility that a specific patient subgroup may benefit from one agent compared with another. They add, “We came away more confident that LMWH should be the default choice for VTE prevention in the ICU.”
Dr. Fernando and coauthors listed multiple disclosures, but declared that they received no financial support. Dr. McMahon and Dr. Holley declared that they have no disclosures.