Things We Do for No Reason™: Universal Venous Thromboembolism Chemoprophylaxis in Low-Risk Hospitalized Medical Patients

In order to understand why chemoprophylaxis fails to benefit low-risk medical patients, it is necessary to critically examine the benefits identified in trials of high-risk patients. Although RCTs and meta-analysis of chemoprophylaxis have consistently demonstrated a reduction in VTE, prevention of asymptomatic VTE identified on screening with ultrasound or venography accounts for more than 90% of the composite outcome in the three key trials.^7-9 Hospitalists do not routinely screen for asymptomatic VTE, and incorporation of these events into composite VTE outcomes inflates the magnitude of benefit gained by chemoprophylaxis. Importantly, the standard of care does not include screening for asymptomatic DVTs, and studies have estimated that only 10% to 15% of asymptomatic DVTs progress to a symptomatic VTE.¹⁰

A meta-analysis of trials evaluating unselected general medical patients (ie, not those with specific high-risk conditions such as acute myocardial infarction) did not show a reduction in symptomatic VTE with chemoprophylaxis (odds ratio [OR], 0.59; 95% CI, 0.29-1.23).¹¹ In the meta-analysis by Wein et al, which did include patients with specific high-risk conditions, chemoprophylaxis produced a small absolute risk reduction, resulting in a number needed to treat (NNT) of 345 to prevent one PE.⁴ This demonstrates that, even in high-risk patients, the magnitude of benefit is small. Population-level data also question the benefit of chemoprophylaxis. Flanders et al stratified 35 Michigan hospitals into high-, moderate-, and low-performance tertiles, with performance based on the rate of chemoprophylaxis use on admission for general medical patients at high-risk for VTE. The authors found no significant difference in the rate of VTE at 90 days among tertiles.¹² These findings question the usefulness of universal chemoprophylaxis when applied in a real-world setting.

The high rates of VTE in the absence of chemoprophylaxis reported in historic trials may overestimate the contemporary risk. A 2019 multicenter, observational study examined the rate of hospital-acquired DVT for 1,170 low- and high-risk patients with acute medical illness admitted to the internal medicine ward.¹³ Of them, 250 (21%) underwent prophylaxis with parenteral anticoagulants (mean Padua Prediction Score, 4.5). The remaining 920 (79%) were not treated with prophylaxis (mean Padua Prediction Score, 2.5). All patients underwent ultrasound at admission and discharge. The average length of stay was 13 days, and just three patients (0.3%) experienced in-hospital DVT, two of whom were receiving chemoprophylaxis. Only one (0.09%) DVT was symptomatic.

It should be emphasized that any evidence favoring chemoprophylaxis comes from studies of patients at high-risk of VTE. No data show benefit for low-risk patients. Therefore, any risk of chemoprophylaxis likely outweighs the benefits in low-risk patients. Importantly, the risks are underappreciated. A 2014 meta-analysis reported an increased risk of major hemorrhage (OR, 1.81; 95% CI, 1.10-2.98; P = .02) in high-risk medically ill patients on chemoprophylaxis.¹⁴ This results in a number needed to harm for major bleeding of 336, a value similar to the NNT for benefit reported by Wein et al.⁴ Heparin-induced thrombocytopenia, a potentially limb- and life-threatening complication of UFH or LMWH exposure, has an overall incidence of 0.3% to 0.7% in hospitalized patients on chemoprophylaxis.³ Finally, the most commonly used chemoprophylaxis medications are administered subcutaneously, resulting in injection site pain. Unsurprisingly, hospitalized patients refuse chemoprophylaxis more frequently than any other medication.¹⁵

The negative implications of inappropriate chemoprophylaxis extend beyond direct harms to patients. Poor stratification and overuse results in unnecessary healthcare costs. One single-center retrospective review demonstrated that, after integration of chemoprophylaxis into hospital order sets, 76% of patients received unnecessary administration of chemoprophylaxis, resulting in an annualized expenditure of $77,652.¹⁶ This does not take into account costs associated with major bleeds.

Unfortunately, the pendulum has shifted from an era of underprescribing chemoprophylaxis to hospitalized medical patients to one of overprescribing. Data published in 2018 suggest that providers overuse chemoprophylaxis in low-risk medical patients at more than double the rate of underusing it in high-risk patients (57% vs 21%).¹⁷

Several national societies, including the often cited American College of Chest Physicians (ACCP) and American Society of Hematology (ASH), provide guidance on the use of VTE chemoprophylaxis in acutely ill medical inpatients.^3,18 The ASH guidelines conditionally recommend VTE chemoprophylaxis rather than no chemoprophylaxis.¹⁸ However, the guidelines do not provide guidance on a risk-stratified approach and disclose that this recommendation is supported by a low certainty in the evidence of the net health benefit gained.¹⁸ Guidelines from ACCP lean towards individualized care and recommend against the use of VTE chemoprophylaxis for hospitalized acutely ill, low-risk medical patients.³