Standard- versus extended-duration anticoagulation for primary venous thromboembolism prophylaxis in acutely ill medical patients.

Background: Venous thromboembolism (VTE) includes two interrelated conditions, deep vein thrombosis (DVT) and pulmonary embolism (PE). Risk factors include dehydration, prolonged immobilization, acute medical illness, trauma, clotting disorders, previous thrombosis, varicose veins with superficial vein thrombosis, exogenous hormones, malignancy, chemotherapy, infection, inflammation, pregnancy, obesity, smoking, and advancing age. It is estimated that hospitalized patients are 100 times more likely to develop VTE and, compared with surgical patients, medical patients often have more severe forms of VTE. VTE carries a significant risk of morbidity and mortality. Prophylactic strategies, including mechanical and pharmacological methods, are recommended for patients at risk of VTE. Pharmacological prophylaxis is considered the standard practice for acutely ill medical patients at risk of developing VTE in the absence of contraindications. For hospitalized patients, the risk of VTE extends beyond hospital stay and up to 90 days, with most events occurring within 45 days of discharge. Despite that, it remains unclear whether extended-duration anticoagulation for primary VTE prophylaxis would provide benefits without added risks or harm.

Objectives: To assess the benefits and risks of standard- versus extended-duration anticoagulation for primary VTE prophylaxis in acutely ill medical patients.

Search methods: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialized Register, CENTRAL, MEDLINE, Embase, CINAHL and Web of Science databases, as well as the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers up to 27 March 2023. We also searched reference lists of all included studies for additional references and searched the last five years of the American Society of Hematology conference proceedings.

Selection criteria: We included randomized controlled trials (RCTs) comparing standard-duration versus extended-duration anticoagulation for primary VTE prophylaxis in acutely ill medical patients (adults being treated in a medical inpatient setting).

Data collection and analysis: We used the standard methodological procedures set by Cochrane. At least two authors independently screened titles and abstracts for inclusion and performed data extraction. Two authors independently assessed the risk of bias (RoB) using the Cochrane RoB 2 tool. We analyzed outcomes data using the risk ratio (RR) with 95% confidence intervals (CIs). We used the GRADE approach to assess the certainty of evidence for each outcome. Our outcomes of interest were assessed in the short term (during the treatment period and within 45 days of hospitalization) and long term (assessed beyond 45 days of hospitalization). Primary outcomes were symptomatic VTE, major bleeding, and all-cause mortality. Secondary outcomes were total VTE, a composite of fatal and irreversible vascular events (including myocardial infarction, non-fatal PE, cardiopulmonary death, stroke), fatal bleeding, and VTE-related mortality.

Main results: A total of seven RCTs fulfilled our inclusion criteria, comprising 40,846 participants. All studies contributing data to our outcomes were at low risk of bias in all domains. Most studies reported the outcomes in the short term. Extended-duration anticoagulation, compared with standard-duration anticoagulation, for primary VTE prophylaxis in acutely ill medical patients reduced the risk of short-term symptomatic VTE (RR 0.60, 95% CI 0.46 to 0.78; standard-duration 12 per 1000, extended-duration 7 per 1000, 95% CI 6 to 10; number needed to treat for an additional beneficial outcome [NNTB] 204, 95% CI 136 to 409; 4 studies, 24,773 participants; high-certainty evidence). This benefit, however, was offset by an increased risk of short-term major bleeding (RR 2.05, 95% CI 1.51 to 2.79; standard-duration 3 per 1000, extended duration 6 per 1000, 95% CI 5 to 8; number needed to treat for an additional harmful outcome [NNTH] 314, 95% CI 538 to 222; 7 studies, 40,374 participants; high-certainty evidence). Extended-duration anticoagulation, compared with standard-duration, results in little to no difference in short-term all-cause mortality (RR 0.97, 95% CI 0.87 to 1.08; standard-duration 34 per 1000, extended-duration 33 per 1000, 95% CI 30 to 37; 5 studies, 38,080 participants; high-certainty evidence), reduced short-term total VTE (RR 0.75, 95% CI 0.67 to 0.85; standard-duration 37 per 1000, extended duration 28 per 1000, 95% CI 25 to 32; NNTB 107, 95% CI 76 to 178; 5 studies, 33,819 participants; high-certainty evidence), and short-term composite of fatal and irreversible vascular events (RR 0.71, 95% CI 0.56 to 0.91; standard-duration 41 per 1000, extended-duration 29 per 1000, 95% CI 23 to 37; NNTB 85, 95% CI 50 to 288; 1 study, 7513 participants; high-certainty evidence). Extended-duration anticoagulation may result in little to no difference in short-term fatal bleeding (RR 2.28, 95% CI 0.84 to 6.22; standard-duration 0 per 1000, extended-duration 0 per 1000, 95% CI 0 to 1; 7 studies, 40,374 participants; low-certainty evidence), and likely results in little to no difference in short-term VTE-related mortality (RR 0.78, 95% CI 0.58 to 1.05; standard-duration 5 per 1000, extended-duration 4 per 1000 95% CI 3 to 6; 6 studies, 36,170 participants; moderate-certainty evidence).

Authors' conclusions: In the short term, extended- versus standard-duration anticoagulation for primary VTE prophylaxis in acutely ill medical patients reduced the risk of symptomatic VTE at the expense of an increased risk of major bleeding. Extended-duration anticoagulation resulted in little to no difference in all-cause mortality. Extended-duration anticoagulation reduced the risk of total VTE and the composite of fatal and irreversible vascular events, but may show little to no difference in fatal bleeding and VTE-related mortality. Further data, with longer follow-up, are needed to determine the optimal agent and duration for primary VTE prophylaxis in acutely ill medical patients.