Key Points:
- Provoked venous thromboembolism (VTE) is a heterogeneous population, and the optimal duration of anticoagulation in patients with enduring risk factors such as obesity, chronic inflammatory disease, or atherosclerotic cardiovascular disease remains uncertain.
- The HI-PRO trial previously showed that 12 months of low-intensity apixaban (2.5 mg twice daily) reduced recurrent VTE compared with placebo. In this extension study, 588 participants were followed for a second year after the study drug was stopped, with anticoagulation resumption at clinician discretion.
- Assignment to one year of low-intensity apixaban reduced the overall 2-year risk of recurrent VTE with no statistically significant difference in major bleeding, but the benefit was not sustained during the second year without active treatment.
Decisions about the duration of anticoagulation after venous thromboembolism (VTE) are guided by whether the event was provoked or unprovoked, while weighing bleeding risk and patient preferences. However, provoked VTE is a heterogeneous group, with post-operative, chronic obstructive pulmonary disease, and obesity-related disease all being considered the same category. Prior meta-analyses have reported recurrence rates of 4.2 per 100 patient-years after non-surgical provoked VTE compared with 10.3 per 100 patient-years with unprovoked VTE. The optimal management of patients with provoked VTE and enduring risk factors remains unknown.
The Extended-Duration Low-Intensity Apixaban to Prevent Recurrence in High-Risk Patients with Provoked Venous Thromboembolism (HI-PRO) trial was an investigator-initiated, randomized, double-blind, placebo-controlled study conducted at a single high-volume academic medical center. Adults with VTE due to a transient provoking factor who had completed at least 3 months of full-intensity anticoagulation and had at least one enduring risk factor (persistent immobility, obesity, heart failure, chronic lung disease, chronic kidney disease, chronic inflammatory or autoimmune disorder, or atherosclerotic cardiovascular disease) were randomized 1:1 to apixaban 2.5 mg twice daily or placebo for 12 months. In the 12-month results published in the New England Journal of Medicine in 2025, low-intensity apixaban reduced symptomatic recurrent VTE compared with placebo without a difference in major bleeding. In the extension study, participants were followed for an additional 12 months after the study drug was stopped, with anticoagulation at the discretion of clinicians and patients while the original treatment assignment remained blinded. The primary efficacy outcome was symptomatic, confirmed recurrent VTE and the principal safety outcome was ISTH major bleeding.
The extension results were presented at the American Heart Association (AHA) Scientific Sessions on November 7, 2026. Among the 588 participants included in the modified intention-to-treat analysis (294 per arm), the average age was 59.5 years, 57% were women, and the mean body mass index was 30.6 kg/m2. Nearly half (48%) presented with deep vein thrombosis alone, 24% with pulmonary embolism alone, and 29% with both. The most common enduring risk factors were chronic inflammatory or autoimmune disorders (52%), obesity (48%), and atherosclerotic cardiovascular disease (29%). During the second year, 95 participants originally assigned to apixaban and 110 originally assigned to placebo received any anticoagulant.
Over 2 years, assignment to 12 months of low-intensity apixaban reduced the overall risk of recurrent VTE compared with placebo (aRR 0.41; 95% CI 0.22 to 0.64, P = 0.001). There was no significant difference in major bleeding (P = 0.88) or clinically relevant non-major bleeding (P = 0.32). However, the hazard risks were non-proportional. In a landmark analysis beginning after year 1, there was no sustained benefit during the second year (aRR 1.23; 95% CI 0.54 to 3.51, P = 0.79), with 13 recurrent VTE events among those originally assigned to apixaban and 8 among those originally assigned to placebo. These results are consistent with the short-acting drug effect of apixaban.
Limitations of the study include that, although intentional by design, this extension study is non-randomized with treatments initiated at the discretion of the clinician or patient. The trial was also conducted at a single academic medical center, which may limit generalizability.
Presenting the results, Dr. Behnood Bikdeli concluded that “1-year treatment with low-intensity apixaban compared with placebo reduced the overall 2-year risk of recurrence. However, the hazard was nonproportional, with loss of benefit within the period without active treatment.” Dr. Bikdeli added that these “results have implications for clinicians and patients with provoked VTE and enduring risk factors for shared decision-making.”